bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–05–31
eighty papers selected by
Cédric Chaveroux, CNRS
  1. Escorting mRNAs - the multifunctional and divergent roles of cap-chaperones in post-transcriptional gene expression.
  2. The Arabidopsis CYSTM α 5' UTR Increases Protein Production from Transgenes in Plants and Bacteria.
  3. Nanopore Sequencing Reveals rRNA Modification Changes in Human Cells Experiencing Oxidative or Inflammatory Stress.
  4. Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.
  5. Immunometabolic reprogramming in rheumatoid arthritis: the epitranscriptomic role of N6-methyladenosine in innate and adaptive immunity.
  6. Resolving METTL5 Specificity: Direct RNA Sequencing Reveals No Compelling Evidence for METTL5 mediated mRNA m6A Methylation in mESCs.
  7. Functional Analysis of the Halastavi árva Virus (HalV) Internal Ribosome Entry Site.
  8. N6-methyladenosine (m6A) post-transcriptional modification regulation of mRNA, an overlooked therapeutic opportunity to leverage mRNA processing in vascular smooth muscle cells.
  9. Dual Roles of m6A Modification: Orchestrating Development and Abiotic Stress Resilience in Plants.
  10. Eukaryotic initiation factor 3d regulates context-dependent pain hypersensitivity through the integrated stress response.
  11. Regulatory mechanisms and therapeutic potential of N6-methyladenosine modification in retinal diseases (Review).
  12. RBM15 transcription activated by EGR1 stimulates gastric cancer proliferation and metastasis by enhancing m6A modification of RREB1.
  13. A multilayered stress-response circuit: The mammalian mitochondrial UPR.
  14. Mitochondrial ribosomal protein MRPL27 supports glioma malignancy through regulation of oxidative phosphorylation.
  15. A transport-independent role for SLC25A12 in mitochondrial stress signalling.
  16. Redox-Sensitive m6A Epitranscriptomic Remodeling in Cadmium Stress and Toxicity.
  17. Yeast Ribosomal Protein Rpl32 Modulates Ribosome Biogenesis, Ribosome Stability and the Cell Cycle.
  18. Ribosome biogenesis mediates the translational increase of nonoptimal codon transcripts during IFN-β stimulation.
  19. CHOP promotes the transition to chronic integrated stress response signaling with suppression of hepatocyte identity.
  20. Trans-kingdom coupling of redox signaling to environmental cell stress responses through multiphase partitioning.
  21. ppGpp regulates transcription elongation via direct and indirect inputs to RNA polymerase pausing and nucleotide addition.
  22. Active RNA synthesis patterns nuclear condensates.
  23. Biomolecular Condensates in Combined and Recurrent Plant Stresses: Integrating Phase Separation, Signal Prioritization, and Cross-Stress Memory.
  24. The SL-I structural element of the 3' UTR region of West Nile virus participates in the regulation of viral translation.
  25. Perturbation of RNA homeostasis impairs mitochondrial respiration during poxvirus infection through excess RNA accumulation.
  26. SARS-CoV-2 N Protein Hijacks the m6A Reader YTHDF2 to Suppress Antiviral Gene Expression.
  27. An RNF4-Based Tool for Tracking Subcellular Localization of PolySUMOylation During Cellular Stress.
  28. Icariin suppresses glycolysis in prostate cancer by upregulating ALKBH5 to mediate EARS2 m6A demethylation.
  29. The dual role of endoplasmic reticulum stress in cerebral ischemia: from adaptive protection to apoptotic induction.
  30. WGCNA-Based Identification of HSPB1 Reveals a HOXA5/METTL1-m7G Regulatory Axis that Promotes Malignant Progression and Suppresses Ferroptosis in Glioblastoma.
  31. An IRES-like cis-acting element located within the EV-A71 coding region drives translation independent of the 5'-IRES and modulates viral fitness through regulated binding of viral RNA to 3D polymerase.
  32. Mitochondrial respiration modulates Hsf1 activation and the heat shock response.
  33. Real-time search-assisted multiplexed quantitative proteomics reveals system-wide cryptic translation initiation in human cancer cells.
  34. Orthogonal regulation of protein abundance.
  35. Redefining Endometrial Decidualization: The Central Role of the ER Stress-Immune-Metabolic Axis.
  36. Mechanism of RACK1-dependent ZAKα activation at stalled and collided ribosomes.
  37. A context-dependent METTL1-m7G-SLC7A11 axis links metabolic stress to epithelial fate in ulcerative colitis.
  38. Heat Shock Protein 27 in Radiation-Induced Trismus: Mechanistic Insights and a Hypothesis-Generating Framework.
  39. p97/VCP as a dual regulator of UPS and autophagy in ovarian cancer: a novel therapeutic target.
  40. NRAS mRNA-Degrading Bifunctional Small Molecules Induce Diverse Cellular Morphological Changes in Cancer Cells.
  41. Urinary Biomarkers in Parkinson's Disease: A Structured Integrative Review of Pathophysiological Pathways.
  42. The role of RNA modifications in the pathological mechanisms and therapeutic targeting of multiple myeloma.
  43. Substrate selectivity of the human RNA m5C methyltransferase NSUN2.
  44. The Content of Small 18S rRNA Fragments Is Regulated Developmentally and in Response to Stress in Plants.
  45. amyloid-predict and LLPS-predict: Predicting phase separation propensities in the intrinsically disordered proteome.
  46. Hepatic cellular stress response pathways exhibit species differences in basal and inducible activity.
  47. RNA-binding protein diversity and NLS arginines regulate FUS mixing in mRNA-rich compartments.
  48. Mapping the GDF15 arm of the integrated stress response in human cells and tissues.
  49. Ras-MAPK inhibition induces AXIN1 loss in colorectal cancer by mTOR associated suppression of protein synthesis.
  50. Reconstitution of protein arginylation pathways in bacteria for robust identification and quantification.
  51. From splicing to disease: the crucial role of serine/arginine protein kinases in cellular regulation.
  52. 3'UTR regulation of axon translation and optic nerve regeneration.
  53. Epitranscriptomic Stability-Variable Extents of N1-Methyladenosine to N6-Methyladenosine Conversion Under Different Experimental Conditions.
  54. RBM47 aggravates carotid atherosclerotic plaque instability through NEDD4L-dependent regulation of TRAF2.
  55. The Role of Sigmar1 in Autophagy Regulation and Disease Therapy.
  56. Tauroursodeoxycholate improves zoledronate-induced vascular endothelial dysfunction by suppressing the GCN2/eIF2α and IRE1/JNK pathways: a potential treatment option for MRONJ.
  57. Type II tRNA cleavage by SLFN14 endoribonuclease variants linked to inherited thrombocytopenia drives global translational repression.
  58. Post-transcriptional RNA-mediated regulation in infection: mechanisms, functions, and analytical approaches.
  59. RNA-Loaded Nanoparticles for Targeted Lung Delivery.
  60. Novel vanadium-dependent haloperoxidases from macroalgae and their expression in response to biotic and abiotic stressors in Saccharina latissima.
  61. Divergent CRD-Dependent Mechanisms Govern RAS Isoform-Selective Recruitment of CRAF and ARAF.
  62. Reactive oxygen species in thoracic aortic dissection: Insights into mechanisms and disease progression.
  63. Cellular Stress and Immune Activation in Celiac Disease: Is the Chaperone System a Key Player?
  64. An Analytical Framework for Phenotypic Selection of Fitness-Conferring Genes.
  65. Myelin basic protein is an RNA chaperone in microglial nuclear retro-transport.
  66. Pseudouridine synthase 7 as a context-specific therapeutic target in cancer.
  67. RNA binding protein YWHAZ mediates specific mRNA translation and regulates cell proliferation and apoptosis in diabetic foot ulcer.
  68. Mitochondrial metabolic reprogramming in diabetic cardiomyopathy.
  69. Remodeling of tRNA modification in Trypanosoma cruzi life forms.
  70. Genome-Wide Analysis of YTH Domain Proteins in Metasequoia glyptostroboides and Functional Validation of MgYTH5 as an m6A Reader.
  71. mRNA splicing in turkey muscle satellite cells is dynamically altered upon thermal challenge.
  72. Dietary effects of early nutrition on muscle mass and accretion in mammals.
  73. High-throughput Phosphoproteomics Reveals the Role of Phosphorylation in Pluripotency and Phase Separation.
  74. Neuronal regulation of infection recovery prevents pathogenic stress and tissue damage.
  75. Effects of residue substitutions on the cellular abundance of proteins.
  76. High-throughput Screening of Sequence Elements Associated with RNA Localization.
  77. Advances in protein engineering.
  78. The regulatory roles of flavonoids, melatonin, and glycine betaine in plant salt stress response.
  79. eIF4G2-Dependent Translation Restrains Pancreatic Cancer Progression.
  80. HIF inhibition: Current strategies and clinical challenges.
  1. J Cell Sci. 2026 Jun 15. pii: jcs264780. [Epub ahead of print]139(12):
    Escorting mRNAs - the multifunctional and divergent roles of cap-chaperones in post-transcriptional gene expression.
    Caleb M Embree, Katherine L B Borden.
      Transcripts undergo a variety of processing steps - including splicing, nuclear export and translation - to ultimately produce their protein product in the required form. Deviations in these steps can produce proteins with altered or ablated function. Central to mRNA processing is the methyl-7-guanosine (m7G) 'cap' on the 5' end of transcripts. This cap engages cap-binding proteins, termed cap-chaperones, which escort transcripts on their path towards protein production. There are two main cap-chaperones: the cap-binding complex (CBC), which was traditionally thought to act only in the nucleus, and the eukaryotic translation initiation factor eIF4E, thought to act in only the cytoplasm. However, studies have shown that both cap-chaperones localize to nuclear and cytoplasmic compartments, complicating the traditional understanding of their housekeeping roles in mRNA processing. In this updated context, this Review provides an overview of cap-chaperone function, describing their roles both in the nucleus and cytoplasm. We discuss mechanisms by which cap-chaperones differentially engage specific mRNA processing machineries and target transcripts, leading to altered mRNA fate. Finally, we briefly review dysregulation of cap-chaperones and the subsequent disruption of mRNA processing observed in cancer. In all, cap-chaperone choice is likely a significant determinant in mRNA fate.
    Keywords:  Cap-binding complex; Cap-binding protein; Cap-chaperone; NCBP2; RNA processing; Translation; eIF4E
    DOI:  https://doi.org/10.1242/jcs.264780
  2. Genes (Basel). 2026 Apr 28. pii: 520. [Epub ahead of print]17(5):
    The Arabidopsis CYSTM α 5' UTR Increases Protein Production from Transgenes in Plants and Bacteria.
    Jasjyot Singh Khanduja, Xingyu Wu, Jun Li, Iain R Searle.
      Background: Translational regulation constitutes a critical layer of gene expression control in plants, yet the contribution of endogenous 5' untranslated regions (5' UTRs) to translational efficiency remains incompletely defined. While viral and synthetic leader sequences have been widely used to enhance protein production, comparatively few native plant 5' UTRs have been systematically characterised. The objective of this study was to identify and functionally evaluate endogenous plant 5' UTR elements that promote translation through post-transcriptional mechanisms. Methods: A 79-nucleotide fragment (CYSTM α) derived from the 5' UTR of Arabidopsis thaliana CYSTM1 (AT1G05340) was cloned upstream of reporter genes and assessed using dual-luciferase assays in transient expression systems (Nicotiana benthamiana and A. thaliana) and in stable transgenic Arabidopsis lines. Translational activity was further evaluated in monocot wheat germ extract and in Escherichia coli. Transcript abundance was quantified by qRT-PCR. Publicly available ribosome profiling and m6A datasets were analysed to assess translational efficiency and RNA modification status. Results: In N. benthamiana and A. thaliana, CYSTM α increases reporter protein production 3-7 fold relative to the control and 30-130% above the benchmark Tobacco Mosaic Virus (TMV) Ω leader, without altering mRNA abundance. The CYSTM α sequence also enhances luciferase translation in monocot wheat germ extract and elevates translation 5-fold in E. coli. CYSTM α contains three motifs that may promote translation, namely three CAA repeats that are associated with translation initiation, an AMAYAA motif that is associated with eIF3 binding, and two N6-adenosine DRACH sites that are associated with cap-independent translation. Additionally, ribosome profiling revealed high translational efficiency (TE = 3.25) of native CYSTM1. Conclusions: CYSTM α represents a compact endogenous 5' UTR element that enhances translation across multiple experimental systems. These findings expand the repertoire of plant-derived translational enhancers and provide insight into sequence features associated with efficient mRNA translation in plants.
    Keywords:  5′ untranslated region (5′UTR); Arabidopsis thaliana CYSTM1 (AT1G05340); mRNA translation; post-transcriptional regulation
    DOI:  https://doi.org/10.3390/genes17050520
  3. ACS Chem Biol. 2026 May 27.
    Nanopore Sequencing Reveals rRNA Modification Changes in Human Cells Experiencing Oxidative or Inflammatory Stress.
    Aaron M Fleming, Cynthia J Burrows.
      Ribosomal RNA (rRNA) modifications are tuned to regulate protein synthesis; however, their temporal dynamics during oxidative or inflammatory stress remain poorly understood. Nanopore direct RNA sequencing using Dorado v5.2.0 modification-aware models for the data analysis was employed to map human rRNA epitranscriptomic marks in a cell line undergoing oxidative stress, inflammatory stress, or ferroptosis. Oxidative stress triggered a global trend of decreased modification occupancy in which six modifications shifted significantly over 48 h, particularly, 18S Ψ573 and 18S m6A1832. Conversely, inflammatory stress induced a complex response involving an acute pulse of hypermodifications at 28S Um1773 and 28S Ψ1779, for example, and chronic hypomodification at specific target sites (e.g., 18S Gm1328 and 28S Gm4228). In this work, the pseudouridine modifications 28S Ψ4296 and 28S Ψ4353 were identified as "universal stress markers" that decreased under all stressors studied, including ferroptosis. Mapping these changes onto the ribosome structure revealed that they reside in functional regions such as the decoding center and A-site finger, supporting a role in functional ribosome reprogramming during stress. Analysis of mitochondrial rRNA (mt-rRNA) revealed modification shifts within the peptidyl transferase center, suggesting a mechanism to attenuate mitochondrial translation during chronic stress. This work demonstrates that oxidative and inflammatory stress drive distinct, time-resolved remodeling of the human rRNA epitranscriptome and provides a framework for using rRNA modifications as biomarkers of cellular health during oxidative or inflammatory stress exposure.
    DOI:  https://doi.org/10.1021/acschembio.6c00154
  4. Muscles. 2026 May 22. pii: 39. [Epub ahead of print]5(2):
    Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.
    Victoria C Sanfrancesco, Daniella Della Mea, David A Hood.
      To maintain homeostatic conditions and optimal function during stressors, mitochondria initiate retrograde signaling. The mitochondrial integrated stress response (ISR) and unfolded protein response (UPRmt) are critical quality control mechanisms activated during instances of mitochondrial perturbations. Restoration of mitochondrial homeostasis is orchestrated by three transcription factors, ATF4, CHOP, and ATF5, which upregulate protective genes to counteract stress. As the health and function of skeletal muscle are heavily dependent on a highly adaptive mitochondrial network, defining how mitochondrial health is maintained across various conditions is essential. Although several studies demonstrate the importance of these responses following instances of stress, the signaling mechanisms required to initiate such pathways remain poorly characterized in skeletal muscle. This review examines how the mitochondrial ISR/UPRmt and related transcription factors respond to organellar stress by emphasizing the molecular events that occur during exercise, aging and muscle disuse. By consolidating the literature, this work aims to highlight the current understanding of mitochondrial stress response signaling within skeletal muscle and thus emphasize areas for future research and potential therapeutic strategies during divergent metabolic conditions.
    Keywords:  ATF4; ATF5; CHOP; adaptation; aging; exercise; integrated stress response; mitochondria; muscle inactivity; skeletal muscle; stress response; unfolded protein response
    DOI:  https://doi.org/10.3390/muscles5020039
  5. Front Immunol. 2026 ;17 1834919
    Immunometabolic reprogramming in rheumatoid arthritis: the epitranscriptomic role of N6-methyladenosine in innate and adaptive immunity.
    Jin Yang, Lei Wan, Hongbo Chen, Shu Li, Yuwei Zhou.
      N6-methyladenosine (m6A) methylation is the most common intramolecular modification in eukaryotic mRNA; its dynamic regulation depends on "writers" (methyltransferases: METTL3/METTL14/WTAP/VIRMA), "erasers" (demethylases: FTO/ALKBH5), and "readers" (binding proteins: YTHDF/YTHDC/IGF2BP families), thereby regulating RNA splicing, nuclear export, translation, and degradation. In rheumatoid arthritis (RA), this epigenetic network is severely disrupted: abnormal expression of writers leads to post-transcriptional activation of pro-inflammatory genes, while an imbalance in erasers compromises the stability of mRNAs encoding key signaling molecules. Together, these factors promote abnormal differentiation of immune cells, invasive proliferation of fibroblast-like synovial cells, and cartilage erosion. At the same time, hypoxia, inflammatory cytokines, and metabolic stress present in the joint microenvironment of RA induce cellular metabolic reprogramming, characterized by a shift toward aerobic glycolysis (Warburg effect), a reorganization of lipid synthesis and oxidation pathways, and an increase in glutamine uptake and catabolism; these changes all contribute to accelerating disease progression. Recent data have revealed a foundational integration between m6A modification and metabolic reprogramming: m6A regulators directly reshape the metabolic network by targeting transcripts encoding the glycolysis-limiting enzyme (HK2), key molecules in lipid metabolism (FASN/CPT1), and amino acid transporters (SLC1A5), thereby coordinating immune inflammation and tissue destruction in RA. This review elucidates the regulatory role of m6A methylation in the metabolic reprogramming of RA and explains how writers, erasers, and readers influence disease progression by participating in glycolysis, lipid metabolism, and glutamine metabolism. By focusing on the central question of whether m6A modification is the root cause of metabolic reprogramming in the pathogenesis of RA, we have integrated existing data to define the "m6A-metabolism-immunity" regulatory axis and identified potential therapeutic strategies targeting this association.
    Keywords:  epigenetics; m6A methylation; metabolic reprogramming; rheumatoid arthritis; synergistic regulation
    DOI:  https://doi.org/10.3389/fimmu.2026.1834919
  6. MicroPubl Biol. 2026 ;2026
    Resolving METTL5 Specificity: Direct RNA Sequencing Reveals No Compelling Evidence for METTL5 mediated mRNA m6A Methylation in mESCs.
    Samuel Le Cam, Magdalena Valenta, Robert Schneider.
      The methyltransferase-like 5 (METTL5) protein has been shown to catalyze m6A deposition on 18S ribosomal RNA. However, whether it also methylates mRNAs remains unclear. To address this, we employed direct RNA sequencing (ONT) for m6A detection on native mRNA molecules. We first validated the quantitative detection of m6A by ONT by treating mESCs with a METTL3 inhibitor. We then compared methylation levels of m6A sites between Mettl5 -KO and WT mESCs. Our analysis provides no compelling evidence for METTL5 mediated mRNA methylation in vivo, indicating that its catalytic activity is restricted to rRNA.
    DOI:  https://doi.org/10.17912/micropub.biology.002169
  7. Viruses. 2026 Apr 23. pii: 492. [Epub ahead of print]18(5):
    Functional Analysis of the Halastavi árva Virus (HalV) Internal Ribosome Entry Site.
    Subash Chapagain, Lauren F Woodburn, Natalie C J Strynadka, Eric Jan.
