bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–08–16
79 papers selected by
Cédric Chaveroux, CNRS
  1. Temporal gating dictates stress-induced transcript export from the nucleus.
  2. m5C Methylation of mRNA: Still More Questions Than Answers.
  3. The integrated stress response kinase GCN2 prevents ZAKα-Dependent inflammatory hyperactivation in macrophages.
  4. Isolation of Subcellular Ribosome Subpopulations Based on Recombinant Peptide Tag-Specific Location-Restricted Illumination-Enhanced Biotinylation.
  5. Targeting the integrated stress response to overcome cancer therapy resistance: From mechanisms to therapeutic opportunities.
  6. Translation elongation in the nervous system.
  7. The p97 adaptor p47/NSFL1C is necessary for stress granule dissolution after heat stress.
  8. mTOR inactivation governs adaptive survival to ribosome biogenesis deficiency.
  9. Stress granules formed during infections with RNA viruses have significant virus-specific differences in generation and composition.
  10. Sparsomycin inhibits translation through a conserved mechanism across all domains of life.
  11. The GCN2-ATF4 signaling axis orchestrates the hepatic transcriptional stress response to short-term sulfur amino acid deprivation.
  12. The Interactions of Tau, RNA, and Stress Granules in Neurodegenerative Disease: A Comprehensive Review.
  13. METTL1-mediated m7G modification of valine tRNAs drives metabolic adaptation in pancreatic ductal adenocarcinoma.
  14. PUF family RNA-binding proteins Puf1 and Puf2 promote transcript degradation in Toxoplasma gondii.
  15. Sense-Antisense RNA duplexes mediate stress-responsive translational control in Plasmodium falciparum.
  16. Mitochondrial RNA polyadenylation: Defining RNA fate through 3' end regulation.
  17. Dynamic Cellular Regulation of Proteasome Translocation and Phase Transition.
  18. rRNA 5'ETS processing contributes to nucleolar organization and nuclear architecture.
  19. Genome-Wide Impact of Human DBR1 Depletion on RNA Processing Networks Reveal a Connection Between Pre-mRNA Splicing, mRNA Surveillance and Stress Granule Dynamics.
  20. Inhibiting Ribosomal RNA Synthesis in C. elegans Protects Against Reductive Stress During de novo Fatty Acid Synthesis Deficiency.
  21. FERONIA Modulates Translational Buffering Capacity of Ribosome-Associated Gene Module in Salt-Stressed Tomato Roots.
  22. 23S rRNA modifications stimulate catalytic activity and prevent the formation of alternative structures.
  23. In vivo clustering of oskar mRNA is driven by RNA concentration, RNA binding proteins, and an RNA palindrome.
  24. MYC-driven BYSL overexpression promotes hepatocellular carcinoma by suppressing nucleolar stress and inactivating the RPL5/RPL11-MDM2-p53 pathway.
  25. Differential Effects of PERK and IRE1α Silencing on Expression of Apoptosis and Autophagy Markers in T-Lymphoblastic Leukemia MOLT-3 Cells.
  26. RNA translational control in skeletal development, homeostasis, and disease.
  27. Targeting IGF2BP3 in Cancer: From Molecular Structure and Biology to Early Drug Discovery.
  28. Crystal structures of type T archaeal ribonuclease P Rpp30, Rpp30/Pop5, and L7Ae provide insights into a reduced RNase P.
  29. Heat Shock Proteins and Exercise in Skeletal Muscle Insulin Resistance: Protective Mechanisms and Therapeutic Potential.
  30. Exploring the BICC1 Interactome in HEK293T Cells: Insights Into RNA-Mediated Protein Networks and Biomolecular Condensates.
  31. Heat shock protein family D member 1 (HSPD1) modulates ribosome-related pathways and protein synthesis in lung adenocarcinoma.
  32. Epigenetic regulation of tubular epithelial cell dysfunction in diabetic kidney disease.
  33. Structural characterization of ribosome recycling and fusidic acid inhibition in Staphylococcus aureus.
  34. ATF4 activates a transcriptional program that chronically suppresses mTOR activity and promotes neurodegeneration in Parkinson disease models.
  35. Quantitative single-base m6A profiling reveals dynamic reprogramming, evolutionary conservation and transcriptional regulation in bacteria.
  36. The role of m6A RNA methylation in skeletal muscle pathophysiology and its targeted therapeutic prospects.
  37. Multicolor Live-Cell mRNA Imaging Using RNA-Regulated Destabilization Domains.
  38. Photothermal therapy triggering organelle stress and metabolic reprogramming to potentiate antitumor immunity.
  39. Cross-species R-DeeP profiling reveals a conserved core of RNA-dependent proteins in yeast.
  40. Principles of ribosome-associated protein quality control during the synthesis of CFTR.
  41. Transfer RNA Modifications in the Immune System Participate in Disease Pathogenesis.
  42. Stabilizing Protein and Protein-RNA Condensates in Low-Melting Agarose Hydrogels for Quantitative Biophysical Measurements.