      Viral internal ribosome entry sites (IRESs) are specialized RNA structures that facilitate cap-independent translation as a strategy to usurp the host translational machinery. The Type 6 IRESs are the most streamlined mechanism to date, as they adopt a three pseudoknot RNA structure to initiate factorless translation initiation by directly recruiting the ribosome and drive translation. The Halastavi árva virus (HalV) IRES represents the most minimalistic subclass identified to date, whereby the IRES lacks specific pseudoknot domains that bind to the 40S subunit but instead recruits pre-assembled 80S ribosomes via a mechanism that is not fully understood. Here, we examined cellular conditions that can support HalV IRES translation. We demonstrated that the HalV IRES is translationally active in insect Sf21 lysates and Drosophila S2 cells, but inactive in mammalian RRL and wheat germ extract. Cells treated with heat shock or serum starvation suppressed HalV IRES activity, whereas virus infection robustly enhanced HalV IRES-mediated translation. Finally, the HalV IRES can support viral translation and replication using a heterologous viral replicon. These findings highlight the context-specific cellular conditions that allow ribosome assembly and translation by a factorless minimalist IRES.
    Keywords:  IRES; RNA; ribosome; tRNA; virus
    DOI:  https://doi.org/10.3390/v18050492
  8. Vascul Pharmacol. 2026 May 22. pii: S1537-1891(26)00075-3. [Epub ahead of print] 107655
    N6-methyladenosine (m6A) post-transcriptional modification regulation of mRNA, an overlooked therapeutic opportunity to leverage mRNA processing in vascular smooth muscle cells.
    Dominick Openko, Michael V Autieri.
      In response to pathological stimuli, VSMCs modulate from a quiescent, contractile phenotype to a synthetic, non-contractile phenotype with increased migration, proliferation, and expression of matrix and pro-inflammatory cytokines. This response necessitates modification in expression of a plethora of mRNA transcripts, which often requires fine-tuning by post-translational changes in the stability of these mRNAs. N6-methyladenosine (m6A) modification can affect the fate of many mRNA transcripts in the cell, especially mRNA stability. Various m6A regulatory proteins, such as writers (methylases), erasers (demethylases), and readers (RNA binding proteins) are involved in various homeostatic processes in the cell, and can become dysregulated in disease states, contributing to vascular pathology. Recently, it has been shown that these m6A modulatory proteins can be targeted therapeutically with small molecule inhibitors to alter their expression and activity in the cell, opening up the possibility that targeting modifiers of the mRNA methylome can be leveraged as a therapeutic opportunity to treat vascular diseases. This review describes the mechanisms and explores roles of m6A modification in mRNA processing and how these changes in the VSMC transcriptome can contribute to pathogenesis and possibly treatment of vascular diseases.
    Keywords:  Vascular disease; Vascular smooth muscle cell; m6a modification; mRNA methylation; mRNA stability
    DOI:  https://doi.org/10.1016/j.vph.2026.107655
  9. Cells. 2026 May 20. pii: 943. [Epub ahead of print]15(10):
    Dual Roles of m6A Modification: Orchestrating Development and Abiotic Stress Resilience in Plants.
    Yang Sun, Wen Qin, Yiting Gong, Yinqiao Jian, Fangling Jiang, Rosa M Rivero, Ron Mittler, Zhen Wu, Rong Zhou.
      RNA N6-methyladenosine (m6A) is a prevalent epitranscriptomic modification that governs plant growth, development, and environmental adaptation. This review synthesizes recent advances in understanding the molecular mechanisms and biological functions of m6A in plants. The m6A landscape is dynamically regulated by methyltransferases (writers), demethylases (erasers), and m6A-binding proteins (readers), which collectively influence mRNA stability, translation efficiency, alternative polyadenylation (APA), and chromatin crosstalk. Functionally, m6A integrates diverse developmental processes-including embryogenesis, organogenesis, flowering, fruit ripening, and leaf senescence-with abiotic stress responses such as salt, drought, cold, and heat. Notably, m6A modification exhibits remarkable species-, cultivar-, and tissue-specific plasticity, enabling precise spatiotemporal gene regulation. Recent breakthroughs have revealed bidirectional crosstalk between m6A and histone modifications, forming a multi-layered regulatory network, while emerging concepts including phase separation, RNA structure dynamics, and stress memory further expand the functional repertoire of m6A. Despite significant progress, plant epitranscriptomics remains mechanistically underexplored, with critical gaps persisting in our understanding of translation initiation mechanisms, upstream regulatory signals controlling writers/erasers activities, and the functional significance of individual m6A sites. This review provided systematic insights into the complexity and specificity of m6A regulation in plants, offering a theoretical foundation for future efforts to decipher and ultimately manipulate this epitranscriptional layer for crop improvement.
    Keywords:  RNA N6-methyladenosine; abiotic stress response; alternative polyadenylation; histone modification; mRNA stability; mRNA translation efficiency; plant development
    DOI:  https://doi.org/10.3390/cells15100943
  10. Neurobiol Pain. 2026 Jul-Dec;20:20 100218
    Eukaryotic initiation factor 3d regulates context-dependent pain hypersensitivity through the integrated stress response.
    Subhaan M Mian, Sera I Nakisli, Brodie J Woodall, Pooja J Patel, Aariz Nackvi, Noura Elhamadany, Kree Goss, Nwasinachi Adriana Ezeji, Muhammad Saad Yousuf.
      Eukaryotic translation initiation factor 3 subunit D (eIF3d) is a noncanonical cap binding protein implicated in selective mRNA translation under stress conditions. Here, we investigate the contribution of eIF3d to pain processing using a heterozygous eIF3d knockout (eIF3d+/-, HET) mouse model. We first validated this model, confirming significant reductions in eIF3d mRNA and protein levels in dorsal root ganglia. Baseline assessments revealed no differences in mechanical, thermal, cold, or spontaneous pain behaviors between HET and eIF3d+/+ (wildtype, WT) mice, indicating intact basal nociceptive function. In pain models involving peripheral inflammation and metabolic stress, including methylglyoxal injection, IL-6 administration, carrageenan injection, and paw incision, HET mice displayed significantly reduced mechanical and cold hypersensitivity. In contrast, HET mice exhibited increased second phase nocifensive behaviors in the formalin test, possibly indicating enhanced central sensitization. Hyperalgesic priming, induced by prostaglandin E2, was comparable between HET and WT mice following IL-6 administration. We further demonstrated that IL-6 administration increased phosphorylation of eIF2α in DRG tissue, which was attenuated in HET mice, consistent with reduced ISR activation and correlating with nocifensive behaviors. Experimental autoimmune encephalomyelitis (EAE)-induced motor signs and pain hypersensitivity were unaffected in eIF3d HETs. These findings demonstrate that eIF3d selectively modulates nociceptive plasticity under defined stress conditions and suggests a context dependent role in the regulation of inflammatory and central pain sensitization.
    Keywords:  Formalin; Inflammation; Integrated stress response; Interleukin 6; Methylglyoxal; Translation; eIF3d
    DOI:  https://doi.org/10.1016/j.ynpai.2026.100218
  11. Mol Med Rep. 2026 Jul;pii: 213. [Epub ahead of print]34(1):
    Regulatory mechanisms and therapeutic potential of N6-methyladenosine modification in retinal diseases (Review).
    Wenyao Zhang, Jinying Chen, Jingxiang Zhong.
      N6‑Methyladenosine (m6A) modification, the most abundant internal chemical modification in eukaryotic messenger RNA, plays a central role in gene expression by dynamically regulating RNA metabolism. The present review systematically summarizes the regulatory mechanisms and pathological significance of m6A modification in major retinal diseases, including diabetic retinopathy, age‑related macular degeneration, retinoblastoma, uveitis and retinitis pigmentosa. Studies indicate that m6A methyltransferases (METTL3), demethylases (FTO and ALKBH5) and reader proteins (the YTH domain‑containing family of proteins) participate in pathological processes such as angiogenesis, inflammatory responses, pyroptosis and photoreceptor degeneration by modulating the stability, translation efficiency and degradation of key gene mRNAs. Furthermore, this review explores the therapeutic potential of targeting m6A‑modifying enzymes (for example, small‑molecule inhibitors STM2457 and FB23‑2) and highlights challenges in tissue specificity, delivery systems and clinical translation. Future research should integrate multi‑omics technologies and precision intervention strategies to advance the application of m6A modification in the diagnosis and treatment of retinal diseases.
    Keywords:  N6‑methyladenosine; RNA modification; age‑related macular degeneration; diabetic retinopathy; epitranscriptomic regulation; retinal diseases; therapeutic target
    DOI:  https://doi.org/10.3892/mmr.2026.13923
  12. Funct Integr Genomics. 2026 May 29. pii: 114. [Epub ahead of print]26(1):
    RBM15 transcription activated by EGR1 stimulates gastric cancer proliferation and metastasis by enhancing m6A modification of RREB1.
    Lu Yang, Yongsheng Chang, Wenjing Li, Xiangjie Fang, Yuyu Wang, Fang Yang, Xiaohe Guo.
      Gastric cancer is one of the most common malignant tumors worldwide, and its morbidity and mortality are among the highest among malignant tumors. RNA binding motif protein 15 (RBM15) has been confirmed to be a proto-oncogene in a variety of tumors, and it is also highly expressed in gastric cancer. However, its specific mechanism of role in gastric cancer progression remains unclear. The relationship between RBM15, ras responsive element binding protein 1 (RREB1), and transcription factor early growth responsive gene-1 (EGR1) was predicted by bioinformatics analysis. Meanwhile, the proliferation, stemness, angiogenesis, invasion, and migration of gastric cancer cells were detected by MTT, sphere formation, tube formation, Transwell, and scratch assays. The N6-methyladenosine (m6A) methylation level of RREB1 was determined by MeRIP assay. The stability of RREB1 mRNA was assessed via Actinomycin D. Binding of RBM15 or insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) to RREB1, and EGR1 to RBM15 was confirmed by RIP and ChIP assay, respectively. A xenograft tumor model was constructed to analyze the effect of RBM15/RREB1 axis on tumor growth in vivo. RBM15 was highly expressed in gastric cancer. Knockdown of RBM15 inhibited the proliferation, stemness, angiogenesis, invasion, and migration of gastric cancer cells. RBM15 enhanced the stability of RREB1 mRNA by driving the m6A modification of RREB1 through recruiting IGF2BP2. EGR1 stimulated the activation of RBM15 transcription, thereby affecting RREB1's expression. The RBM15/RREB1 axis promotes gastric cancer tumor growth in vivo. This study confirmed that EGR1 activated RBM15 transcription, which mediated the m6A modification of RREB1 mRNA by recruiting IGF2BP2, thereby promoting malignant progression in gastric cancer. The discovery of this pathway provides a new perspective for revealing the pathogenesis of gastric cancer.
    Keywords:  Early growth responsive gene-1; Gastric cancer; N6-methyladenosine methylation modification; RNA binding motif protein 15; Ras responsive element binding protein 1
    DOI:  https://doi.org/10.1007/s10142-026-01878-0
  13. FEBS J. 2026 May 29.
    A multilayered stress-response circuit: The mammalian mitochondrial UPR.
    Paulina Czechowicz, Anna Więch-Walów, Sylwia Kozioł, Jakub Dudzik, James F Collawn, Rafal Bartoszewski.
      Mitochondrial proteotoxic stress activates the mammalian UPRmt through a multilayered mechanistic architecture rather than a linear pathway. At its core lies an import-gated sensing logic: reduced preprotein import and mito-nuclear stoichiometric imbalance activates the integrated stress response (ISR) toward the translation of ATF4, CHOP, and the mitochondria-targeted transcription factor ATF5. These factors cooperatively reprogram transcription to expand the chaperone-protease capacity while transiently reducing the nuclear-encoded OXPHOS load. Parallel translational mechanisms that include eIF2α-dependent repression, stress-granule triage, and miRNA-driven selective silencing reduce the mitochondrial precursor import and maintain proteostatic symmetry between the cytosol and mitochondria. Within the organelle, LONP1- and CLPP-dependent proteolysis, mitoribosome pausing, and tRNA-processing checkpoints further dampen nascent chain pressure. Epigenetic licensing by demethylases and acetyltransferases links metabolic and bioenergetic status to promoter accessibility at UPRmt loci. Together, these import-gated, translational, and epigenetic control layers form a coherent mechanistic circuit ensuring that mitochondrial recovery is matched to folding, assembly, and metabolic capacity. We propose a unified framework explaining how these layers cooperate to determine adaptive versus maladaptive outcomes.
    Keywords:  Integrated stress response (ISR); Mitochondrial protein import stress; Mitochondrial proteostasis; Mitochondrial stress signaling; Mitochondrial unfolded protein response (UPRmt)
    DOI:  https://doi.org/10.1111/febs.70607
  14. Cell Mol Life Sci. 2026 May 25.
    Mitochondrial ribosomal protein MRPL27 supports glioma malignancy through regulation of oxidative phosphorylation.
    Jingyao Gu, Boya Zhou, Lin Ji, Haoyang Yuan, Haibo Ji, Mingxiao Zhu, Chunyan He, Xueping Gu, Suji Yan, Yin Wang.
      Glioma is a highly invasive primary brain tumor with a poor prognosis and currently lacks effective treatment methods. Increasing evidence indicates that mitochondrial oxidative phosphorylation (OXPHOS) is crucial for the development of glioma; however, the regulatory mechanisms controlling mitochondrial protein synthesis and energy metabolism are not yet fully understood. Analysis of the TCGA and CGGA databases reveals that MRPL27 is highly expressed in glioma tissues and is significantly associated with poor patient survival. Silencing MRPL27 significantly inhibits the proliferation, migration, and tumor growth of glioma cells, while inducing cell apoptosis. Mechanistically, the absence of MRPL27 impairs the mitochondrial oxidative phosphorylation process, reduces ATP production, disrupts redox balance, and increases oxidative stress. Notably, MRPL27 deficiency specifically reduces the protein content of mitochondrial-encoded oxidative phosphorylation components without altering their transcriptional levels, indicating its role in post-transcriptional regulation of mitochondrial protein expression. In summary, these findings suggest that MRPL27 is a key regulator of mitochondrial translation and energy metabolism in glioma, and emphasize the significance of mitochondrial ribosome regulation as a potential metabolic weakness for therapeutic intervention.
    Keywords:  Glioma progression; MRPL27; Mitochondrial translation; Oxidative phosphorylation
    DOI:  https://doi.org/10.1007/s00018-026-06236-8
  15. Nat Cell Biol. 2026 May 27.
    A transport-independent role for SLC25A12 in mitochondrial stress signalling.
    Liu Jiang, Lan Li, Jialiang Guan, Ying Liu.
      Mitochondria are central hubs for energy production and cellular adaptation to stress. When mitochondria are damaged, cells activate protective signalling pathways to restore homeostasis and ensure survival. One such pathway, known as the integrated stress response (ISR), reduces overall protein synthesis while enhancing the production of stress-responsive proteins. The mitochondrial carriers SLC25A12 and SLC25A13 transport similar metabolites but are expressed in different tissues and linked to distinct genetic diseases. Here we show that SLC25A12 plays a previously unrecognized role in stress signalling that is independent of its transport activity. SLC25A12 interacts with the mitochondrial protease OMA1, enabling activation of ISR during mitochondrial damage. This signalling function is disrupted by a disease-linked mutation but preserved in transport-deficient variants. Our findings reveal SLC25A12 as a dual-function mitochondrial protein, acting as both a metabolite transporter and a regulator of stress signalling, and suggest that defective ISR activation may contribute to certain SLC25A12-associated pathologies.
    DOI:  https://doi.org/10.1038/s41556-026-01973-1
  16. Free Radic Biol Med. 2026 May 25. pii: S0891-5849(26)00823-3. [Epub ahead of print]
    Redox-Sensitive m6A Epitranscriptomic Remodeling in Cadmium Stress and Toxicity.
    Shuyan Niu, Yán Wāng.
      Environmental stressors that disrupt redox homeostasis pose a significant threat to metabolic balance, tissue integrity, and organismal development. Increasing evidence identifies N6-methyladenosine (m6A), a dynamic and stress-responsive RNA modification, as a central regulator that translates oxidative cues into functional changes in RNA metabolism and cellular behavior. Redox imbalance can recalibrate the activity, localization, and substrate selectivity of m6A writers, erasers, and readers, thereby reshaping transcriptomic programs that control inflammation, antioxidant defense, proteostasis, mitochondrial quality, and stress-adaptive cell fate decisions. These m6A-dependent responses manifest across diverse tissues, including the liver, kidney, pancreas, lung, brain, and reproductive organs, where they influence unfolded protein responses, β-cell resilience, epithelial plasticity, fibrotic remodeling, neurodegenerative processes, and gametogenic stability. m6A dysregulation also contributes to placental stress signaling, developmental vulnerability, and intergenerational transmission of metabolic and reproductive outcomes following environmental perturbation. In this work, we integrate emerging evidence to propose a unified framework illustrating how redox-sensitive m6A signaling orchestrates cellular and physiological responses to environmental stress, using cadmium as an exemplar due to its well-established role as an oxidative stress inducer. We highlight mechanistic convergence across tissues, note sources of exposure specificity, and discuss technological advances that are redefining the resolution of m6A mapping. Finally, we outline opportunities for leveraging m6A as a biomarker, mechanistic probe, and potential therapeutic target in the study of environmental cadmium stress and associated diseases.
    Keywords:  Cellular stress; Environmental stress; Epigenetic inheritance; Mitochondrial dysfunction; Oxidative signaling pathways; Post-transcriptional regulation
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.319
  17. Mol Biol Cell. 2026 May 27. mbcE25100479
    Yeast Ribosomal Protein Rpl32 Modulates Ribosome Biogenesis, Ribosome Stability and the Cell Cycle.
    Stephen M Doris, Elizabeth S Noblin, Raphyel Rosby, Susan A Gerbi.
      How does the cell coordinate its two major activities of cell growth and cell division? To explore this, we have genetically depleted yeast ribosomal protein Rpl32 of the 60S ribosomal subunit, which is an essential protein for cell proliferation. 3-4 hours after Rpl32 depletion, the cell cycle arrests at G1. We have undertaken a kinetic analysis of the early cellular events to deduce the pathway from Rpl32 depletion to G1 arrest. Rpl32 depletion blocks pre-rRNA processing of the initial 35S pre-rRNA, thus preventing ribosomal biogenesis and nuclear export of 60S ribosomal subunits. Interestingly, the L25-GFP reporter transiently accumulates in a focal spot that resembles the nucleolar body/Cajal body. Amazingly, the inhibition of ribosome biogenesis in the nucleus is signalled to the cytoplasm where mature 18S and 25S rRNAs are degraded in a ribophagy-independent manner; Rpl32 protease-degradation uses de-ubiquitination. Nonetheless, the ribosomes that remain after degradation are sufficient for translation whose efficiency is unchanged through 6 hours after Rpl32 depletion, and the cell size and vacuole increase in size. The level of cyclin 1 mRNA is rapidly diminished after Rpl32 depletion and is a likely factor for the arrest of the cell cycle at G1.
    DOI:  https://doi.org/10.1091/mbc.E25-10-0479
  18. Can J Microbiol. 2026 Jan 01. 72 1-13
    Ribosome biogenesis mediates the translational increase of nonoptimal codon transcripts during IFN-β stimulation.
    Brenna N Hay, Rachel Smid, Nathan Louie, Huan Zhong, Stephane Flibotte, Eric Jan, Leonard J Foster.
      The interferon response is a signalling pathway unique to vertebrates that links the innate and adaptive immune responses. Interferons signal through a cascade of factors including the JAK-STAT pathway to induce the transcription of hundreds of interferon-stimulated genes (ISGs). Although the main interferon signal transduction pathways and ISGs have been elucidated, translational regulation of ISG transcripts is not fully understood. Prior work demonstrated that ribosomal protein RPL28 negatively regulates a subset of ISGs; however, we find that this effect may be due to a reduction in overall ribosome abundance. Multi-omics analysis of RNA-seq and LC-MS/MS data reveal proteins, including several ISGs, that are translationally up-regulated in IFN-β-stimulated cells depleted of ribosome biogenesis factor BOP1. Analysis of codon usage demonstrates a significant reduction in codon optimality for proteins that are translationally up-regulated during BOP1 knockdown and IFN-β stimulation. Using reporter constructs, we demonstrate that codon nonoptimal reporters are translated more than codon-optimized reporters in BOP1-depleted IFN-β cells. We propose that ribosome biogenesis may in part regulate the translational fine-tuning of integral ISG protein production to ensure optimal interferon responses, with potential effects extending beyond this pathway.
    Keywords:  codon optimality; interferon response; ribosome biogenesis; translational regulation
    DOI:  https://doi.org/10.1139/cjm-2025-0032
  19. bioRxiv. 2026 May 15. pii: 2026.05.13.724984. [Epub ahead of print]
    CHOP promotes the transition to chronic integrated stress response signaling with suppression of hepatocyte identity.
    Theo F Velarde, Kaihua Liu, Zewei Zhang, Reed C Adajar, Chaoxian Zhao, Huojun Cao, D Thomas Rutkowski.
      The transcription factor CHOP promotes cell death during ER stress, but it is strongly induced even by moderate stresses that do not result in appreciable cell death. Its role during less severe stresses-especially in intact tissues in vivo -is poorly understood. Here, we both deleted and restored CHOP specifically in hepatocytes and challenged animals with ER stress in vivo . We found that CHOP influenced stress-dependent hepatocyte gene expression through two previously unappreciated mechanisms. It directly suppressed the expression of transcriptional master regulators of hepatocyte identity and metabolism. And more broadly, it exacerbated ER stress through the promotion of protein synthesis, which led to persistent activation of the integrated stress response (ISR) despite dephosphorylation of eIF2α. This shift to second-phase ISR signaling was phenocopied by deletion of the protective UPR sensor ATF6α, suggesting that it reflects a transition from an acute stress response to a chronic one. Our findings show that CHOP augments the capacity of the ISR and UPR to continue to mount a protective response even after eIF2α phosphorylation has been suppressed. In vivo , where ISR signaling intersects with hepatocyte gene regulatory networks, this transition favors lipid dysregulation, highlighting a pathway through which CHOP impacts tissue function independent of cell death.
    DOI:  https://doi.org/10.64898/2026.05.13.724984
  20. bioRxiv. 2026 May 15. pii: 2025.05.09.653213. [Epub ahead of print]
    Trans-kingdom coupling of redox signaling to environmental cell stress responses through multiphase partitioning.
    Elsy Ngwa, Xi Chen, Stefanie Schmieder, Aaron Maurais, Victor Svistunov, Qianni Peng, Ian Moore, Wayne I Lencer, Eranthie Weerapana, Krishnan Raghunathan, Jay R Thiagarajah.
      Reactive Oxygen Species (ROS) signaling is a conserved biological process with parallel functions in all evolutionary branches of life. Here, we identify Receptor for Activated C Kinase 1 (RACK1) as a conserved redox-regulated hub that integrates ROS signals to coordinate cellular stress responses. Using cysteine reactivity profiling in intestinal epithelial cells, we demonstrate that RACK1 undergoes NOX1-dependent oxidation at multiple residues, with C286 serving as a key regulatory site. Functional studies reveal that RACK1 negatively regulates NFκB signaling through redox-dependent interactions with upstream signaling complexes. Upon stress stimulation, RACK1 dynamically redistributes into membrane-less condensates that act as redox-privileged microenvironments enriched for hydrogen peroxide. We find that oxidized RACK1 condensates are conserved through evolution with analogous stress response behavior in bacteria and yeast indicating a ubiquitous and ancient stress sensor-effector system. Functionally, redox-dependent RACK1 activity links environmental stress to translational control, with oxidation promoting inhibition of protein synthesis. Furthermore, RACK1 mediates responses to diverse pathogen-associated stimuli, including viral and bacterial infection, highlighting its role in epithelial innate immune responses. Collectively, these findings establish RACK1 as a cellular node for redox signaling, operating within condensate-based microdomains to spatially encode oxidative signals and regulate environmental stress pathways in cells.
    Significance Statement: This study defines a mechanism by which cells achieve specificity in redox signaling through compartmentalization within condensates. By identifying RACK1 as a redox sensor-effector, we reveal an ancient and broadly conserved system linking environmental stress to innate immune signaling and translational control. The discovery of redox-privileged condensates provides a conceptual framework for understanding how transient ROS signals are stabilized and interpreted in epithelial biology, with implications for inflammatory diseases, host-pathogen interactions, and fundamental cellular stress responses.
    DOI:  https://doi.org/10.1101/2025.05.09.653213
  21. bioRxiv. 2026 May 14. pii: 2026.05.13.724835. [Epub ahead of print]
    ppGpp regulates transcription elongation via direct and indirect inputs to RNA polymerase pausing and nucleotide addition.
    Andreas U Mueller, Rachel A Mooney, Michael D Engstrom, Yu Bao, Michael B Wolfe, Balendra Sah, Jonathan Buscher, Jason Saba, James Liu, Seth A Darst, Robert Landick.
      The signaling molecules guanosine 5'-tri/diphosphate 3'-diphosphate, (p)ppGpp, control bacterial protein synthesis rates and cell growth by targeting transcription, translation, NTP synthesis, and other functions. In lineages like E. coli , (p)ppGpp produced in response to charged-tRNA deficiency directly targets transcribing RNAP polymerase (RNAP) to match its pace to the pioneering ribosome on the nascent RNA (transcription-translation coupling). However, the mechanism by which (p)ppGpp slows RNAP is poorly defined. (p)ppGpp may allosterically stimulate RNAP pausing, inhibit catalysis, promote backtracking, compete for substrate GTP, inhibit GTP synthesis, or uncouple transcription-translation by inhibiting translation. Using a combination of cryo-EM, biochemical assays, and quantitative nascent elongating transcript sequencing (qNET-seq), we establish that (p)ppGpp allosterically regulates pausing and nucleotide addition via distinct motions of the RNAP swivel module and both competes with and lowers GTP in vivo. (p)ppGpp stimulates swiveling at pause sites to delay escape but may also inhibit counter-swiveling required in every round of nucleotide addition.
    Highlights: ppGpp biases RNAP toward swiveling and away from a catalytically-competent stateppGpp effects on RNAP conformation explain ppGpp stimulation of RNAP pausingppGpp stimulation of RNAP pausing in vivo is mediated mainly by reduced GTP levelsppGpp may allosterically slow RNAP and increases gene occupancy in vivo.
    DOI:  https://doi.org/10.64898/2026.05.13.724835
  22. Cell Syst. 2026 May 26. pii: S2405-4712(26)00095-5. [Epub ahead of print] 101613
    Active RNA synthesis patterns nuclear condensates.
    Andriy Goychuk, Salman F Banani, Pradeep Natarajan, Ming M Zheng, Haoran Wang, Giuseppe Dall'Agnese, Richard A Young, Mehran Kardar, Jonathan E Henninger, Arup K Chakraborty.
      Biomolecular condensates are membraneless compartments that organize biochemical processes in cells. In contrast to well-understood mechanisms describing how condensates form and dissolve, the principles underlying condensate patterning-including their size, number, and spacing in the cell-remain largely unknown. We hypothesized that RNA, a key regulator of condensate formation and dissolution, influences condensate patterning. Using nucleolar fibrillar centers (FCs) as a model condensate, we found that inhibiting ribosomal RNA synthesis significantly alters the patterning of FCs. Physical theory and experimental observations support a model whereby active RNA synthesis generates a non-equilibrium state that arrests condensate coarsening and thus contributes to condensate patterning. Altering FC condensate patterning by expression of the FC component treacle ribosome biogenesis factor 1 (TCOF1) impairs ribosomal RNA processing, linking condensate patterning to biological function. These results reveal how non-equilibrium states driven by active chemical processes regulate condensate patterning, which is important for cellular biochemistry and function.
    Keywords:  biomolecular condensates; non-equilibrium regulation; nucleolus; patterning; phase separation; transcription
    DOI:  https://doi.org/10.1016/j.cels.2026.101613
  23. Int J Mol Sci. 2026 May 18. pii: 4520. [Epub ahead of print]27(10):
    Biomolecular Condensates in Combined and Recurrent Plant Stresses: Integrating Phase Separation, Signal Prioritization, and Cross-Stress Memory.
    Sajid Ali, Yong-Sun Moon.
      Plants frequently encounter overlapping, sequential, and recurrent stresses, but the cellular mechanisms that organize responses to these complex conditions remain incompletely understood. Biomolecular condensates are membrane-less assemblies formed through phase separation and multivalent molecular interactions, and they can regulate RNA metabolism, protein sequestration, signaling specificity, transcriptional control, and stress recovery. This review evaluates the hypothesis that plant condensates may contribute to the organization of combined and recurrent stress responses by modulating molecular accessibility, transcript fate, proteostasis, and regulatory crosstalk. We synthesize current knowledge on stress granules, processing bodies, nuclear condensates, plastid-associated condensate-like assemblies, and other stress-responsive compartments, with emphasis on their possible roles in signal filtering, RNA triage, and recovery-associated reprogramming. We also distinguish established evidence from emerging hypotheses, particularly regarding condensate-mediated signal prioritization and stress memory. Current data support condensates as rapid stress-responsive organizers, but direct evidence for their persistence after recovery or their causal roles under simultaneous multi-stress conditions remains limited. By integrating phase separation biology with plant multi-stress physiology, this review proposes a testable conceptual framework and identifies methodological priorities for future studies in plant stress resilience and crop improvement.
    Keywords:  biomolecular condensates; cross-stress acclimation; phase separation; plant stress responses; signal prioritization; stress memory
    DOI:  https://doi.org/10.3390/ijms27104520
  24. J Gen Virol. 2026 May;107(5):
    The SL-I structural element of the 3' UTR region of West Nile virus participates in the regulation of viral translation.
    Cristina Romero-López, Pilar Bueno-Arribas, Alfredo Berzal-Herranz.
      The genome of West Nile virus (WNV) is a positive, ssRNA molecule, which encodes a single ORF flanked by UTRs (5' and 3' UTRs). These UTRs are enriched with structural RNA elements that play critical roles in the viral cycle, including translation, replication and encapsidation. The 3' UTR is crucial for translation control by the combined enhancer and repressor activities of different structural elements. This manuscript provides new roles for the 3' UTR SL-I element as a translation inhibitor in WNV in cis. This inhibitory effect is primarily observed in a cap-dependent translation context, most likely affecting multi-round translation efficiency. The molecular mechanism underlying this phenomenon appears to involve the recruitment of the 40S ribosomal subunit by the 3' UTR. We have previously demonstrated that the 3' UTR recruits the 40S subunit at two independent sites and influences its proper positioning at the 5' UTR. The present work identifies the SL-I element as a critical regulator of WNV translation at late stages of protein synthesis. This can be due, at least partially, to the modulation of the 40S positioning at the 3' UTR, as detected by selective 2'-hydroxyl acylation analysed by primer extension (SHAPE) analyses. These findings provide new insights into the role of the 3' UTR SL-I element in translation regulation and suggest that WNV translation is a finely tuned process dependent on the coordinated and well-balanced interplay of multiple partners.
    Keywords:  3′ UTR; RNA genome; West Nile virus (WNV); West Nile virus translation regulation
    DOI:  https://doi.org/10.1099/jgv.0.002268
  25. Proc Natl Acad Sci U S A. 2026 Jun 02. 123(22): e2605194123
    Perturbation of RNA homeostasis impairs mitochondrial respiration during poxvirus infection through excess RNA accumulation.
    Djamal Brahim Belhaouari, Anil Pant, Santiago Navarro-Forero, Fernando Cantu, Zhilong Yang.
      Induction of RNA degradation in infected cells is a strategy used by many viruses to promote efficient replication. Vaccinia virus, the prototype poxvirus and the vaccine platform for smallpox and mpox, encodes two decapping enzymes to accelerate mRNA and double-stranded RNA (dsRNA) degradation during infection, through functional coordination with host cell RNA exonuclease. Previous studies have largely focused on RNA degradation as a mechanism for regulating viral gene expression and evading innate immune sensing. Here, we show that impaired RNA degradation in vaccinia virus-infected cells, due to either depletion of viral decapping enzymes or cellular exonuclease, severely compromises mitochondrial respiration and integrity. We further demonstrated that accumulation of excess dsRNA and mRNA, including pseudouridine-modified RNAs, is sufficient to induce profound defects in mitochondrial respiration and integrity. Notably, this impairment occurs independently of interferon induction and dsRNA innate immune sensor Protein Kinase R. Moreover, excess RNA suppresses respiration in purified cell-free mitochondria and physically associates with mitochondria in cell-free and cellular contexts, supporting an immune-independent mechanism. Excess mRNA and dsRNA reduce mitochondrial membrane potential in both cells and purified mitochondria, indicating disruption of the proton gradient as the mechanism underlying impaired mitochondrial respiration and integrity. Together, these findings identify excess mRNA and dsRNA as perturbants of mitochondrial homeostasis in cells with dysfunctional RNA degradation during vaccinia virus infection, revealing a paradigm-shift concept linking RNA metabolism to mitochondrial function. The finding carries broad implications for understanding RNA and mitochondrial biology and RNA-based therapeutics and vaccines.
    Keywords:  RNA degradation; dsRNA; mRNA; mitochondrial respiration; poxvirus
    DOI:  https://doi.org/10.1073/pnas.2605194123
  26. Viruses. 2026 Apr 24. pii: 496. [Epub ahead of print]18(5):
    SARS-CoV-2 N Protein Hijacks the m6A Reader YTHDF2 to Suppress Antiviral Gene Expression.
    Peihan Wu, Shuai Wang, Xu Li.
      The m6A RNA methylation pathway plays a critical role in host antiviral defense. Host cells employ m6A readers such as YTHDF2 to regulate viral RNA fate through diverse mechanisms, including degradation, translational control, and immune recognition. However, we found that YTHDF2 is essential for SARS-CoV-2 replication, suggesting that a virus may exploit this host machinery to its advantage. Through integrative RNA-proteome analysis, we identified the SARS-CoV-2 nucleocapsid (N) transcript as the most heavily m6A-modified viral transcript and a direct interactor of YTHDF2. The N protein forms a complex with YTHDF2 in the cytoplasm and redirects this host RNA decay machinery toward host antiviral transcripts. N suppresses ISG15, IFIT1, MX1 and pro-inflammatory cytokines in a largely YTHDF2-dependent manner, an effect that is lost in YTHDF2-knockout cells. These findings reveal a viral immune evasion strategy wherein a viral protein actively hijacks an m6A reader to silence antiviral gene expression, establishing the N-YTHDF2 axis as a therapeutic target against SARS-CoV-2 and other coronaviruses.
    Keywords:  SARS-CoV-2; YTHDF2; host–virus interaction; immune evasion; innate immunity; interferon-stimulated genes; m6A RNA methylation; nucleocapsid protein
    DOI:  https://doi.org/10.3390/v18050496
  27. Biomolecules. 2026 May 20. pii: 748. [Epub ahead of print]16(5):
    An RNF4-Based Tool for Tracking Subcellular Localization of PolySUMOylation During Cellular Stress.
    Joseph S Floramo, Yaguang Zhao, Lorna Cohen, Kristin Gallik, David Brass, Tao Yang.
      SUMOylation is a rapid and dynamic process that orchestrates the switch between complex assembly and disassembly and between protein stabilization and turnover, making it particularly suitable for regulating stress responses. While proteomic methodologies exist for analyzing SUMOylated proteins under stress conditions, methods/tools for visualizing polySUMOylation dynamics have not been established. Here, we develop a polySUMOylation tracking tool by fluorescently labeling the polySIM domains derived from RNF4, which can reliably track polySUMO location and relate polySUMOylation levels to puncta number and intensity under various stress conditions, such as serum starvation, oxidative stress, and genotoxic stress. Furthermore, we extend its utility for tracking polySUMOylation across multiple cellular contexts in both control and stressed states. Collectively, this tracking tool enables deeper investigation of polySUMOylation dynamics and advances our understanding of how polySUMOylation regulates cellular processes in stress responses and disease pathogenesis.
    Keywords:  cellular stress; microscopy; nuclear puncta; polySUMOylation
    DOI:  https://doi.org/10.3390/biom16050748
  28. J Mol Histol. 2026 May 25. pii: 173. [Epub ahead of print]57(3):
    Icariin suppresses glycolysis in prostate cancer by upregulating ALKBH5 to mediate EARS2 m6A demethylation.
    HaiFeng Ying, Ming Ruan, WenHua Zhu, XiaoJing Wang.
      Prostate cancer (PCa) is among the most frequently occurring cancers in men. Its occurrence and progression are closely related to metabolic reprogramming, with abnormally active glycolysis being a notable feature sustaining rapid proliferation. Recent years have seen growing interest in the regulatory role of epigenetic modifications, particularly N⁶-methyladenosine (m6A) RNA methylation. AlkB homolog 5 (ALKBH5), as an m6A demethylase, may influence glycolysis in PCa by regulating target genes, offering new directions for mechanistic studies and therapy. The impact of different concentrations of Icariin (ICA) on PCa cell viability was first assessed using Cell Counting Kit-8 assays. Colony formation and Transwell assays were used to evaluate the effects of ICA on cell proliferation and migration, respectively. Apoptosis was detected by Annexin V-fluorescein isothiocyanate (FITC)/Propidium Iodide (PI) double staining. Glycolysis was evaluated by measuring the extracellular acidification rate (ECAR), oxygen consumption rate (OCR), and levels of glucose, lactate, and adenosine triphosphate (ATP). Methylated RNA immunoprecipitation-PCR was used to assess the effect of ICA on m6A methylation. The messenger RNA (mRNA) and protein expression of methyltransferase-like 3 (METTL3), METTL14, WTAP, fat mass and obesity-associated protein (FTO), and ALKBH5 were detected by quantitative real-time PCR and Western blot, respectively. Stable ALKBH5-knockdown and glutamyl-tRNA synthetase 2 (EARS2)-overexpressing PCa cell lines were constructed for functional studies. The half-life of EARS2 mRNA after ALKBH5 knockdown was determined using an actinomycin D assay to evaluate mRNA stability. RNA immunoprecipitation (RIP) experiments were performed to verify the interaction between ALKBH5 and EARS2 mRNA. In addition, a xenograft model was established by injecting PCa cells for in vivo validation. Immunohistochemistry (IHC) was used to detect protein expression in tumor tissues. ICA inhibited the proliferation (reduced cell viability, decreased colony formation), metastasis (impaired migration and invasion), and promoted apoptosis of PCa cells in a concentration-dependent manner, with no significant effect on cell viability at concentrations below 25 µM. ICA also concentration-dependently suppressed glycolysis in PCa cells. Treatment with 25 µM ICA reduced the global m6A methylation level and specifically upregulated the mRNA and protein expression of the demethylase ALKBH5, while the expression of other m6A-related regulatory factors was not significantly affected. Functional experiments showed that ALKBH5 knockdown or EARS2 overexpression promoted PCa cell proliferation, metastasis, and glycolysis (increased ECAR, glucose uptake, lactate production, ATP levels, and glycolysis-related protein expression; decreased OCR), and attenuated the inhibitory effects of ICA on these processes. RIP experiments confirmed that ALKBH5 interacts with EARS2 mRNA and that ALKBH5 reduces EARS2 mRNA stability via m6A demethylation, thereby downregulating its expression. In vivo, ICA effectively inhibited tumor growth in mice. IHC results showed that ICA upregulated ALKBH5 expression and downregulated the expression of hexokinase 2, lactate dehydrogenase A, and pyruvate kinase M2 in tumor tissues. These inhibitory effects of ICA were weakened by ALKBH5 knockdown. ICA suppresses the progression of PCa by inhibiting glycolysis, a process in which upregulation of ALKBH5 mediates m6A demethylation of EARS2 mRNA, leading to its destabilization and decreased expression. These findings were further validated in vivo.
    Keywords:  ALKBH5; Glycolysis; Icariin; Prostate cancer; m6A modification
    DOI:  https://doi.org/10.1007/s10735-026-10825-z
  29. Front Mol Neurosci. 2026 ;19 1837766
    The dual role of endoplasmic reticulum stress in cerebral ischemia: from adaptive protection to apoptotic induction.