  43. Adaptation of the Transcriptome and miRNAome in Response to Hepatocellular Hypoxia.
  44. BOULE is Essential for the Dynamic Disassembly of Heat Shock Granules in Male Germ Cells.
  45. Adaptation of OXPHOS biogenesis to cellular requirements.
  46. Targeting the unfolded protein response in cancer: mechanisms, small-molecule inhibitors, and translational challenges.
  47. CSTF2-mediated 3'UTR shortening drives oncogenic activation of GPC3 in hepatocellular carcinoma.
  48. Tumour-Derived Extracellular Vesicles Containing dsRNA Induce Degradation of Ribosomal Protein mRNA in Platelets.
  49. Pre-Existing Heterogeneity Predicts Rare Proteostasis-Stress Programs Across Diverse Perturbations.
  50. Complementary intra- and extracellular AGR2 activities support epithelial ovarian cancer cell aggressiveness.
  51. Stress-induced remodeling of membrane-bound organelles in budding yeast.
  52. Cross-Family Mechanistic Analysis of Plant Alkaloids Against Neglected Arboviruses and Related RNA Viruses.
  53. In trans RNA replication of a defective self-amplifying RNA lowers RNA replication but enhances protein translation.
  54. Nonhistone Post-translational Modifications as Integrative Signaling Networks in Podocyte Injury and Glomerular Disease.
  55. The Amino Acid-Neurodegeneration Axis: Excitotoxicity and Oxidative Stress as Context-Dependent Amplifiers of Metabolic Dysfunction.
  56. The pseudouridine synthase PUSL1 modifies U39 of mitochondrial tRNAs and is linked to human neurological phenotypes.
  57. Transcriptomic profiles of the maternal-to-zygotic transition for Drosophila embryos exposed to acute and chronic heat stress.
  58. DACH1 SUMOylation protects against diabetic cardiomyopathy by suppressing endoplasmic reticulum stress.
  59. piR‑164552 promotes malignant progression in head and neck squamous cell carcinoma via the RBM4/EIF4E2 signaling axis: Insights from multi‑omics and functional analyses.
  60. Chemical Modification Strategies for Therapeutic Oligonucleotides: Mechanism Compatibility, Design Trade-Offs, and Translational Barriers.
  61. Lineage-specific retention of the plastid tilS-trnI(CAU) module and its variable relationship with codon usage evolution in green algae.
  62. Ubiquitination-Mediated Regulation of Brassinosteroid Signaling.
  63. Regulation and roles of mammalian mitophagy.
  64. Selective cellular vulnerability and resilience in amyloidosis: insights from the 2025 International Society of Amyloidosis Workshop.
  65. Regulation of Translation by PKA Signaling Pathway.
  66. Development of a protein synthesis network at the sarco/endoplasmic reticulum in adult cardiac myocytes.
  67. p62/SQSTM1: From an autophagy receptor to a condensate organizer of selective autophagy and stress signaling.
  68. Dendritic translation and neuroproteasome-mediated degradation of endogenous tau revealed by STARFISH.
  69. Med9 Is a Novel eIF4E-Interacting Protein in Saccharomyces cerevisiae.
  70. RAN Translation-Coupled Decay of the C9orf72 GGGGCC Repeat Transcript by the RNA Exosome Suppresses Dipeptide Repeat Production.
  71. Sensitivity Analysis in Translation Averaging.
  72. A live-cell autophagy reporter reveals reversible vacuolation in naked mole-rat skin fibroblasts under lysosomal stress.
  73. Cardiovascular Diseases and Cancer: Convergent Proteostasis Networks at the Crossroads of Mechanisms and Therapeutic Opportunities.
  74. Metabolomic Analysis of Intracellular Amino Acid Profile Differences Between Cisplatin-Resistant and Cisplatin- Sensitive CALU-1 Lung Cancer Cells.
  75. Lactylation in kidney diseases: a review of regulatory mechanisms and therapeutic prospects.
  76. Spatiotemporal Control of microRNA-Target Interactions.
  77. URG7-Driven Homeostatic Adaptation Protects SH-SY5Y Cells from 6-OHDA Neurotoxicity.
  78. From PLP1 Misfolding to Oligodendrocyte Degeneration: A Proteostasis-Centered Framework for Pelizaeus-Merzbacher Disease.
  79. Liquid-Liquid Phase Separation (LLPS) in Tumor Biology: Special Focus on the Process of Transcription.
  1. Genes Dev. 2026 Aug 11.
    Temporal gating dictates stress-induced transcript export from the nucleus.