    Jiehong Wang, Ying Shen.
      Endoplasmic reticulum (ER) stress is a critical determinant of neuronal fate following cerebral ischemia, functioning as both an adaptive survival mechanism and a potent inducer of cell death. Ischemic insult and subsequent reperfusion profoundly disrupt ER proteostasis, calcium homeostasis, and redox balance, leading to activation of the unfolded protein response (UPR). While transient UPR activation promotes neuronal survival by attenuating protein synthesis, enhancing protein folding capacity, and facilitating degradation of misfolded proteins, sustained or excessive ER stress converts this adaptive response into a pro-apoptotic program that accelerates neuronal loss. This review systematically summarizes the molecular basis of ER stress in cerebral ischemia, with a particular focus on the spatiotemporal regulation of the three canonical UPR branches-PERK, IRE1α, and ATF6. We highlight how these pathways initially coordinate cytoprotective responses but subsequently drive apoptosis through CHOP induction, mitochondrial dysfunction, oxidative stress, and inflammatory signaling. The reciprocal amplification between ER stress, reactive oxygen species, and inflammatory cascades establishes a pathological network that propagates ischemic brain injury. Importantly, accumulating evidence indicates that therapeutic modulation of ER stress must be precisely timed and pathway-specific. Selectively enhancing adaptive UPR signaling while suppressing maladaptive PERK-CHOP and IRE1α-JNK pathways represents a promising strategy for neuroprotection. By integrating recent mechanistic and translational studies, this review positions ER stress as a central regulatory hub in ischemic stroke and provides a framework for the development of targeted interventions aimed at improving neurological recovery.
    Keywords:  ER stress signaling; cerebral ischemia; endoplasmic reticulum stress; neuroprotection; unfolded protein response
    DOI:  https://doi.org/10.3389/fnmol.2026.1837766
  30. Neurochem Res. 2026 May 27. pii: 177. [Epub ahead of print]51(3):
    WGCNA-Based Identification of HSPB1 Reveals a HOXA5/METTL1-m7G Regulatory Axis that Promotes Malignant Progression and Suppresses Ferroptosis in Glioblastoma.
    Hongchao Li, Yusheng Chen, Yanyan Zhu, Shanbao Ke, Danting Wu.
      Glioblastoma (GBM) is the most aggressive primary brain tumor with a dismal prognosis. Ferroptosis is implicated in GBM pathogenesis. Heat shock protein B1 (HSPB1) is associated with tumor progression, yet its precise function and regulatory mechanism in GBM ferroptosis remain elusive. Differentially expressed genes were identified from the GSE151352 dataset. WGCNA was employed to identify GBM-associated modules, which were then intersected with genes from the FerrDb V2 database. HSPB1 expression and prognostic value were validated using TCGA and GEPIA databases, and clinical specimens. Functional assays (EdU, TUNEL, and Transwell) and ferroptosis indicators (lipid ROS, Fe2+, GSH) were assessed following HSPB1 modulation. Bioinformatics tools predicted METTL1-mediated m7G modification of HSPB1, and results were validated by RIP, dual-luciferase reporter assay, and mRNA stability assays. Transcriptional regulation of HSPB1 by HOXA5 was predicted and confirmed. A subcutaneous xenograft model was used to evaluate the METTL1-HSPB1 axis in vivo. Analysis revealed 2985 DEGs. WGCNA identified a GBM-correlated "red" module; intersection with ferroptosis genes pinpointed HSPB1. HSPB1 was significantly overexpressed in GBM, correlating with poor patient survival. HSPB1 knockdown suppressed GBM cell proliferation, migration, invasion, and induced ferroptosis. Mechanistically, METTL1 mediated m7G modification to HSPB1 mRNA to enhance its stability. Concurrently, HOXA5 bound to the HSPB1 promoter to activate its transcription. Silencing either METTL1 or HOXA5 downregulated HSPB1, inhibiting GBM malignant phenotypes. In vivo, the METTL1-HSPB1 axis promoted tumor growth. METTL1 stabilizes HSPB1 mRNA through m7G methylation, and HOXA5 transcriptionally activates HSPB1 expression. This regulation promotes GBM malignant progression.
    Keywords:  Ferroptosis; Glioblastoma; Heat shock protein B1; Homeobox A5; Methyltransferase like 1; N7-methylguanosine methylation; Weighted gene co-expression network analysis
    DOI:  https://doi.org/10.1007/s11064-026-04784-w
  31. J Virol. 2026 May 27. e0035526
    An IRES-like cis-acting element located within the EV-A71 coding region drives translation independent of the 5'-IRES and modulates viral fitness through regulated binding of viral RNA to 3D polymerase.
    Yifan Xing, Qi Liu, Meixian Fu, Hao Zheng, Tong Zhao, Xixi Chen, Xia Cai, Jian-Er Long.
      Enterovirus A71 (EV-A71) is a leading cause of hand, foot, and mouth disease and is occasionally associated with severe neurological complications in young children. Previous studies of EV-A71 and related enteroviruses suggested that the virus possibly contains additional cis-acting elements (CAEs) within the major open reading frame (ORF) regulating viral protein translation. To systematically explore CAEs in the EV-A71 genome and characterize their functions, we utilized bicistronic reporter plasmids to screen the entire genome, identifying internal ribosome entry site (IRES)-like CAEs within the VP3-VP1 and 2A-2B coding regions. We demonstrate that EV-A71 translation can occur independently of the 5'-IRES and that the element within 2A-2B specifically facilitates this alternative initiation. Furthermore, the IRES-like CAE significantly modulates viral propagation by altering the expression of viral proteins including VP1 and 3D polymerase and shifting the ratio of positive-sense to negative-sense genomic RNA. Disruption of its RNA structure via synonymous mutations reduced viral genome replication, progeny production, and fitness. Mechanistically, these impairments correlated with decreased RNA binding to the viral 3D polymerase. These findings illuminate the multifaceted roles of coding-region IRES-like CAEs in viral infection and fitness, reveal a noncanonical mechanism for enteroviral protein synthesis independent of the 5'-IRES, and provide a framework to identify RNA structures and synonymous mutations for attenuated vaccine design and antiviral strategies.IMPORTANCEThe biological significance of cis-acting elements (CAEs) within viral coding regions, particularly their impact on infectivity and fitness, remains poorly understood. Here, we characterize an internal ribosome entry site (IRES)-like CAE in Enterovirus A71 (EV-A71), the causative agent of hand, foot, and mouth disease. Through genome-wide screening, we identified novel IRES-like CAEs and demonstrate that EV-A71 translation can proceed independently of the 5'-IRES, with the 2A-2B element specifically mediating this alternative initiation. The 2A-2B CAE and its associated RNA secondary structure are essential for viral infectivity and fitness. Synonymous mutations disrupting local stem-loop structures impair viral RNA binding to the 3D polymerase, resulting in reduced fitness. These findings reveal a noncanonical mechanism for IRES-independent enteroviral protein synthesis, elucidate how RNA structures and synonymous mutations in coding-region CAEs modulate viral replication, and inform attenuated vaccine design and antiviral strategies while revealing the evolutionary implications of these regulatory elements.
    Keywords:  3D polymerase; IRES-independent translation; IRES-like cis-acting element; RNA structure; enterovirus A71; infectious clone; viral fitness
    DOI:  https://doi.org/10.1128/jvi.00355-26
  32. bioRxiv. 2026 May 11. pii: 2026.05.07.723568. [Epub ahead of print]
    Mitochondrial respiration modulates Hsf1 activation and the heat shock response.
    D W McDonald, A Dea, R Sava, Y J Kim, L Joos, D Pincus, M L Duennwald.
      Cells employ a bevy of transcriptional and post-translational stress responses to tolerate the burden of misfolded proteins induced by stress. In particular, the heat shock response facilitates the upregulation of molecular chaperones and protein remodeling factors that mediate proteostasis in response to accumulated misfolded proteins in the nucleus and cytosol. However, in response to stress neurons struggle to induce a canonical heat shock response, highlighting our poor understanding of how neurons maintain proteostasis. Specifically, the ability of post-mitotic respiring cells to regulate the heat shock response in comparison to their rapidly dividing, predominantly glycolytic counterparts has been under-studied. In this study, we employ yeast models that are easily manipulated to generate energy via glycolysis or mitochondrial respiration by changing the carbon source in the media. Using this model, we demonstrate that Hsf1 activity, the heat shock response and proteostasis are impaired in respiring cells. Interestingly, our data show that reduced Hsf1 activity regulates viability of respiring cells, with respiring cells poorly tolerating constitutively activated Hsf1. Finally, we describe alternative post-translational programming of the molecular chaperones Hsp70 and Hsp104 that plausibly enables respiring cells to mediate proteostasis despite a dampened heat shock response. Our findings offer new insights into possible proteostatic strategies employed by cells in different metabolic conditions.
    DOI:  https://doi.org/10.64898/2026.05.07.723568
  33. Genome Biol. 2026 May 28.
    Real-time search-assisted multiplexed quantitative proteomics reveals system-wide cryptic translation initiation in human cancer cells.
    Hiroko Kozuka-Hata, Tomoko Hiroki, Aya Kitamura, Naoaki Miyamura, Tetsu Akiyama, Jun-Ichiro Inoue, Kouhei Tsumoto, Masaaki Oyama.
       BACKGROUND: It is generally considered that eukaryotic translation initiation prominently occurs from the first AUG codon by ribosomal scanning from the 5-cap end of each mRNA. In order to identify cryptic internal translation initiation sites defined by alternative AUG codons on a proteome-wide scale, we generate a customized amino acid sequence database which contain differential AUG-guided tryptic peptide fragments computationally predicted from well-curated Swiss-Prot human protein reference sequences and applied it for high-resolution mass spectrometry-based proteomic analysis.
    RESULTS: The ultra-deep proteomic detection based on the real-time search platform on Orbitrap Eclipse Tribrid mass spectrometry system leads to identification of not only more than 26,000 unique peptides from already annotated human protein coding sequences but also 794 novel peptide fragments defined by alternative downstream translation initiation in human cancer cells. Very notably, Tandem Mass Tag-based multiplex quantitative analysis of patient-derived glioblastoma initiating cells uncovers epidermal growth factor-dependent translational regulation on a wide range of differential AUG-guided non-canonical proteoforms as well as cancer-related transcription factors and cell cycle/cell division regulators in a cell-type specific manner.
    CONCLUSIONS: Our study provides the first proteome-wide evidence of downstream AUG-guided cryptic translation initiation dynamics in human cancer cells.
    DOI:  https://doi.org/10.1186/s13059-026-04120-z
  34. Trends Biochem Sci. 2026 May 25. pii: S0968-0004(26)00133-7. [Epub ahead of print]
    Orthogonal regulation of protein abundance.
    Wenxin He, Mingming Han, Wenjing Qiao, Cong Gao, Liming Liu, Jing Wu, Guipeng Hu.
      Precise regulation of protein abundance is essential for cellular function and physiology. Conventional approaches are often limited by insufficient resolution or unintended crosstalk. In contrast, orthogonal control technologies enable programmable and precise modulation of protein abundance while remaining insulated from native networks. In this review, we summarize the development and application of regulation technologies with different orthogonality across multiple levels. Orthogonal transcriptional control primarily involves the design and engineering of orthogonal RNA polymerases and transcription factors; orthogonal translational regulation focuses on advances in genetic codon expansion and post-translational modifications; targeted protein degradation and compartmentalized regulation are also discussed. Finally, we highlight the integration across the different levels described above. This review might bring disruptive insights and conceptual breakthroughs to precision medicine and sustainable biomanufacturing.
    Keywords:  central dogma; genetic engineering; orthogonal regulation; protein biosynthesis; protein localization; synthetic biology
    DOI:  https://doi.org/10.1016/j.tibs.2026.04.013
  35. Int J Mol Sci. 2026 May 14. pii: 4382. [Epub ahead of print]27(10):
    Redefining Endometrial Decidualization: The Central Role of the ER Stress-Immune-Metabolic Axis.
    Özdem Karaoğlan, Özgül Tap, İbrahim Ferhat Ürünsak.
      Decidualization in the human endometrium is not merely a hormone-dependent differentiation process; rather, it represents a multilayered adaptive program characterized by the tight integration of immune regulation, metabolic reprogramming, and cellular stress responses. In this review, endoplasmic reticulum (ER) stress and the associated unfolded protein response (UPR) are proposed as central regulatory mechanisms governing this process. Triggered by increased protein synthesis and secretory demand, UPR activation under physiological conditions preserves proteostasis and supports the secretory capacity of stromal cells. In contrast, chronic or dysregulated activation leads to a maladaptive response characterized by apoptosis, inflammation, and metabolic dysfunction. UPR signaling pathways shape immune tolerance through their effects on macrophage polarization, uterine natural killer (uNK) cell function, and T cell balance. At the metabolic level, adenosine monophosphate-activated protein kinase (AMPK) regulates cellular adaptation through bidirectional interactions with mitochondrial function and redox homeostasis. Within this framework, the ER stress-immune-metabolic axis operates not as a linear pathway but as a dynamic network incorporating multiple feedback loops, thereby constituting a critical threshold mechanism that determines the success of decidualization. Disruption of this axis provides a shared mechanistic basis for pathologies such as recurrent implantation failure, pregnancy loss, and preeclampsia. From a therapeutic perspective, agents including chemical chaperones, UPR modulators, AMPK activators, and anti-inflammatory compounds hold translational potential by targeting these pathological feedback circuits. However, key knowledge gaps remain, particularly regarding the cell type-specific and temporal regulation of ER stress, the molecular boundaries defining the transition from adaptive to pathological states, and interspecies differences. Future studies employing single-cell omics approaches and functional in vivo models will be essential to elucidate the dynamic organization of this axis and to enable the development of targeted and personalized therapeutic strategies.
    Keywords:  endometrial decidualization; endoplasmic reticulum stress; immune regulation; metabolic reprogramming; unfolded protein response
    DOI:  https://doi.org/10.3390/ijms27104382
  36. Mol Cell. 2026 May 29. pii: S1097-2765(26)00288-1. [Epub ahead of print]
    Mechanism of RACK1-dependent ZAKα activation at stalled and collided ribosomes.
    Anna Constance Vind, José Francisco Martínez, Zhenzhen Wu, Andrii Bugai, Kelly Mordente, Giancarlo Abis, Sébastien Chamois, Sofia Ramalho, Catarina Pechincha, Laura Ryder, Qiuyan Chen, Mads Rasmussen, Xinyao Shi, Dandan He, Jesper Q Svejstrup, Peter Haahr, David Gatfield, Maria R Conte, Torben Heick Jensen, Melanie Blasius, Simon Bekker-Jensen.
      Despite a growing interest in the ribotoxic stress response (RSR), it remains unknown how the upstream p38- and JNK-activating MAP3 kinase ZAKα senses translational impairment. Combining AlphaFold3 prediction and RNA crosslinking and immunoprecipitation (CLIP), we uncover that ZAKα dynamically monitors the mRNA exit channel of elongating ribosomes. This is accomplished by ZAKα via direct interactions with the ribosomal proteins RACK1 and RPS27 as well as 18S rRNA helix-26. In this conformation, the RNA-binding S (sensing) and C-terminal domain of ZAKα span across the mRNA exit channel. Loss of ribosome processivity and mRNA stasis stabilizes the interaction allowing for kinase activation. Prolonged binding of ZAKα to stalled and collided ribosomes is associated with sequestration of the sterile alpha-motif (SAM) domain on RACK1, which allows for transient ZAKα dimerization, activation loop trans-autophosphorylation, and RSR activation. Our findings highlight how ZAKα senses both stalled and collided ribosomes in human cells through overlapping mechanisms.
    Keywords:  ZAK-alpha; ribosome collision; ribosome stalling; ribotoxic stress response; translation surveillance
    DOI:  https://doi.org/10.1016/j.molcel.2026.04.034
  37. Int J Biol Sci. 2026 ;22(10): 5142-5160
    A context-dependent METTL1-m7G-SLC7A11 axis links metabolic stress to epithelial fate in ulcerative colitis.
    Lichao Yang, Qi Sun, Zhixian Jiang, Baojia Yao, Caimei Yang, Ganglei Liu, Lianwen Yuan.
      Ulcerative colitis (UC) is characterized by chronic intestinal inflammation accompanied by epithelial barrier dysfunction and profound metabolic stress; however, how metabolic cues are integrated to determine epithelial cell fate remains incompletely understood. Here, we identify a context-dependent METTL1-m7G-SLC7A11 regulatory axis that links metabolic stress to intestinal epithelial outcomes during UC progression. By integrating analyses of human UC tissues, DSS-induced acute and chronic colitis mouse models, and mechanistic in vitro experiments, we demonstrate that METTL1 enhances N7-methylguanosine (m7G) modification of SLC7A11 mRNA, thereby stabilizing the transcript and sustaining SLC7A11 expression in inflammatory settings. Functionally, SLC7A11 exhibits glucose-dependent dual effects. Under glucose-replete conditions, SLC7A11 supports cystine uptake, glutathione synthesis, and redox homeostasis, protecting epithelial integrity and limiting inflammation. In contrast, under glucose deprivation-a characteristic feature of inflamed UC mucosa-persistent SLC7A11 activation induces disulfide stress, cytoskeletal collapse, and disulfidptosis-associated epithelial injury. In vivo, inhibition of the METTL1/m7G/SLC7A11 axis exacerbates chronic DSS-induced colitis but alleviates acute DSS-induced colitis, revealing a switch from adaptive to maladaptive signaling with escalating metabolic stress. Collectively, these findings establish the METTL1-m7G-SLC7A11 axis as a metabolic rheostat that integrates inflammatory cues and nutrient availability to determine epithelial cell fate in UC, highlighting the importance of stage- and context-specific therapeutic strategies.
    Keywords:  Disulfidptosis; METTL1; Metabolic stress.; N7-methylguanosine (m7G); SLC7A11; Ulcerative colitis
    DOI:  https://doi.org/10.7150/ijbs.133562
  38. Biomedicines. 2026 May 12. pii: 1091. [Epub ahead of print]14(5):
    Heat Shock Protein 27 in Radiation-Induced Trismus: Mechanistic Insights and a Hypothesis-Generating Framework.
    Erkan Topkan, Efsun Somay, Doga Topkan, Sukran Senyurek, Duriye Ozturk, Ugur Selek.
      Radiation-induced trismus (RIT) is a common and function-limiting late complication of radiotherapy for head and neck cancers, particularly when the masticatory muscles and temporomandibular joint receive high doses. Despite advances in intensity-modulated radiotherapy, RIT remains a significant survivorship problem, and robust biological biomarkers capable of predicting individual susceptibility are lacking. Heat shock protein 27 (HSP27; HSPB1) is a small heat shock protein that regulates multiple cellular stress responses, including proteostasis, cytoskeletal dynamics, redox homeostasis, apoptosis, and inflammatory signaling. In head and neck malignancies, HSP27 overexpression has been associated with treatment resistance and fibrosis-prone tissue remodeling. Experimental studies further demonstrate that HSP27 promotes transforming growth factor-β-mediated myofibroblast differentiation and extracellular matrix deposition, whereas pharmacologic or genetic inhibition attenuates radiation- or bleomycin-induced pulmonary fibrosis in vivo. Evidence from skeletal muscle biology also indicates that HSP27 modulates muscle integrity, denervation-associated atrophy, inflammatory signaling, and cytoskeletal stability. Although HSP27 has been widely investigated in radiation responses, fibrosis, and skeletal muscle stress adaptation, its potential involvement in the pathogenesis of RIT has not been systematically examined. This review proposes a conceptual framework in which HSP27 functions as an integrative molecular mediator linking radiation-induced oxidative stress, endothelial injury, and fibro-atrophic remodeling within the masticatory apparatus. By integrating current evidence on the epidemiology, dosimetric determinants, imaging correlates, and pathophysiology of RIT with the structural and functional biology of HSP27, this review provides the first tissue-specific synthesis of molecular stress signaling and clinical mechanisms relevant to RIT susceptibility. We further suggest that HSP27 signaling may influence susceptibility to fibro-neuromuscular injury in irradiated masticatory tissues. Given the absence of direct experimental or clinical evidence in this setting, these considerations are derived from mechanistic convergence across related biological systems and should be interpreted as biologically plausible but unproven, with potential implications for future biomarker development and biologically informed prevention strategies.
    Keywords:  fibro-atrophic remodeling; head and neck radiotherapy; heat shock protein 27 (HSP27); masticatory muscle injury; oxidative stress; radiation fibrosis; radiation toxicity; radiation-induced trismus
    DOI:  https://doi.org/10.3390/biomedicines14051091
  39. J Mol Histol. 2026 May 25. pii: 178. [Epub ahead of print]57(3):
    p97/VCP as a dual regulator of UPS and autophagy in ovarian cancer: a novel therapeutic target.
    Ilkay Corumluoglu, Ebru Alimogullari.
      Ovarian cancer is among the most lethal gynecologic malignancies worldwide, with high mortality rates largely attributable to late diagnosis and the development of therapeutic resistance. Cellular proteostasis in cancer cells is tightly regulated by the ubiquitin-proteasome system (UPS) and autophagy, two major protein quality control pathways. Key proteins involved in these pathways, including p97/valosin-containing protein (p97/VCP), ubiquitin (Ub), p62/SQSTM1, and LC3B, have been implicated in cancer progression; however, their coordinated regulation in ovarian cancer remains incompletely understood. In this study, we investigated the expression and regulation of UPS- and autophagy-related proteins in the human ovarian cancer cell line MDAH-2774 under pharmacological modulation of autophagy. Cells were treated with rapamycin (10 µM), an autophagy inducer, or chloroquine (50 µM), an autophagy flux inhibitor, for defined incubation periods. Protein expression levels and cellular localization of p97/VCP, Ub, p62, and LC3-II were analyzed using Western blotting, immunofluorescence staining, and siRNA-mediated p97/VCP silencing. Our results demonstrated that p97/VCP and ubiquitin were expressed at relatively high levels in ovarian cancer cells, whereas autophagy markers p62 and LC3B showed reduced basal expression, suggesting dysregulated autophagic activity. Rapamycin treatment markedly increased p97/VCP expression, supporting its involvement in autophagy induction. In contrast, chloroquine treatment significantly reduced p97/VCP levels while inducing a pronounced accumulation of Ub, p62, and LC3-II (p < 0.05), consistent with impaired autophagic flux and disrupted proteasomal degradation. Furthermore, siRNA-mediated suppression of p97/VCP significantly decreased the expression of p97/VCP, LC3-II, ubiquitin, and the autophagy-modulating responses to rapamycin and chloroquine compared with control siRNA (p < 0.05). p97/VCP suppression was associated with alterations in endoplasmic reticulum-associated degradation (ERAD) and a concomitant reduction in unfolded protein response (UPR)-related protein levels, indicating increased cellular stress. Collectively, these findings highlight p97/VCP as a central regulator of proteostasis in ovarian cancer through its coordinated roles in both the UPS and autophagy pathways. Dysregulation or pharmacological inhibition of p97/VCP may exacerbate proteotoxic stress by disrupting the balance between autophagy and UPR signaling, potentially contributing to tumor progression and therapy resistance. Further mechanistic studies are warranted to elucidate the underlying signaling networks and to evaluate p97/VCP-mediated proteostasis pathways as potential therapeutic targets in ovarian cancer.
    Keywords:  Autophagy; Chloroquine; Ovarian cancer; Proteasome; Proteostasis; Rapamycin; p97/VCP
    DOI:  https://doi.org/10.1007/s10735-026-10838-8
  40. JACS Au. 2026 May 25. 6(5): 2730-2742
    NRAS mRNA-Degrading Bifunctional Small Molecules Induce Diverse Cellular Morphological Changes in Cancer Cells.
    Mao Jiang, Daniel Hösle, Yang Liu, Sonja Sievers, Peng Wu.
      Therapeutic targeting of the oncogenic NRAS protein, which is constitutively activated in human cancers, with small molecules is a promising yet challenging anticancer strategy. Therefore, targeting the NRAS mRNA poses a feasible alternative that will likely yield new biological consequences due to the new mechanism of regulation at the post-transcriptional level. We report herein the first examples of a reversely regulating NRAS mRNA-degrading ribonuclease targeting chimeric small molecules (NRAS-RIBOTAC), which were assembled by conjugating a reported 4-aminoquinazoline G4-NRAS binder with a biphenyl RNase L binder. Among the obtained NRAS-RIBOTACs, 5 impacted G4-containing NRAS mRNA expression while it did not significantly impact the expression of NRAS protein in MD-MB-231 cells, which could be explained by the fact that the G4-containing NRAS transcript only accounts for a trace amount in comparison with the dominant G4-lacking NRAS mRNA. Furthermore, we report here for the first time the phenotypic evaluation of RIBOTACs in the unbiased phenotypic profiling method, cell painting assay. In comparison with the monovalent ribonuclease recruiter and G4-NRAS mRNA binder, selected RIBOTACs showed significant activities in inducing cellular morphological changes and demonstrated a new biological performance that is reflected by the diverse cellular morphological changes in cancer cells.
    Keywords:  NRAS mRNA; RNA degradation; anticancer; cellular morphological profile; ribonuclease-targeting chimera
    DOI:  https://doi.org/10.1021/jacsau.5c01600
  41. Med Sci (Basel). 2026 May 17. pii: 258. [Epub ahead of print]14(2):
    Urinary Biomarkers in Parkinson's Disease: A Structured Integrative Review of Pathophysiological Pathways.
    Halyne Queiroz Pantaleão Santos, Nairo Massakazu Sumita, Carlos Alberto-Silva, Marcela Bermudez Echeverry.
       BACKGROUND/OBJECTIVES: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by complex and interconnected pathophysiological mechanisms, including mitochondrial dysfunction, oxidative stress, neuroinflammation, lysosomal impairment, and altered neurotransmitter metabolism. Unlike cerebrospinal fluid or blood, urine offers a truly non-invasive source of biomarkers, reflecting systemic metabolic changes and renal protein excretion linked to neurodegeneration. This review aims to critically synthesize current evidence on urinary biomarkers in PD and to organize this heterogeneous literature into pathophysiologically meaningful domains.
    METHODS: A comprehensive literature search of human studies investigating urinary biomarkers in PD was performed. Eligible studies were comprehensively analyzed and classified according to dominant biological pathways. To facilitate interpretation, findings were organized into six thematic domains: genetic and protein-based biomarkers; metabolic pathways and mitochondrial dysfunction; oxidative stress and neuroinflammation; gut-brain-axis-related metabolites; hormonal and systemic biomarkers; and emerging exploratory markers. Results were summarized in domain-specific tables and integrated using a conceptual framework.
    RESULTS: A total of 32 human studies met the inclusion criteria, revealing diverse urinary molecular signatures associated with PD across multiple biological domains. Genetic and protein-based markers, including LRRK2-related proteins, α-synuclein species, and lysosomal lipids, showed potential for disease stratification. Metabolomic studies consistently identified alterations in acylcarnitines, organic acids, and amino acid metabolism, reflecting mitochondrial dysfunction. Biomarkers related to oxidative stress, immune activation, gut microbiota metabolism, and hormonal regulation further highlighted the systemic nature of PD. However, most individual biomarkers lacked disease specificity and exhibited methodological heterogeneity.
    CONCLUSIONS: Current evidence supports urine as a valuable source of systemic biomarkers reflecting multiple pathophysiological processes in PD. While single urinary markers remain insufficient for clinical application, integrated omics-based approaches-particularly metabolomics and peptidomics/proteomics-hold promise for identifying combinatorial biomarker signatures. Future longitudinal and standardized studies are required to enhance specificity and translational potential for non-invasive diagnosis and disease monitoring in PD.
    Keywords:  mitochondrial dysfunction; neurodegenerative disorders; oxidative stress; proteomics
    DOI:  https://doi.org/10.3390/medsci14020258
  42. Mol Cell Probes. 2026 May 23. pii: S0890-8508(26)00013-7. [Epub ahead of print]88 102073
    The role of RNA modifications in the pathological mechanisms and therapeutic targeting of multiple myeloma.
    Hao Chen, Hefei Ren, Xin Wang, Chang Liu, Liansheng Jiang, Shuyue Zang, Tingyu Liu, Sijie Wang, Weiwen Huang, Lin Zhou.
      Multiple myeloma (MM) remains largely incurable despite major therapeutic advances, underscoring the need to define novel pathogenic mechanisms and druggable targets. Epitranscriptomic dysregulation, encompassing reversible chemical modifications on RNA, has emerged as a post-transcriptional regulatory layer that may contribute to MM biology. This focused review discusses the emerging roles of major RNA modifications and their regulators in MM pathogenesis, bone disease, drug resistance, and immune escape. We summarize representative experimental and translational studies on RNA-modifying enzymes, non-coding RNAs, and the bone marrow microenvironment, with emphasis on mechanisms directly validated in MM. Evidence derived from AML, solid tumors, or pan-cancer analyses is discussed as hypothesis-generating and requiring MM-specific validation. We summarize MM-supported evidence that m6A demethylases such as FTO and ALKBH5, as well as writers such as METTL3 and NSUN2, may regulate the stability and translation of disease-relevant transcripts. We also discuss emerging cross-cancer data on the m7G writer METTL1 as a hypothesis-generating framework that requires MM-specific validation. We delineate how RNA modification-dependent non-coding RNA networks and extracellular vesicle cargo remodel osteoclast and osteoblast function, linking the epitranscriptome to osteolytic bone disease. We further describe RNA modification-driven drug resistance circuits and immune escape pathways involving FTO, METTL3, H19, MALAT1, YTHDF1, and m5C-defined molecular subtypes. Finally, we summarize current epitranscriptomic therapeutic strategies, including small molecule inhibitors of writers, erasers, and readers, RNA-based therapeutics targeting pathogenic non-coding RNAs, and RNA modification-derived prognostic signatures for risk stratification. Collectively, this review discusses RNA-modification machinery as a potentially actionable regulatory layer in MM and outlines key challenges for clinical translation.
    DOI:  https://doi.org/10.1016/j.mcp.2026.102073
  43. Nature. 2026 May 27.
    Substrate selectivity of the human RNA m5C methyltransferase NSUN2.
    Jacob Canepa, Victor M Ruiz-Arroyo, Netanya S Schlamowitz, Yunsun Nam.
      Specific deposition of RNA modifications is important for regulating gene expression1,2. 5-Methylcytosine (m5C) is a common epitranscriptomic modification, and NSUN2 is a key enzyme responsible for m5C methylation of various types of RNA. Dysregulation of NSUN2 is associated with numerous diseases, including cancers and neurological disorders3. The versatility of NSUN2 complicates our understanding of its substrate specificity and molecular roles in biology and disease. Here we show how NSUN2 interacts with RNA substrates at distinct stages of its catalytic cycle to modify cytidines. Furthermore, we show the role of RNA structure in facilitating NSUN2 activity at multiple tRNA positions. We identify RNA duplexes surrounding the m5C modification site as crucial recognition elements for methylation, which enabled us to derive a minimized substrate that captures the preferred features of an NSUN2 substrate-a dual-stem structure containing the CNNRR motif at the 5' end of the first stem. Insights into the mechanisms underlying substrate-specific NSUN2 enzymatic activity provide opportunities for understanding and therapeutically targeting NSUN2-dependent methylation. Overall, our work highlights the roles of RNA structure and sequence in defining substrate specificity and regulating RNA-modifying enzymes.
    DOI:  https://doi.org/10.1038/s41586-026-10582-9
  44. Plants (Basel). 2026 May 15. pii: 1512. [Epub ahead of print]15(10):
    The Content of Small 18S rRNA Fragments Is Regulated Developmentally and in Response to Stress in Plants.
    Angelina A Malysheva, Taissiya S Lopatchenko, Kamilla G Osikova, Tatyana Kan, Anna S Nizkorodova, Ruslan V Kryldakov, Bulat K Iskakov, Andrey V Zhigailov.
      Protein synthesis is a crucial biosynthetic process in all organisms, including plants. The integrity of the translational machinery, especially ribosomes, can be compromised during rapid cell division in ontogenesis or in response to environmental stress. In this study, Northern blotting was employed to analyze total RNA from various angiosperms, focusing on small 5'- and 3'-terminal 18S rRNA fragments. Stem-loop array RT-PCR was employed to map the cleavage sites within the target regions. Severe stress, such as extreme drought, induced the accumulation of three distinct 18S rRNA fragments across diverse angiosperm taxa, indicating that this phenomenon is likely universal. In rapidly dividing cells, such as those found in in vitro callus cultures and germinating wheat embryos, high levels of discrete 5'-terminal fragments were observed, while 3'-terminal fragments were absent. The stem-loop array RT-PCR mapping identified specific sites of 18S rRNA strand breaks. Structural annotation of the 3D model of the plant 40S subunit revealed spatial clustering of these sites in proximity to the RPS6 binding region. Notably, wheat cultivars that are tolerant to osmotic stress exhibited significantly higher levels of 18S rRNA fragmentation than sensitive cultivars. This suggests a regulatory mechanism rather than a mere byproduct of apoptotic-like regulated cell death. Additionally, fragmented ribosomes were gradually eliminated during embryo maturation, indicating a process of programmed functional ribophagy. Our findings suggest that a potential inability of plant tissues to selectively retain functional ribosomes might contribute to a decline in generative potential. Monitoring the integrity of the translational machinery could improve breeding efficiency and aid in preserving long-term stored germplasm.
    Keywords:  18S rRNA; 40S ribosomal subunit; SLA-RT-PCR; discrete fragmentation; osmotic stress
    DOI:  https://doi.org/10.3390/plants15101512
  45. Proc Natl Acad Sci U S A. 2026 Jun 02. 123(22): e2531932123
    amyloid-predict and LLPS-predict: Predicting phase separation propensities in the intrinsically disordered proteome.
    Samuel Lobo, Leif Griem, M Scott Shell, Joan-Emma Shea.
      Amyloid formation and liquid-liquid phase separation (LLPS) are two important phenomena in cellular biology, linked to both normal physiological functions and various pathologies. Here, we present a computational framework that scores amyloid propensities (amyloid-predict) or LLPS propensities (LLPS-predict) from protein language model embeddings, enabling rapid proteome-wide annotation of peptides and residues. amyloid-predict achieves classification performance that exceeds existing AI and physics-based tools on a hexapeptide benchmark while enabling substantially faster high-throughput screening; notably, amyloid-predict is sensitive to subtle mutational effects and is influenced by sequence patterning and context rather than amino acid composition alone. We apply these protein language model classifiers to all the IDRs in the human proteome and uncover several protein categories with significant enhancement in amyloid and/or LLPS propensity, suggesting insights into the biological roles of these protein categories. For example, signaling receptors, carbohydrate-binding proteins, and Ca2+ binding proteins are enriched in aggregation propensity, while mRNA-binding proteins, ribonucleoprotein complex, and nuclear matrix proteins are enriched in LLPS propensity. Interestingly, we observe patterns of both high amyloid and LLPS propensity in several amyloid-forming and prionic proteins. Together, these results provide side-by-side landscapes of LLPS and amyloid potential across the disordered human proteome while offering a rapid screening tool for basic biology, disease-mechanism studies, and rational design of peptide therapeutics.
    Keywords:  amyloids; intrinsically disordered proteins; liquid–liquid phase separation; neurodegenerative disease; protein language models
    DOI:  https://doi.org/10.1073/pnas.2531932123
  46. Toxicol Sci. 2026 May 28. pii: kfag061. [Epub ahead of print]
    Hepatic cellular stress response pathways exhibit species differences in basal and inducible activity.
    Hannah Coghlan, Sophie Regan, Bhavik Chouhan, Dominic Williams, Rowena Sison-Young, Andrew R Jones, Ian M Copple.
      Cellular stress response pathways such as the NRF2 oxidative stress response, endoplasmic reticulum (ER) stress response and macroautophagy afford protection against many forms of drug toxicity, including the liver toxicity associated with the formation of reactive drug metabolites. In many cases, clinical drug-induced liver injury is poorly predicted by preclinical toxicology studies. To maximize the translatability of preclinical toxicology studies and inform species selection, we have investigated the relative hepatic stress response capacities of humans and preclinical animal species commonly used in toxicology testing. In control liver tissue, the basal gene and protein expression of stress response pathway components was found to be greater in rodents than non-rodent preclinical species and humans. In addition, following in vitro exposure to pharmacological modulators of autophagy and the NRF2 and ER stress responses, rodent hepatocytes generally displayed a greater capacity, relative to those of non-rodent preclinical species and humans, for adaptation to cellular stress. In all, our results indicate that rodent preclinical species possess a greater basal and adaptive hepatic capacity for mitigation of chemical insult than non-rodent preclinical species and humans. This study represents the first to provide a comprehensive comparison of stress response pathway capacity of humans and the animal species most commonly used for preclinical drug safety assessment. Our findings can be used to inform the selection of species for safety testing of drugs with a liability for reactive metabolite-mediated liver toxicity, and to interpret the findings of such studies.
    Keywords:  Preclinical species; autophagy; drug-induced liver injury; oxidative stress response; unfolded protein response
    DOI:  https://doi.org/10.1093/toxsci/kfag061
  47. Cell Rep. 2026 May 28. pii: S2211-1247(26)00508-5. [Epub ahead of print]45(6): 117430
    RNA-binding protein diversity and NLS arginines regulate FUS mixing in mRNA-rich compartments.
    Diane Valenti, Vandana Joshi, Serhii Pankivskyi, Hoang Hung Cai, Loic Hamon, Bénédicte Desforges, Amandine Molliex, Julien Duez, Julian Bursztyka, Laurianne Davignon, Alexandre Maucuer, Guillaume Bollot, David Pastré.
      Despite being prone to condensation, many RNA-binding proteins (RBPs) do not form large condensates in cells. This issue is still widely researched, particularly because aggregation of RBPs, such as FUS, is the hallmark of some neurodegenerative diseases. Elevated RNA levels and protein chaperone activity have already emerged as key factors preventing aberrant phase separation. Here, we explored the role of RBP diversity in mRNA-rich condensates. While FUS and its partners form distinct compartments when probed one by one, increasing RBP diversity buffers FUS spatial segregation. In addition, we found that frequently mutated arginine residues in the nuclear localization signal (NLS) at the C-terminal end promote FUS mixing with multiple RBPs. Therefore, we anticipate that pathological NLS mutations in FUS not only alter its active nuclear import but also regulate FUS interactions with its partners in mRNA-rich compartments with putative consequences for the onset and progression of FUS-related neurodegenerative diseases.
    Keywords:  ALS; CP: molecular biology; FUS pathological mutations; LCDs; MLOs; NLS domain; RGG domains; RNA; RNA-binding proteins; amino acid sequence; biomolecular condensates; homotypic/heterotypic interactions; membrane less organelles; phase separation; stress granules
    DOI:  https://doi.org/10.1016/j.celrep.2026.117430
  48. Commun Biol. 2026 May 27.
    Mapping the GDF15 arm of the integrated stress response in human cells and tissues.
    Janell L M Smith, Kamaryn T Tanner, Jack Devine, Anna S Monzel, Taivan Batjargal, Maxwell Z Wilson, Alan A Cohen, Martin Picard.