    Noah S Helton, Benjamin Dodd, Stephanie L Moon.
      Prior studies have largely focused on transcriptional and translational control during stress, but how regulated nuclear mRNA export contributes to the stress response remains unresolved. We show that nuclear mRNA export is progressively inhibited during arsenite and heat stress in human cells. In contrast to previous work largely in yeast that suggests nuclear export of stress-induced transcripts is prioritized through sequence-specific mechanisms, we found that mRNA export is governed by temporal gating, in which the timing of mRNA biogenesis determines the nucleocytoplasmic distribution of mRNAs during stress. Using single-molecule mRNA imaging and transcriptome-wide analyses, we observe the majority of stress-induced mRNAs, including heat shock protein transcripts, accumulate in the nucleus during stress. However, a subset of stress-induced mRNAs, notably HMOX1, JUN, and FOS, escape nuclear retention. mRNAs transcribed early during stress, including those encoding immediate early genes, redox mediators, and protein chaperones, are exported from the nucleus prior to the global inhibition of mRNA export. In contrast, mRNAs transcribed later are retained in the nucleus until stress is resolved. Reporter RNA assays confirm that transcriptional timing determines mRNA export competence. This work reveals that the timing of mRNA production, rather than transcript-specific sequence features, is the major determinant of nuclear export efficiency of stress-induced transcripts in human cells.
    Keywords:  heat shock proteins; heat shock response; integrated stress response; nuclear export; stress-induced genes
    DOI:  https://doi.org/10.1101/gad.353896.126
  2. Cells. 2026 Jul 25. pii: 1336. [Epub ahead of print]15(15):
    m5C Methylation of mRNA: Still More Questions Than Answers.
    Elena S Babaylova, Elizaveta A Zolotenkova, Alexey A Malygin.
      mRNA plays a pivotal role in cellular processes of genetic information transfer, and post-transcriptional modifications of its nucleotides enable regulation of these processes with each particular mRNA. m5C methylation is a specific RNA modification that is rather common in tRNA, rRNA, lncRNA and other types of non-coding RNAs, whereas in mRNA it is found not very often. However, the functioning of m5C-methylated mRNAs differs from the non-methylated ones quite dramatically. Of the eight m5C RNA methyltransferases in humans, only two, NSUN2 and NSUN6, were found to be capable of modifying the main portion of cellular mRNAs. A deficiency of NSUN2 and NSUN6 causes global changes in the transcriptome and translatome, and a corruption of the NSUN2 gene in humans is associated with neurodegenerative diseases and intellectual disability. Despite intensive research of m5C mRNA methylation in recent years, many aspects of this phenomenon and its significance remain problematic and far from understood. In this review, we discuss the available information on mRNA methylome biogenesis, methods for its study and analysis, effects of m5C modification on mRNA life, and place it in the general context of cell biology, attempting to draw the biological relevance of m5C mRNA methylation. We highlight the main inconsistencies and difficulties that arise, analyze their possible causes, and propose potential directions for further research that could clarify the controversial issues and provide a link between the NSUN2 deficiency and neurodegenerative diseases.
    Keywords:  ALYREF; NSUN2; NSUN6; YBM1; gene expression; m5C RNA methylation; mRNA; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/cells15151336
  3. J Biol Chem. 2026 Aug 14. pii: S0021-9258(26)02324-0. [Epub ahead of print] 113452
    The integrated stress response kinase GCN2 prevents ZAKα-Dependent inflammatory hyperactivation in macrophages.
    R D Requião, L F Lima-Silva, P Estevão, Wlg Costa, N C Zani, I C Vasconcelos, Iep Silva, T T Xu, Hma Prado, B Steingenberger, M H Bengtson, P J Murray, P M Moraes-Vieira.
      Macrophages orchestrate inflammation through rapid and extensive proteome remodeling, yet the translational programs governing macrophage activation remain poorly defined. Here, we show that classically activated macrophages (LPS+IFNγ-treated) and alternatively activated macrophages (IL-4-treated) engage fundamentally distinct translational trajectories. Whereas alternatively activated macrophages sustain elevated protein synthesis, classically activated macrophages undergo a rapid but transient increase in translation that is subsequently restrained by the integrated stress response (ISR) kinase General Control Nonderepressible 2 (GCN2). Using puromycin incorporation, polysome profiling, and quantitative proteomics, we demonstrate that GCN2-mediated phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) limits global translation and constrains the pro-inflammatory response. Genetic loss of GCN2 results in excessive translation and hyperinflammation driven by the ribosome-associated stress sensor ZAKα (MAP3K20). Importantly, pharmacological inhibition of ZAKα in GCN2-deficient macrophages selectively normalizes tumor necrosis factor α (TNFα) secretion, establishing a functional regulatory axis in which GCN2 suppresses ZAKα-dependent inflammatory signaling. Together, these findings redefine translational control as a central checkpoint in macrophage activation, revealing how GCN2 mitigates ribosomal stress to prevent inflammatory hyperactivation, with potential therapeutic implications for TNFα-driven inflammatory diseases.