      Mitochondrial stress activates the integrated stress response (ISR) and triggers cell-cell communication through the secretion of the metabokine growth differentiation factor 15 (GDF15). However, the gene network underlying the ISR remains poorly defined across metabolically diverse cellular states and tissues. Using RNAseq data from fibroblasts subjected to eleven metabolic perturbations, including genetic and pharmacological mitochondrial OxPhos defects, we show that the ISR has multiple arms. To quantify the GDF15 arm of ISR activation in human cells, we developed an ISRGDF15 index. We validate the ISRGDF15 index in datasets from optogenetic and small molecule activation of ISR kinases, demonstrating its rapid kinetics preceding to GDF15 gene expression. We then deploy the ISRGDF15 index across 44 postmortem human tissues, confirm its correlation with age, and report that the ISRGDF15 is upregulated in the heart of individuals with acute causes of death in the emergency room, whereas it was upregulated in the brain of individuals who died after protracted hospital inpatient stays. These data highlight distinct arms of the ISR and clarify genes related to the GDF15 ISR arm, yielding an ISRGDF15 index that can be used to investigate tissue-specific and age-related ISR activation in both in vitro cultures and human tissues.
    DOI:  https://doi.org/10.1038/s42003-026-10312-x
  49. Cell Commun Signal. 2026 May 27. pii: 324. [Epub ahead of print]24(1):
    Ras-MAPK inhibition induces AXIN1 loss in colorectal cancer by mTOR associated suppression of protein synthesis.
    Nachiyappan Venkatachalam, Li Wang, Niyumi Muthukumarana, Robert Ihnatko, Jeroen Krijgsveld, Olga Skabkina, Antonia Leipertz, Yubin Chen, Ping Sui, Qing Zheng, Panpan Tong, Xi Liu, Arnaud Descot, Matthias Schewe, Gabriele Diamante, Rene Jackstadt, Christoph Brochhausen, Johannes Betge, Kim Boonekamp, Michael Boutros, Georg Stoecklin, Matthias Ebert, Johanna Schott, Tianzuo Zhan.
       BACKGROUND: AXIN1 is a central regulatory hub of many oncogenic pathways in colorectal cancer (CRC). As the main scaffold protein and least abundant component of the beta-catenin destruction complex, changes in AXIN1 levels tightly control Wnt signaling activity. How other cancer pathways beyond Wnt signaling regulate cellular AXIN1 levels is incompletely understood.
    METHODS: Colorectal cancer cell lines, murine and patient-derived intestinal and cancer organoids were used as model systems. Changes in AXIN1 levels upon drug perturbation were profiled by immunoblot, qPCR and RNA-seq. Ubiquitin-affinity immunoprecipitation assays and mass spectrometry were used to determine mechanisms of AXIN1 loss. To characterize effects on protein synthesis, we performed polysome and ribosome profiling (Ribo-seq).
    RESULTS: We show that targeting the Ras-MAPK pathway using clinically approved MEK1/2 inhibitors induces AXIN1 loss across a panel of CRC cell lines and patient-derived organoids. In contrast to GSK3 inhibitors, MEK1/2 inhibition neither affects protein stability nor post-translational modifications of AXIN1 and only caused a minor reduction of AXIN1 transcript levels. Co-treatment with tankyrase inhibitors could partially prevent loss of AXIN1 upon MEK1/2 inhibition. Using isogenic CRC cell lines and murine intestinal organoids, we show that APC truncations strongly reduce basal cellular AXIN1 levels, but do not alter dynamics of AXIN1 loss after MEK1/2 inhibition. Polysome profiling and Ribo-seq revealed that MEK1/2 inhibitors reduce global protein synthesis via an mTOR associated pathway. This translational repression is sufficient to cause significant AXIN1 loss, as treatment with mTOR or S6K inhibitors phenocopies the effect of MEK1/2 inhibitors.
    CONCLUSION: Our study demonstrates that AXIN1 protein homeostasis is critically controlled by Ras-MAPK signaling at the level of protein synthesis, and that MEK1/2 inhibitors cause AXIN1 loss by global translational repression.
    Keywords:  AXIN1; Colorectal cancer; Destruction complex; MEK inhibitor; Ras-MAPK; Translation; Wnt; mTOR
    DOI:  https://doi.org/10.1186/s12964-026-02963-4
  50. Commun Biol. 2026 May 23.
    Reconstitution of protein arginylation pathways in bacteria for robust identification and quantification.
    Xin Lan, Richard M Searfoss, Daniel Lee, Sahil Bhaskaran, Thilini Abeywansha, Benjamin A Garcia, Zongtao Lin, Yi Zhang.
      ATE1 is a conserved enzyme that catalyzes the covalent addition of arginine to proteins bearing N-terminal or mid-chain Asp and Glu residues. N-terminal (Nt) arginylation can also occur on Cys, Asn, and Gln following enzymatic conversion, often marking proteins for degradation. Essential for development, this pathway contributes to protein quality control and stress responses. Despite growing insight into ATE1 structure and function, the mechanisms governing its substrate selectivity and coordination with upstream oxygenase and deamidase remain poorly defined. Here, we reconstitute the human processing cascades that generate Nt-arginylated proteins in E. coli, enabling step-resolved analysis of arginylation outcomes in a cellular context. By co-expressing human ADO, NTAN1, or NTAQ1 with ATE1 in a modular system, we achieved efficient conversion of Nt-Cys, Asn, and Gln into arginylation-permissive forms, recapitulating key features of upstream processing. Using this platform, we demonstrated that N-terminal processing is efficient and that ATE1 preferentially modifies protein N-termini over internal acidic residues. Mid-chain arginylation of α-synuclein was detectable but occurred at low frequency, with no major differences in site selectivity observed across the ATE1 isoforms tested. Together, this bacterial reconstitution system provides a scalable experimental platform for quantitative, protein-level analysis of ATE1 substrate specificity under defined conditions.
    DOI:  https://doi.org/10.1038/s42003-026-10275-z
  51. Mol Biol Rep. 2026 May 29. pii: 859. [Epub ahead of print]53(1):
    From splicing to disease: the crucial role of serine/arginine protein kinases in cellular regulation.
    Rilang Sa, Xuemin Zhang, Mandi Wu, Lan Yu.
      The Serine/Arginine Protein Kinase (SRPK) family plays a critical role in regulating RNA splicing and associated phosphorylation events, thereby governing essential cellular processes such as splicing regulation, proteome diversification, and signaling pathway activation. Growing evidence implicates SRPKs in the pathogenesis of various diseases, underscoring their potential as promising therapeutic targets. In this review, we systematically summarize current knowledge on the structural characteristics of SRPKs, their mechanistic involvement in disease pathogenesis, and emerging therapeutic strategies, based on comprehensive searches of databases including PubMed, Google Scholar, and X-mol. We further provide mechanistic insights into SRPK-mediated disease regulation, assess recent advances in the development of SRPK-targeted inhibitors, and discuss key challenges and future research directions in the field. This review aims to offer guidance for subsequent studies and to facilitate the translation of SRPK-related mechanisms into precision medicine applications.
    Keywords:  Phosphorylation; Signaling pathways; Splicing regulation; Targeted inhibitors; The SRPK family; Therapeutic potential
    DOI:  https://doi.org/10.1007/s11033-026-11653-w
  52. Mol Neurodegener. 2026 May 29.
    3'UTR regulation of axon translation and optic nerve regeneration.
    Minjuan Bian, Emma L Huie, Xin Xia, Michael Nahmou, Savana A Maxfield, Liang Li, Liang Liu, Ziming Luo, Christina Tsien, Katherine J Healzer, Heather V Chang, Kristina Russano, Jeffrey L Goldberg.
       BACKGROUND: In the adult mammalian central nervous system (CNS), failure of axon regeneration limits recovery after traumatic injury or in neurodegenerative disease. Local protein translation has been implicated in the regulation of axon growth in highly compartmentalized neurons. 3' untranslated regions (3'UTRs) of mRNAs play critical roles in RNA localization and modification. Here we studied the regulation of 3'UTRs in growth cone and axon regeneration.
    METHODS: Using fluorescence recovery after photobleaching (FRAP), we examined dynamic changes of mRNA 3'UTRs-related local translation in distal growth cones of primary neurons, initially comparing 3'UTRs from Gap43, normally localized to axons, and gamma-actin (Actg1), normally distributed to soma and axon. Local translation patterns in response to trophic factors and depolarization stimuli were analyzed, with or without translation inhibitor anisomycin. Adeno-associated viral vectors were used to express constitutively active Src with specific 3'UTRs after optic nerve injury in vivo. Axon growth and Src signaling were detected to identify function of 3'UTRs in axon regeneration. Statistical analysis was performed using one-way ANOVA or Kruskal-Wallis test, two-tailed unpaired t-test or Mann-Whitney test for data sets with different distributions.
    RESULTS: We discovered different 3'UTRs led to differences in local translational regulation in growth cones in vitro, including in response to relevant signals such as brain-derived neurotrophic factor (BDNF), forskolin, ciliary neurotrophic factor (CNTF), depolarization and repolarization. In vivo, we found that addition of 3'UTRs from Gap43 or Actg1 to a construct expressing constitutively active Src, which normally regulates growth cone and axon elongation, increased Src mRNA and protein localization, and Src activity measured by phospho-FAK in the optic nerve and optic tract, and the 3'UTR of Gap43 promoted more long-distance axon regeneration after optic nerve injury.
    CONCLUSIONS: Together these data enhance our understanding of the complexity of 3'UTR-mediated regulation of local axon translation, and point to potential therapeutic avenues for growth cone-related protein expression and local translation via 3'UTR manipulation.
    Keywords:  3’UTR; AAV; Axon regeneration; FAK; FRAP; Forskolin; Local translation; Src; Trophic factors
    DOI:  https://doi.org/10.1186/s13024-026-00952-2
  53. Biomolecules. 2026 May 12. pii: 712. [Epub ahead of print]16(5):
    Epitranscriptomic Stability-Variable Extents of N1-Methyladenosine to N6-Methyladenosine Conversion Under Different Experimental Conditions.
    Frank Morales Shnaider, Hasna Kanan, Shrikant Patel, Norman H L Chiu.
      The growing interest in epitranscriptomes has emphasized the need for accurate quantification of RNA modifications. However, the stability of RNA modifications under different experimental conditions remains poorly characterized. In this study, we use N1-methyladenosine (m1A) as a model for assessing stability. After exposing m1A ribonucleoside to various conditions that are commonly used in RNA protocols, the sample was analyzed using untargeted high-resolution mass spectrometry. Under alkaline or neutral pH, different extents of m1A were converted to N6-methyladenosine (m6A). Complete m1A-to-m6A conversion occurred at elevated temperatures. The m1A-to-m6A conversion was also dependent on the initial m1A concentration; the higher the concentration, the higher the rate of conversion. This poses a challenge to comparative studies if the initial amount of m1A in the control and sample of interest are not equal. No demethylation or depurination was detected. However, trace amount of N1-methylinosine was detected as a result of non-enzymatic deamination of m1A. Furthermore, the m1A-to-m6A conversion was consistently observed in a biological sample. To eliminate the bias that resulted from m1A-to-m6A conversion, the standard addition method was adopted. This report highlighted the challenges of having different extents of m1A-to-m6A conversion under specific experimental conditions and demonstrated a viable solution for resolving the issue.
    Keywords:  RNA modifications; epitranscriptome; quantification; stability
    DOI:  https://doi.org/10.3390/biom16050712
  54. Int Immunopharmacol. 2026 Aug 15. pii: S1567-5769(26)00734-4. [Epub ahead of print]183 116888
    RBM47 aggravates carotid atherosclerotic plaque instability through NEDD4L-dependent regulation of TRAF2.
    Jia Xiang, Zhenghong Qin, Yunrun Liu, Songwen Tan, Guoxiang Tong.
       BACKGROUND: Atherosclerotic plaque instability is linked to dysregulated cellular stress responses and protein homeostasis within the vascular wall. RNA-binding motif protein 47 (RBM47) modulates mRNA stability and protein expression, but its contribution to the regulation of plaque stability and associated cellular injury has not been fully elucidated.
    METHODS: Utilizing murine and cellular models of atherosclerosis, we systematically evaluated the role of RBM47 in plaque stability-associated cellular responses. Bioinformatics analyses predicted NEDD4L and TNF receptor-associated factor 2 (TRAF2) as potential downstream targets of RBM47, implicating their possible involvement in protein homeostasis and plaque instability.
    RESULTS: In atherosclerotic mice, reduced plaque stability was associated with enhanced cellular stress and increased RBM47 expression. Consistently, in H₂O₂-treated HA-SMCs, aggravated cellular injury coincided with marked upregulation of RBM47 and NEDD4L. The interaction between NEDD4L and TNF receptor-associated factor 2 (TRAF2) was further confirmed. Functional analyses showed that silencing RBM47 reduced NEDD4L expression, thereby attenuating NEDD4L-mediated TRAF2 ubiquitination and degradation. These molecular changes were associated with reduced cellular injury, improved plaque stability, and attenuation of atherosclerotic progression.
    CONCLUSION: RBM47 enhances NEDD4L expression by stabilizing its mRNA, leading to altered TRAF2 protein homeostasis and plaque instability. These findings highlight RBM47 and its downstream signaling as potential targets for atherosclerosis intervention.
    Keywords:  Atherosclerosis; Plaque stability; RBM47; mRNA stability
    DOI:  https://doi.org/10.1016/j.intimp.2026.116888
  55. Int J Mol Sci. 2026 May 17. pii: 4492. [Epub ahead of print]27(10):
    The Role of Sigmar1 in Autophagy Regulation and Disease Therapy.
    Huanqing Ge, Yusi Lin, Junda Li, Renwen Zhang, Cangcang Xu.
      Sigmar1 is a multifunctional molecular chaperone protein located on the Mitochondria-associated endoplasmic reticulum membranes (MAM). Recent studies have shown that Sigmar1 is not only a regulatory protein involved in cellular stress responses but also plays a significant role in the process of autophagy. It regulates the initiation and progression of autophagy by influencing multiple autophagy-related signaling pathways and interacting with key proteins such as LC3 and GABARAP. This regulation exhibits a dual nature. On one hand, it can induce protective autophagy, helping cells cope with stress such as oxidative stress and endoplasmic reticulum stress, thereby playing a protective role in the progression of diseases such as neurodegenerative disorders and cardiovascular diseases. On the other hand, in certain cancers, Sigmar1 may also promote tumor cell survival through autophagy regulation, thereby exacerbating disease progression. Consequently, developing agonists and antagonists targeting Sigmar1 has become a highly promising therapeutic strategy. This review provides a systematic overview of recent advances in the biological characterization of Sigmar1 and its molecular mechanisms in regulating autophagy. It summarizes the multifaceted roles of Sigmar1 in various diseases and discusses current research progress and the application prospects of Sigmar1 agonists and antagonists, aiming to establish a theoretical foundation for the development of novel Sigmar1-based therapeutic strategies for human diseases.
    Keywords:  Sigmar1; agonists and antagonists; autophagy; disease therapy; regulatory mechanism
    DOI:  https://doi.org/10.3390/ijms27104492
  56. Acta Biochim Biophys Sin (Shanghai). 2026 Apr 28. Vol.(1): 1-15
    Tauroursodeoxycholate improves zoledronate-induced vascular endothelial dysfunction by suppressing the GCN2/eIF2α and IRE1/JNK pathways: a potential treatment option for MRONJ.
    Zijian Pan, Qizhang Wang, Zhiwei Cao, Chengzhi Zhao, Xueer Zhou, Jian Pan.
      Medication-related osteonecrosis of the jaw (MRONJ), a severe complication of antiresorptive agents, such as zoledronate (ZOL), significantly affects patients' quality of life. Impaired angiogenesis and vascular endothelial cell (EC) function are core features of MRONJ, although the underlying mechanisms remain largely unknown. In this study, we show that ZOL induces human umbilical vein endothelial cell (HUVEC) dysfunction, which is characterized by suppressed cell viability, migration, tube formation, and angiogenesis-osteogenesis uncoupling. ZOL triggers reactive oxygen species (ROS) accumulation and apoptosis in vascular ECs. Most importantly, we first demonstrate that ZOL activates the general control nonderepressible 2 (GCN2)/eukaryotic translation initiation factor 2A (eIF2α) pathways, leading to suppressed protein synthesis and increased expressions of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) in vascular ECs. Moreover, the inositol-requiring enzyme 1 (IRE1)/c-Jun N-terminal kinase (JNK) pathway, a branch of the unfolded protein response (UPR), is activated after ZOL treatment. Tauroursodeoxycholate (TUDCA), a chemical chaperone, partially alleviates the deleterious effects of ZOL on vascular ECs in vitro. Local application of the TUDCA-loaded silk fibroin methacryloyl (SilMA) hydrogel significantly improves mucosal healing and bone regeneration in a rat MRONJ model. These results reveal novel mechanisms underlying MRONJ and suggest that TUDCA is a promising therapeutic candidate for ameliorating MRONJ.
    Keywords:  bisphosphonate; integrated stress response; medication-related osteonecrosis of jaw; tauroursodeoxycholate; type H vessel; unfolded protein response; vascular endothelial cell
    DOI:  https://doi.org/10.3724/abbs.2025254
  57. PLoS Biol. 2026 May 29. 24(5): e3003830
    Type II tRNA cleavage by SLFN14 endoribonuclease variants linked to inherited thrombocytopenia drives global translational repression.
    Chengchao Ding, Xinyi Ashley Liu, Fushun Zhang, Saori Uematsu, Shu-Bing Qian, Yan Xiang.
      Schlafens proteins (SLFNs) are interferon-inducible regulators of RNA metabolism that influence antiviral defense and cell fate. Human SLFN14 is a ribosome-associated endoribonuclease whose pathogenic variants cause autosomal dominant inherited thrombocytopenia (IT), but the molecular basis of this disorder remains unclear. Here, using HEK293T cells expressing human SLFN14 variants, we show that SLFN14 represses global protein synthesis through selective cleavage of type II tRNAs. IT-linked mutations alter SLFN14 RNA substrate specificity, enhancing depletion of type II tRNAs while reducing rRNA cleavage. This shift promotes ribosome stalling at codons decoded by type II tRNAs, triggering global translational arrest, stress signaling, and cell death. These findings reveal how altered RNA targeting by SLFN14 can drive disease and highlight selective tRNA targeting as a mechanism than regulates translation and cell fate.
    DOI:  https://doi.org/10.1371/journal.pbio.3003830
  58. Trends Parasitol. 2026 May 25. pii: S1471-4922(26)00124-8. [Epub ahead of print]
    Post-transcriptional RNA-mediated regulation in infection: mechanisms, functions, and analytical approaches.
    Mame Massar Dieng, Jean-Claude Twizere, Youssef Idaghdour.
      Infectious pathogens extensively rewire host RNA processing, yet most studies examine individual processing mechanisms in isolation. In this review, we synthesize evidence that alternative splicing, N6-methyladenosine (m6A) methylation, and adenosine-to-inosine (A-to-I) RNA editing collectively shape infection outcomes across viral, bacterial, and parasitic pathogens by modulating host defense and pathogen replication. We highlight how pathogens hijack or are constrained by these mechanisms, with particular emphasis on underexplored bacterial and parasitic systems. We then propose a metatranscriptomics framework that integrates long-read and direct RNA sequencing with specialized computational tools to jointly profile splicing, m6A, and A-to-I editing in host and pathogen. Such integrative analyses will reveal convergent regulatory nodes and guide the development of host-directed therapies.
    Keywords:  RNA editing; RNA post-transcriptional processes; host–pathogen interactions; m(6)A methylation; metatranscriptomics; splicing
    DOI:  https://doi.org/10.1016/j.pt.2026.05.001
  59. Biomedicines. 2026 May 08. pii: 1069. [Epub ahead of print]14(5):
    RNA-Loaded Nanoparticles for Targeted Lung Delivery.
    Mark John Siringan, Xiaoyang Chen, Jiawei Huo.
      The lung represents a promising yet underexploited target for RNA therapeutics due to its large surface area and accessibility via non-invasive inhalation delivery. Despite rapid advances in RNA-based modalities, including small interfering RNA (siRNA), microRNA (miRNA), messenger RNA (mRNA), and CRISPR-Cas systems, efficient pulmonary delivery remains a major challenge. Multiple biological barriers, such as mucus and surfactant layers, mucociliary clearance, immune surveillance, and limited cellular uptake of negatively charged nucleic acids, significantly restrict therapeutic efficacy. In addition, aerosolization processes may introduce mechanical stress, compromising RNA integrity. Nanoparticle-based delivery systems have emerged as a central strategy to address these limitations. By protecting RNA cargo, enhancing mucus penetration, and promoting cellular internalization, engineered nanoparticles enable more effective pulmonary delivery. In this review, we adopt a barrier-centered perspective to examine the key biological obstacles to lung-targeted RNA delivery and highlight recent advances in nanoparticle-mediated strategies, with a focus on lipid nanoparticles, polymeric systems, and inorganic nanomaterials. We further discuss design principles that govern RNA stability, transport, and intracellular release and critically compare the strengths, limitations, and translational potential of each platform, including considerations of toxicity, biodegradability, and clinical readiness. Finally, we outline emerging clinical applications of RNA-loaded nanoparticles, using lung cancer as a representative disease model, and discuss remaining challenges and future directions. Continued innovation in nanoparticle engineering and delivery strategies is expected to accelerate the clinical translation of RNA therapeutics for pulmonary diseases.
    Keywords:  RNA therapeutics; lung cancer; lung targeting; nanoparticle delivery
    DOI:  https://doi.org/10.3390/biomedicines14051069
  60. Mar Life Sci Technol. 2026 May;8(2): 404-418
    Novel vanadium-dependent haloperoxidases from macroalgae and their expression in response to biotic and abiotic stressors in Saccharina latissima.
    Timo Jensen, Mira Wilkens, Holger Rehmann, Maria Mucke, Dominik Bents, Petra Janning, Andreas Brockmeyer, Stefan Veltel, Matthias Peipp, Antje Labes, Wolfgang Bilger, Levent Piker.
      Vanadium-dependent haloperoxidases (vHPOs) are essential enzymes in macroalgae, known for their ability to catalyze halogenation reactions using halides and hydrogen peroxide. These enzymes facilitate the biosynthesis of halogenated compounds that contribute to the defense mechanisms of algae and are considered to play a crucial role in the oxidative stress response. Using a transcriptomic approach, we discovered and analyzed about 70 novel vHPO sequences from nine different macroalgae species collected in the Baltic Sea. All sequences were carefully selected for their universal catalytic center characterized by structurally conserved residues essential for catalysis and vanadate-binding. Mass spectrometry provided evidence for eight of those proteins in extract fractions of the brown alga Saccharina latissima. Using RT-qPCR, we also investigated the role of vHPO gene expression in stress response on a subset of S. latissima vHPO transcripts by exposing it to different stressors including copper excess, oxidative stress, and biotic stress mimicked by elicitor treatment using a S. latissima tissue homogenate. The optimal quantum yield of photosystem ll served as a physiological plant stress parameter (F V/F M). Our data support the hypothesis that these enzymes are involved in mitigating oxidative stress, as suggested by up-regulation in gene expression following H2O2 and elicitor treatments, and are likely involved in environmental stress response. This work advances our understanding of vHPO function in marine algae and highlights their potential role in responding to environmental stress.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-026-00367-4.
    Keywords:  Algae; Gene expression; Saccharina latissima; Stress; Transcriptomics; Vanadium-dependent haloperoxidases
    DOI:  https://doi.org/10.1007/s42995-026-00367-4
  61. bioRxiv. 2026 May 11. pii: 2026.05.08.723844. [Epub ahead of print]
    Divergent CRD-Dependent Mechanisms Govern RAS Isoform-Selective Recruitment of CRAF and ARAF.
    Shrhea Banerjee, Sravani Malasani, Shriti Banerjee, Maria Celeste López Vásquez, Shane McSorley, Zhihong Wang.
      RAF kinases interpret signals from the three major RAS isoforms to initiate MAPK pathway activation, yet the molecular logic that governs isoform-specific RAS recruitment and the early events that relieve RAF autoinhibition are not yet fully understood. In particular, how the modular N-terminal regulatory architecture of CRAF and ARAF, anchored by the multifunctional cysteine-rich domain (CRD), discriminates among HRAS, KRAS, and NRAS has remained a central unresolved question. Here, we combine quantitative biophysical measurements with structural and dynamic analyses to define how RAS isoform identity and CRD engagement shape the earliest steps of RAF activation. These studies reveal unexpectedly divergent modes of RAS recognition between CRAF and ARAF and expose previously unappreciated functions of the CRD in modulating RAS affinity and intramolecular regulatory contacts. We further identify a direct link between RAS binding and destabilization of RAF autoinhibition, providing mechanistic insight into how RAS initiates the transition from an inactive monomer to an activation-competent assembly. Finally, we show that emerging KRAS inhibitors variably perturb KRAS-CRAF interactions, offering insight into how these therapeutics influence early RAS-RAF signaling events. Together, this work uncovers distinct biophysical principles that govern RAS-RAF selectivity and reveals a regulatory role for the CRD that reframes our understanding of RAF activation and its dysregulation in RAS-driven cancers.
    Significance: Proteins in the RAS-RAF signaling pathway control cell growth and are frequently mutated in cancer. Despite their importance, how different RAS proteins selectively recruit RAF kinases has remained incompletely understood. This study reveals that the cysteine-rich regulatory region of RAF plays a central role in distinguishing RAS isoforms and controlling RAF activation. These insights clarify early steps in MAPK signaling and may guide the development of improved therapies targeting RAS-driven cancers.
    DOI:  https://doi.org/10.64898/2026.05.08.723844
  62. Redox Biol. 2026 May 15. pii: S2213-2317(26)00217-X. [Epub ahead of print]94 104219
    Reactive oxygen species in thoracic aortic dissection: Insights into mechanisms and disease progression.
    Mingzhou Jiang, Fandi Mo, Genmao Cao, Shiyi Li, Weiguo Fu, Lixin Wang.
      Thoracic aortic dissection (TAD) is a life-threatening vascular disorder defined by disruption of the aortic intima and progressive degeneration of the medial layer, accompanied with false lumen formation. Accumulating evidence supports a pivotal contribution of reactive oxygen species (ROS) to the initiation and progression of TAD, primarily by driving oxidative stress-associated cellular events. This review summarizes the ROS production mechanism in TAD pathogenesis and discusses how ROS contribute to disease progression through oxidative stress, inflammatory signaling, and structural degradation of the aortic wall. We further examine the multilayered regulatory networks governing ROS activity, including transcriptional and epigenetic regulation, metabolic reprogramming, that collectively shape vascular dysfunction in TAD. In addition, we discuss potential ROS-targeted therapeutic treatments, including inhibition of ROS-generating enzymes, enhancement of antioxidant systems, modulation of downstream signaling pathways, and correction of metabolic reprogramming. We also critically discuss the translational limitations of current redox-targeted approaches, emphasizing the lack of disease specificity, limited clinical validation, and the challenge of selectively suppressing pathological ROS. This review aims to synthesize current evidence linking ROS dysregulation to the onset and progression of TAD, while highlighting emerging therapeutic strategies and their potential clinical implications.
    Keywords:  Endothelial dysfunction; Oxidative stress; Reactive oxygen species (ROS); Thoracic aortic dissection; Vascular dysfunction
    DOI:  https://doi.org/10.1016/j.redox.2026.104219
  63. Biology (Basel). 2026 May 19. pii: 805. [Epub ahead of print]15(10):
    Cellular Stress and Immune Activation in Celiac Disease: Is the Chaperone System a Key Player?
    Giuseppe Vergilio, Giusy Vultaggio, Rosalia Gagliardo, Letizia Paladino, Francesca Rappa.
      Celiac disease (CD) is a chronic immune-mediated enteropathy triggered by the ingestion of gluten in genetically predisposed individuals. While the adaptive immune response to deamidated gliadin peptides represents a central pathogenic mechanism, growing evidence suggests that epithelial stress and innate immune activation play a fundamental role in the onset and persistence of the disease. Heat shock proteins (Hsps), central regulators of cellular proteostasis, have emerged as potential mediators at the interface between epithelial distress and immune signaling. This review discusses the involvement of major Hsp families, including Hsp27, Hsp60, Hsp70, and Hsp90, in the pathophysiology of CD. The altered expression of Hsp27 and Hsp70 in the intestinal mucosa reflects a persistent state of epithelial stress that often persists despite a strict gluten-free diet (GFD). We focus specifically on Hsp60, whose extracellular release under stress conditions may allow it to function as a damage-associated molecular pattern (DAMP), engaging Toll-like receptors and promoting NF-κB- and inflammasome-dependent inflammatory pathways. Although direct mechanistic evidence linking Hsp60 to CD remains limited, the convergence of epithelial stress signs, Toll-like receptor (TLR) upregulation, and prolonged innate immune activation supports the hypothesis of a stress-induced inflammatory amplification circuit in the coeliac mucosa. Further studies are essential to clarify the pathogenic relevance and potential therapeutic implications of this proposed axis.
    Keywords:  Toll-like receptors (TLRs); celiac disease; epithelial stress; heat shock protein 60 (Hsp60); innate immune activation
    DOI:  https://doi.org/10.3390/biology15100805
  64. Bull Math Biol. 2026 May 29. pii: 99. [Epub ahead of print]88(6):
    An Analytical Framework for Phenotypic Selection of Fitness-Conferring Genes.
    Marc Sturrock, Anna Sturrock.
      Phenotypic selection can cause the transient, selective upregulation of fitness-conferring genes in isogenic cell populations under stress, producing selective enrichment of the fitness gene relative to a neutral reference gene. While computational models have shown that such enrichment requires noisy gene expression and a cellular memory linking growth rate to gene expression (Ciechonska et al. 2022), the precise mechanistic requirements and the analytical principles governing enrichment have remained unclear. Here, we present an exact analytical framework that unifies enrichment mechanisms across both growth-driven and death-driven selection regimes. By analysing a stochastic model of explicit mRNA and protein dynamics, we prove that when selection acts via cell division, the fitness advantage of faster growth is exactly cancelled by the penalty of faster protein dilution. We show that this cancellation is bypassed by translational feedback but not by transcriptional feedback alone; for genes with regulated (switching) promoters, the promoter-state memory provides an independent route to enrichment without translational feedback. Conversely, when selection acts via cell death, this exact cancellation is bypassed, allowing selective enrichment to emerge from baseline gene expression noise without any assumptions about growth-related feedback loops or regulated vs constitutive expression. We derive an exact fluctuation-response relation demonstrating that, in all cases, enrichment scales with the super-Poissonian component of unperturbed protein noise times the relevant memory timescale. All analytical predictions are corroborated by stochastic simulations of a finite-population Moran model. These results have implications for the emergence of drug resistance: by transiently enriching survival-conferring phenotypes, phenotypic selection can extend the window during which cell division occurs under stress, increasing the opportunity for permanent genetic mutations to arise.
    Keywords:  Drug resistance; Fluctuation–response relation; Phenotypic selection; Selective enrichment; Stochastic gene expression; Translational feedback
    DOI:  https://doi.org/10.1007/s11538-026-01670-y
  65. bioRxiv. 2026 May 17. pii: 2026.05.14.725089. [Epub ahead of print]
    Myelin basic protein is an RNA chaperone in microglial nuclear retro-transport.
    Guy Lam, Zhao Yang Xu, Adrien M Vaquié, Stavros Vagionitis, Michael Perry, Omar de Faria, Georgios Solomou, John H Stockley, Gemma C Girdler, Daniel Yamamoto, Juan A Oses, Qianqian Zhang, Gregory Jordan, Laura R Morcom, Jacob Stillman, Hani Mousa, Alma Burlingame, Murray Stewart, Hauke B Werner, András Lakatos, Harry Bulstrode, Dorothy P Schafer, Joanne Jones, Ragnhildur T Karadottir, David H Rowitch.
      CNS oligodendrocytes generate myelin, an RNA-containing proteolipid substance that enhances axonal transmission. In multiple sclerosis (MS), myelin debris is phagocytosed by microglia (MG), and prior studies have detected myelin-derived mRNA in MG nuclei, suggesting a retrograde transport pathway. We report myelin basic protein (MBP) is a nucleic acid-binding and trafficking protein. We found that retro-transport of myelin RNA into the MG nucleus was phagocytosis and importin-dependent. Transcriptomic and proteomic analyses of MG nuclei revealed enrichment of myelin mRNAs and proteins, with MBP singularly detected in soluble and chromatin-associated fractions. MBP bound mRNA with high affinity (Kd ≈ 0.30 nM) and was sufficient to facilitate MG RNA nuclear import in vitro and in vivo . Functionally, MBP mediated the delivery of small interfering RNAs for targeted knockdown of toll-like receptor 4 . These findings indicate MBP as an RNA-binding protein capable of MG nuclear import, providing insight into neuroinflammatory pathology of MS.
    DOI:  https://doi.org/10.64898/2026.05.14.725089
  66. J Pharmacol Exp Ther. 2026 May 02. pii: S0022-3565(26)01130-4. [Epub ahead of print]393(6): 104931
    Pseudouridine synthase 7 as a context-specific therapeutic target in cancer.
    Karen Abundiz-Yañez, Luis Córdova-Bahena, Nohemí Salinas-Jazmín, Angel J Trejo-León, Marco A Velasco-Velázquez.
      Human pseudouridine synthase 7 (PUS7) catalyzes the isomerization of uridine to pseudouridine in RNA substrates. Although its catalytic region has been characterized, further studies are needed to clarify the mechanisms underlying its substrate recognition and specificity. PUS7 promotes tumor progression in glioblastoma, pancreatic adenocarcinoma, neuroblastoma, hepatocellular carcinoma, and colorectal cancer by altering RNA stability, translational fidelity, and splicing, ultimately regulating key oncogenic processes such as cell proliferation, self-renewal, metabolic reprogramming, and stress responses. Additionally, PUS7 can promote tumor progression through noncatalytic mechanisms, as observed in colorectal cancer, where it forms protein-protein complexes that activate oncogenic signaling pathways. Conversely, PUS7 exhibits tumor-suppressive functions in gastric carcinoma and papillary thyroid carcinoma by targeting mRNAs and miRNAs that regulate gene expression linked to reduced tumor aggressiveness. These findings indicate that PUS7 may represent a context-dependent therapeutic target and underscore the need for further research to clarify the molecular basis of its effects in cancer. Such knowledge may guide the development of new therapeutic strategies for PUS7-driven tumors. SIGNIFICANCE STATEMENT: Recent studies reveal that dysregulated pseudouridine synthase activity contributes to the progression of malignancies such as glioblastoma, pancreatic adenocarcinoma, neuroblastoma, colorectal cancer, and hepatocellular carcinoma. Here, we review the pseudouridine synthase's structure-function relationships and context-specific activities. The evidence discussed will help the development of selective therapeutic strategies targeting RNA modification pathways.
    Keywords:  Cancer therapeutic target; Pseudouridine; Pseudouridine synthase 7; Pseudouridine synthase 7 inhibitor; RNA pseudouridylation
    DOI:  https://doi.org/10.1016/j.jpet.2026.104931
  67. Front Med (Lausanne). 2026 ;13 1751279
    RNA binding protein YWHAZ mediates specific mRNA translation and regulates cell proliferation and apoptosis in diabetic foot ulcer.
    Tianjian Zha, Junjie Yao, Hao Wang, Qiang Cao, Jian Zhang, Zhao Chen, Jie Wang.
       Background: Diabetic foot ulcer (DFU), a condition marked by high rates of recurrence, amputation, and mortality, represents one of the major challenges in diabetes management. RNA-binding proteins (RBPs) are pivotal for post-transcriptional regulation in diabetic complications. However, the aberrantly expressed RBP genes and their regulatory mechanisms in DFU remain unclear. This study aimed to investigate the potential functions and molecular interactions of YWHAZ, a dysregulated RBP identified in DFU tissues.
    Methods: YWHAZ was selected for further investigation based on its dysregulation in DFU tissues as identified through an independent public RNA-seq dataset. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry were used to validate YWHAZ expression. The biological behavior of HaCaT cells with YWHAZ knockdown (Si_YWHAZ) was compared with that of control cells. Differentially expressed genes (DEGs) were identified by RNA-seq. Additionally, improved RNA immunoprecipitation (iRIP)-seq was employed to investigate potential binding interactions of YWHAZ in DFU tissues.
    Results: YWHAZ was significantly upregulated and validated as an RBP in DFU by RT-qPCR and immunohistochemistry. Cellular experiments revealed that Si_YWHAZ facilitated proliferation and migration while inhibiting apoptosis, consistent with its upregulation in DFU. RNA-seq identified 1,072 DEGs in Si_YWHAZ cells. Upregulated genes were significantly enriched for cell proliferation-related processes and included AREG, FOSL1, HAS2, and IL7R, whereas downregulated genes were associated with cell adhesion, including LAMB3, SLAMF7, COL12A1, and ITGA5. iRIP-seq results demonstrated that YWHAZ interacts with a large number of mRNAs and is located in the CD and intron region of the genome. Furthermore, the ABLIFE algorithm indicated that YWHAZ binds to GC-rich motifs. Integrated iRIP-seq and RNA-seq analyses identified 57 DEGs that were selectively bound by YWHAZ, most of which were downregulated. Notably, SREBF1, which is positively associated with type 2 diabetes risk. KEGG pathway analysis revealed that SREBF1 is enriched in both the insulin resistance and insulin signaling pathways.
    Conclusion: The study results suggest the cellular functions and molecular targets of YWHAZ, indicating its potential regulatory role in DFU development. This study provides valuable insights into the regulatory mechanisms of YWHAZ in DFU for future investigations.
    Keywords:  SREBF1; YWHAZ; diabetic foot ulcer; iRIP-seq; proliferation
    DOI:  https://doi.org/10.3389/fmed.2026.1751279
  68. Biomed Pharmacother. 2026 May 28. pii: S0753-3322(26)00595-0. [Epub ahead of print]200 119559
    Mitochondrial metabolic reprogramming in diabetic cardiomyopathy.
    Yuting Zhou, Hao Tian, Zhongyuan Xia, Yonghong Xiong.
      Diabetes mellitus represents a major global health challenge and is strongly associated with cardiovascular complications, among which diabetic cardiomyopathy (DCM) is a major contributor to heart failure. Increasing evidence indicates that mitochondrial dysfunction plays a central role in DCM pathogenesis. However, mitochondrial abnormalities in the diabetic heart reflect not merely cellular injury but a coordinated process of mitochondrial metabolic reprogramming, characterized by altered substrate utilization, impaired oxidative phosphorylation, and disruption of mitochondrial quality control. Under diabetic conditions, chronic hyperglycemia, insulin resistance, and lipid overload induce profound metabolic remodeling in cardiomyocytes. These disturbances promote excessive reactive oxygen species production, mitochondrial DNA damage, and dysfunction of the electron transport chain. Concurrently, cardiomyocytes undergo a shift in substrate preference, including enhanced glycolysis, dysregulated fatty acid oxidation, and altered amino acid metabolism. Such metabolic inflexibility compromises ATP production and contributes to lipotoxicity, oxidative stress, and cardiomyocyte apoptosis. Recent studies have revealed that mitochondrial metabolic reprogramming is governed by complex regulatory networks, including signaling pathways such as AMPK/PGC-1α, PI3K/Akt/mTOR, hypoxia-inducible factor-1α, and TGF-β/Smad, together with epigenetic mechanisms and mitochondrial quality control processes. Disruption of mitochondrial dynamics, mitophagy, and mitochondrial biogenesis further promotes the accumulation of dysfunctional mitochondria and accelerates disease progression. In this review, we summarize current advances in the mechanisms underlying mitochondrial metabolic reprogramming in diabetic cardiomyopathy and discuss emerging therapeutic strategies targeting mitochondrial metabolism. By integrating mitochondrial biology with cardiovascular metabolism, this review provides a comprehensive framework for understanding DCM pathogenesis and highlights potential directions for precision therapeutic intervention.
    Keywords:  Diabetic cardiomyopathy; Mitochondrial metabolic reprogramming; Mitochondrial quality control; Oxidative phosphorylation; Substrate utilization
    DOI:  https://doi.org/10.1016/j.biopha.2026.119559
  69. PLoS Pathog. 2026 May;22(5): e1014249
    Remodeling of tRNA modification in Trypanosoma cruzi life forms.
    Herbert Guimaraes de Sousa Silva, Janaina de Freitas Nascimento, Marilene Souza Braga, Ana Paula de Jesus Menezes, Ariel M Silber, Matthew K Waldor, Julia Pinheiro Chagas da Cunha, Satoshi Kimura.
      Trypanosoma cruzi, the etiological agent of Chagas disease, infects millions of people in the Americas. This parasite undergoes drastic changes in its morphology and metabolism between infective and noninfective forms through global remodeling of its proteome. Chemical modification of tRNA (tRNA modification) contributes to the control of protein expression by modulating the codon decoding process. However, knowledge of tRNA modification profiles, the enzymes that create modifications and their regulation in different cellular conditions is largely restricted to relatively few model organisms. Here, we profile tRNA modifications in both infective and noninfective forms of T. cruzi to probe their dynamic changes. Genome mining of tRNA modifying enzymes identified 65 putative tRNA-modifying enzymes in T. cruzi for 27 species of tRNA modifications, most of which were detected in T. cruzi tRNA by liquid chromatography mass spectrometry analyses. tRNA sequencing detected reverse transcription-derived signatures at 170 sites in T. cruzi tRNAs that are likely derived from 19 tRNA modifications. tRNA modifications and tRNA modification enzymes are differentially modulated across the life stages of T. cruzi. We found that hydroxywybutosine (OHyW) at position 37 on tRNAPhe(GAA) had a reduced level in the infective form (metacyclic trypomastigote) and the associated modification enzyme Tyw1a exhibited reduced expression in this stage. Knockout of Tyw1a increased the differentiation from epimastigote (noninfective form) to metacyclic trypomastigote, suggesting that changes in OHyW37 modification levels alter the rate of metacyclogenesis. Overall, our findings suggest that tRNA modification changes during the life stages of T. cruzi contribute to the differentiation of this parasite.
    DOI:  https://doi.org/10.1371/journal.ppat.1014249
  70. Plants (Basel). 2026 May 14. pii: 1497. [Epub ahead of print]15(10):
    Genome-Wide Analysis of YTH Domain Proteins in Metasequoia glyptostroboides and Functional Validation of MgYTH5 as an m6A Reader.
    Bao Li, Xin Hu, Wenhui Guo, Huijuan Yin, Yuke Ma, Kongshu Ji, Qiong Yu.
      N6-methyladenosine (m6A) is an important epigenetic modification of eukaryotic RNA, playing a significant role in various biological processes. Metasequoia glyptostroboides (M. glyptostroboides) is an ancient tree species in China, with a long history and excellent genetic characteristics. In this study, we identified six MgYTH genes in the genome of M. glyptostroboides, elucidating their phylogenetic relationships, conserved domains, gene structures, conserved motifs, chromosome locations, and prediction of LLPS. The analysis of the cis-regulatory elements in the promoter region suggested that MgYTH genes are associated with drought and the ABA-responsive expression patterns signaling pathway, which was further supported by expression pattern analysis. In addition, to directly evaluate the m6A binding ability of MgYTH proteins, we selected MgYTH5 as the representative for homology modeling analysis and electrophoretic mobility shift assay (EMSA). The results demonstrated that MgYTH5 has the ability to bind m6A in vitro, thereby providing biochemical evidence that MgYTH5 can bind m6A-modified RNA in vitro mRNAs. The subcellular localization results showed that MgYTH5 is located in the cytoplasm. These findings provide new insights into the epigenetic regulation mechanisms in gymnosperms and provide a resource for future functional studies in this species.
    Keywords:  Metasequoia glyptostroboides; YTH domain; stress and gene expression analysis
    DOI:  https://doi.org/10.3390/plants15101497
  71. PLoS One. 2026 ;21(5): e0349761
    mRNA splicing in turkey muscle satellite cells is dynamically altered upon thermal challenge.
    Ashley A Powell, Gale M Strasburg, Sandra G Velleman, Kent M Reed.
      Regulation of gene expression at the transcriptional and post-transcriptional levels is essential for proper development and growth, with tightly coordinated cellular processes supporting key biological functions. While transcription determines the available mRNA pool, post-transcriptional modifications such as alternative splicing (AS) increase transcriptome complexity and enable the production of diverse protein isoforms. In muscle, AS is critical in generating muscle-specific proteins required for normal development and function and may be particularly susceptible to disruption by thermal stress. This study examines how thermal challenges-both cold and heat-affect muscle biology by analyzing AS events during the proliferation and differentiation of skeletal muscle satellite cells (SCs). Isoform identification and AS analyses were performed on RNA-seq data from a prior study of skeletal muscle SCs derived from commercial turkeys and exposed to three temperature conditions (33°C, 38°C, or 43°C) during proliferation or differentiation. Analyses revealed 61,266 predicted splicing events across 5,202 annotated genes. Significant differential splicing was observed in all temperature comparisons, and between proliferating and differentiating cells at each temperature. Additionally, there was a strong association between differentially spliced genes (DASs) and differentially expressed genes (DEGs). This study provides a comprehensive catalog of splice isoforms for future functional analyses, many of which are likely to result in protein variants that influence SC proliferation, differentiation, and ultimately, muscle development and performance.
    DOI:  https://doi.org/10.1371/journal.pone.0349761
  72. Best Pract Res Clin Endocrinol Metab. 2026 May 07. pii: S1521-690X(26)00033-3. [Epub ahead of print] 102111
    Dietary effects of early nutrition on muscle mass and accretion in mammals.
    Morteza Hosseini Ghaffari, Anuj Malik, Nisha Nisha, Helga Sauerwein, Harald Michael Hammon.
      Skeletal muscle serves as the primary protein reservoir in neonates and is a major determinant of early postnatal growth. This period features exceptionally high muscle protein synthesis, driven by increased sensitivity to feeding-induced insulin and amino acid signals that converge on the mechanistic target of rapamycin complex 1 (mTORC1). These signals regulate postnatal metabolic activation and anabolic responsiveness, rather than driving developmental transitions. This review summarizes the endocrine, nutrient-sensing, and energy-sensing pathways that regulate early-life skeletal muscle accretion, highlighting translational efficiency, ribosomal capacity, and myonuclear accretion as key determinants of growth. Evidence from translational neonatal models, particularly the pig, demonstrates coordinated control of muscle anabolism by insulin/IGF signaling, amino acid sensing, and cellular energy status, and shows how prematurity and intrauterine growth restriction disrupt these processes, resulting in anabolic resistance. Colostrum and milk support muscle growth primarily by enhancing intestinal maturation, nutrient delivery, and postprandial endocrine responses, whereas direct programming via milk-derived extracellular vesicles remains uncertain.
    Keywords:  early-life nutrition; mTORC1 signaling; muscle protein synthesis; neonatal skeletal muscle
    DOI:  https://doi.org/10.1016/j.beem.2026.102111
  73. Proteomics. 2026 May 25. e70147
    High-throughput Phosphoproteomics Reveals the Role of Phosphorylation in Pluripotency and Phase Separation.
    Yanna Tang, Haiming Huang, Ting Wu, Jialin Du, Lu Pang, Hongyun Yang, Haixia Li, Jinhuan Wei, Qian Ma.
      Phosphorylation is a key post-translational modification involved in many cellular processes. Embryonic stem cells (ESCs), characterized by their self-renewal capacity and pluripotent differentiation potential, are widely used in studies of developmental biology and regenerative medicine. However, existing phosphoproteomic data for ESCs remain limited in throughput, restricting our understanding of phosphorylation-mediated regulatory mechanisms. In this study, we performed high-throughput phosphoproteomic profiling and identified 3711 phosphoproteins and 11,410 phosphosites. Integrated analyses showed that nearly half of the interacting proteins of the core pluripotency factors OCT4, SOX2, and NANOG are phosphorylated. Moreover, we found that phosphorylation is more prevalent in scaffold proteins involved in phase separation compared to clients and regulators, and is highly enriched in specific membraneless organelles, such as those in stress granules and Cajal bodies. Together, these findings provide a valuable resource for phosphoproteomics and offer important insights into the role of phosphorylation in pluripotency and phase separation.
    Keywords:  embryonic stem cells; phosphorylation; pluripotency
    DOI:  https://doi.org/10.1002/pmic.70147
  74. bioRxiv. 2026 May 12. pii: 2026.05.08.723879. [Epub ahead of print]
    Neuronal regulation of infection recovery prevents pathogenic stress and tissue damage.
    Phillip Wibisono, Sagi Levy, Jingru Sun.
      Neural regulation of innate immunity is increasingly recognized, yet how the nervous system controls immune resolution after pathogen clearance remains poorly understood. Using Caenorhabditis elegans as a genetically tractable model, we identify the AIA interneurons as critical regulators of both infection-phase homeostasis and post-infection recovery. Acute silencing or genetic ablation of AIA neurons during Salmonella enterica infection results in reduced host survival with heightened activation of conserved immune and stress pathways, including PMK-1/p38 MAPK, insulin/IGF-1 signaling, and the XBP-1-mediated unfolded protein response (UPR). AIA-deficient animals exhibit excessive immune and stress response gene expression and increased intestinal tissue damage, demonstrating that immune hyperactivation is detrimental. Strikingly, selective silencing of AIA neurons during the recovery phase after pathogen clearance significantly impairs survival, revealing that neural activity is required not only for defense but also for resolution. This recovery defect is rescued by knockdown of xbp-1 , but not pmk-1 or daf-16 , indicating that unresolved ER stress is the principal driver of post-infection mortality. Consistently, AIA silencing during recovery sustains UPR activation and exacerbates epithelial barrier damage. Together, our findings establish AIA interneurons as central coordinators of immune homeostasis that limit pathological stress responses during infection and actively promote infection resolution. These findings provide mechanistic insight into how the nervous system not only restrains excessive immune and stress responses during infection but also actively resolves stress signaling and preserves tissue integrity during post-infection recovery.
    DOI:  https://doi.org/10.64898/2026.05.08.723879
  75. Elife. 2026 May 28. pii: RP103721. [Epub ahead of print]13
    Effects of residue substitutions on the cellular abundance of proteins.
    Thea K Schulze, Kresten Lindorff-Larsen.
      Multiplexed assays of variant effects (MAVEs) make it possible to measure the functional impact of all possible single amino acid residue substitutions in a protein in a single experiment. Combination of variant effect data from several such experiments provides the opportunity to conduct large-scale analyses of variant effect scores measured across proteins, but can be complicated by variations in the phenotypes that are probed across experiments. Thus, using variant effect datasets obtained with similar MAVE techniques can help reveal general rules governing the effects of amino acid variation for a single molecular phenotype. In this work, we accordingly combined data from six individual variant abundance by massively parallel sequencing (VAMP-seq) experiments and analysed a total of 31,614 variant effect scores reporting solely on the impact of single amino acid residue substitutions on the cellular abundance of proteins. Using our combined variant effect dataset, we derived and analysed a collection of amino acid substitution matrices describing the average impact on cellular abundance of all residue substitution types in different structural environments. We found that the substitution matrices predict the cellular abundance of protein variants with surprisingly high accuracy when given structural information only in the form of whether a residue is buried or exposed. We thus propose our substitution matrix-based predictions as strong baselines for future abundance model development.
    Keywords:  VAMP-seq; amino-acid substitution matrices; biochemistry; chemical biology; human; molecular biophysics; protein abundance; protein-protein interactions; structural biology
    DOI:  https://doi.org/10.7554/eLife.103721
  76. Comput Struct Biotechnol J. 2026 ;35(1): 0107
    High-throughput Screening of Sequence Elements Associated with RNA Localization.
    Xinquan Zeng, Yusen Lin, Meiting Cai, Jingxia Lin, Yongjun Zhang, Mingze Yao, Jiajian Zhou.
      RNA molecules localize to specific subcellular compartments to perform their biological functions correctly. However, the mechanisms underlying RNA transport and subcellular localization remain poorly understood. In this study, we introduced SRLE-seq (Screening RNA Localization Elements by Sequencing) to identify and prioritize functional sequence elements associated with RNA localization. Our approach successfully recovered known elements and identified 2 novel elements linked to nuclear retention by screening randomized MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) fragments. Within our screening library of 6-mer sequences, SRLE-seq identified 110 6-mers exhibiting functions related to nuclear retention and 49 6-mers associated with nuclear export. Notably, we found that the nuclear retention score derived from SRLE-seq improves predictions of RNA subcellular localization, achieving 72% accuracy when incorporated into a deep learning model. Further experiments demonstrated that these localization-associated 6-mers exert their effects through the regulation of RNA-binding proteins. Our study presents a highly efficient method for prioritizing RNA localization elements via sequencing, establishing a valuable resource for further investigation of RNA-binding protein-mediated RNA subcellular localization.
    DOI:  https://doi.org/10.34133/csbj.0107
  77. Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00158-3. [Epub ahead of print]402 61-87
    Advances in protein engineering.
    Huong Lan Vuong, Hien Thi Thu Le.
      Protein engineering (PE) has been applied to various medicines, food, and environments. Contributions of proteins have been reported with remarkable results in protein therapeutics, antibody engineering, enzyme synthesis, and more specific functions in industrial processes. Therefore, this chapter highlights the most recent PE advances in a battle against mainly human diseases and biomedical sciences. The application of PE will be reviewed, focusing on developing innovative techniques, including evolution, rational design, semi-rational design, and hybrid approaches to protein design in applications. In addition, we provide key achievements of PE in CRISPR/Cas systems, high-through data, and synthetic biology with updated results. Current challenges of using PE, ethical considerations, and various approaches for protein therapeutics are also discussed. In this chapter, the updated findings provide a comprehensive overview of the transformative potential of PE for researchers in the application areas of human disease, especially in cancer therapeutics.
    Keywords:  Mutations; Protein engineering; Protein structures; Synthetic biology
    DOI:  https://doi.org/10.1016/bs.ircmb.2025.11.002
  78. Front Plant Sci. 2026 ;17 1774962
    The regulatory roles of flavonoids, melatonin, and glycine betaine in plant salt stress response.
    Wenrong Yang, Zhaohui Jiang, Junwen Kong, Yanxiu Zhao, Shuangshuang Zhao.
      Salt stress, one of the most detrimental environmental constraints, severely impairs plant growth and productivity by inducing ionic imbalance, osmotic stress, and oxidative damage. In response, plants synthesize a diverse array of secondary metabolites that help maintain cellular turgor, improve water uptake, restore osmotic homeostasis, scavenge reactive oxygen species, and fine-tune growth and development-collectively enhancing salt tolerance. Although considerable progress has been made in characterizing individual metabolites, the intricate interplay between the regulation of secondary metabolism and plant salt stress adaptation remains poorly understood. This review summarizes recent advances in understanding how secondary metabolites respond to salt stress, with a particular focus on flavonoids, melatonin, and glycine betaine. We highlight emerging mechanisms governing their biosynthesis and accumulation under saline conditions and discuss the regulatory networks that coordinate their functions. Finally, we identify critical knowledge gaps and propose future research directions aimed at elucidating the interaction networks among these key secondary metabolites and their upstream regulatory hubs, with the goal of breeding crops with broad-spectrum stress resistance.
    Keywords:  biosynthesis; plant tolerance; regulatory network; salt stress; secondary metabolites
    DOI:  https://doi.org/10.3389/fpls.2026.1774962
  79. Cancer Res. 2026 May 27.
    eIF4G2-Dependent Translation Restrains Pancreatic Cancer Progression.
    Justin Powers, Lai Wei, Justin Chak Ting Cheung, Pardis Ahmadi, Hiroki Kobayashi, Alvaro Curiel-Garcia, Stella Kang, Elizabeth Valenzuela, Marko Jovanovic, Alejandro Chavez, Iok In Christine Chio.
      The lethality of pancreatic ductal adenocarcinoma (PDAC) is driven in part by cellular plasticity that facilitates dedifferentiation and dissemination. Although transcriptional programs underlying these processes are well characterized, the contribution of translational control to PDAC cell-state regulation in vivo needs to be further understood to develop strategies to restrain malignant plasticity. Using a genome-wide CRISPR/Cas9 screen in immunocompetent hosts, we identified the non-canonical initiation factor eIF4G2 (DAP5/NAT1) as a translational checkpoint that restrains PDAC progression. Loss of eIF4G2 accelerated tumor growth, promoted poorly differentiated, basal-like histology, and triggered widespread metastasis. Ribosome profiling revealed that eIF4G2 supports translation of a discrete cohort of mRNAs with long, GC-rich, structured 5' untranslated regions, including tumor suppressors such as Pten and transcriptional regulators such as Crebbp. Accordingly, loss of eIF4G2 was accompanied by secondary transcriptional enrichment of migration and wound-healing programs and induction of basal-like markers. In human PDAC, eIF4G2 expression was reduced in poorly differentiated lesions, and functional eIF4G2 perturbation in patient-derived PDAC cells increased clonogenic growth, whereas enforced eIF4G2 expression suppressed colony formation. Computational inference from human PDAC datasets revealed that reduced eIF4G2 activity correlated with increased metastasis, enhanced basal-like features, and poorer patient survival. Together, these findings establish non-canonical translation initiation as a determinant of PDAC cell-state control and identify eIF4G2 as a barrier to malignant plasticity and metastatic dissemination.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-4299
  80. Redox Biol. 2026 May 21. pii: S2213-2317(26)00218-1. [Epub ahead of print]94 104220
    HIF inhibition: Current strategies and clinical challenges.
    Anna Więch-Walów, Sylwia Bartoszewska, Anna Barton, Paulina Czechowicz, Jakub Dudzik, Ben Wielockx, James F Collawn, Rafal Bartoszewski.
      Cellular metabolism, redox balance, and viability are tightly constrained by oxygen availability. Reduced oxygen tension activates a conserved hypoxic signaling network centered on hypoxia-inducible factors (HIFs), which coordinate transcriptional and post-transcriptional programs that promote metabolic adaptation, angiogenesis, erythropoiesis, and redox balance. While HIF signaling is essential for development and tissue homeostasis, its dysregulation contributes to disease-associated dysfunction in cancer, ischemic disease, and chronic inflammatory disorders. Accordingly, therapeutic strategies aimed at modulating this pathway have gained considerable interest. This review critically examines current strategies aimed at suppressing HIF signaling, with a particular emphasis on approaches that reduce HIF-α protein abundance, inhibit transcriptional activity, or interfere with HIF complex formation. We discuss RNA-based therapies, small-molecule modulators of HIF stability, and noncanonical HIF inhibitors - including topoisomerase inhibitors, proteasome inhibitors, and metabolic modulators - that exert their effects independently of classical oxygen-dependent degradation. Emerging evidence indicates that many chemically diverse HIF inhibitors converge on translation-centered mechanisms, including inhibition of mTOR signaling, activation of eIF2α-dependent stress responses, and disruption of hypoxia-specific translational control. These pathways represent a dominant and previously underappreciated layer of HIF regulation. By contrasting stability-, translation-, and transcription-centered strategies, we highlight key therapeutic constraints imposed by oxygen availability, redox balance, and HIF isoform specificity. The clinical success of HIF-2α-specific allosteric inhibitors underscores the importance of exploiting unique structural vulnerabilities, whereas the lack of analogous pockets in HIF-1α necessitates alternative approaches. We propose that durable suppression of hypoxia-driven pathology will likely require integration of isoform-specific targeting with translational control mechanisms that decouple HIF signaling from generalized cytotoxic stress.
    Keywords:  Belzutifan; Epigenetic modifiers; HIF inhibition; HIF-2 inhibitors; Hypoxia-targeted therapy; Isoform-selective inhibition; Proteasome inhibition; RNA interference; Topoisomerase inhibitors
    DOI:  https://doi.org/10.1016/j.redox.2026.104220
This page is being maintained by Thomas Krichel. It was last updated on 2026‒05‒31 at 6:48.