    Keywords:  GCN2 signaling; Translation control; ZAKα pathway; inflammation regulation; macrophage activation
    DOI:  https://doi.org/10.1016/j.jbc.2026.113452
  4. J Vis Exp. 2026 Jul 24.
    Isolation of Subcellular Ribosome Subpopulations Based on Recombinant Peptide Tag-Specific Location-Restricted Illumination-Enhanced Biotinylation.
    Adele Xu, Kitra Cates, Craig Kerr, Kelsie Wysong, Maria Barna.
      Growing evidence suggests that mRNA translation is a highly compartmentalized process within a cell, and that subcellular trafficking and localization of specific mRNAs is key to ensuring that proteins with compartment-specific functions are produced in the ideal milieu and in appropriate quantities. However, techniques for subcellular isolation and characterization of the ribosomes that translate these mRNAs have been limited to date, such that much remains unknown about how the composition of translational machinery contributes to regulation of localized mRNA translation. Here, we demonstrate AviTag-specific Location-restricted Illumination-enhanced Biotinylation (ALIBi), a method that combines epitope tagging, a newly developed optogenetically activated split-biotin ligase, and affinity purification to rapidly and specifically label and isolate ribosomes localized to any subcellular compartment of interest. First, CRISPR/Cas9 editing is used to fuse an AviTag peptide, a tobacco etch virus (TEV) protease cleavage site, and a FLAG epitope tag to a ribosomal protein. The split biotin ligase, fused to an organelle-targeting domain, is expressed in this cell line and is inactive under normal biotin concentrations. Upon activation by supplemental biotin and blue light illumination, the ligase biotinylates AviTagged ribosomes in the immediate vicinity, allowing for affinity purification of biotinylated ribosomes and associated proteins and mRNAs on streptavidin-coated beads. Non-denaturing elution via TEV protease cleavage yields samples suitable for downstream characterization of core ribosomal proteins, ribosome-associated proteins, and ribosome-bound mRNAs via RNA sequencing or mass spectrometry proteomics. In this protocol, we review design principles for fusing AviTag to a ribosomal protein and targeting the split biotin ligase enzyme to the organelle of interest. We demonstrate activation of the ALIBi system, cell lysis, affinity purification, and sample elution. Finally, we discuss typical results and troubleshooting.
    DOI:  https://doi.org/10.3791/66881
  5. Biochim Biophys Acta Rev Cancer. 2026 Aug 14. pii: S0304-419X(26)00158-7. [Epub ahead of print] 189686
    Targeting the integrated stress response to overcome cancer therapy resistance: From mechanisms to therapeutic opportunities.
    Chenliang Zhang, Liping Li, Ting Zhang.
      Drug resistance remains a major obstacle in cancer therapy, underscoring the urgent need to identify new targets and therapeutic strategies to overcome resistance. The integrated stress response (ISR), an evolutionarily conserved mechanism that enables cells to adapt to various internal and external stresses, plays a critical role in determining cell fate and has emerged as a key player in therapy resistance. However, targeting the ISR to overcome treatment resistance remains challenging. In this review, we systematically outline the regulatory mechanisms of the ISR in cancer cells and its crosstalk with other oncogenic signaling pathways. We further summarize the molecular mechanisms by which ISR signaling contributes to therapeutic resistance, along with recent advances in targeting the ISR and the current landscape of drug development. In addition, we explore the potential of leveraging ISR-induced cell death pathways to sensitize tumors to therapy and overcome resistance. We also discuss the current status, challenges, and future directions for clinical translation of ISR-targeting strategies, and provide perspectives aimed at advancing their therapeutic application.
    Keywords:  ATF4; Amino acid homeostasis; Drug resistance; Integrated stress response; Proteostasis; Selective translation; Stress granule; Tumor therapy; eIF2α
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189686
  6. Trends Neurosci. 2026 Aug 11. pii: S0166-2236(26)00142-6. [Epub ahead of print]
    Translation elongation in the nervous system.
    Alexander R Mikesell, Anne E Willis, Sarah Loerch, Zachary T Campbell.
      Protein synthesis is a highly energy-dependent process that consists of initiation, elongation, termination, and ribosome recycling. Historically, initiation has been viewed as the major site of translation regulation. However, growing recognition of elongation as a regulatory node has highlighted the importance of eukaryotic elongation factor (eEF)1A-dependent decoding, eEF2-catalyzed ribosome translocation, conditional elongation factors, ribosome speed, and tRNA dynamics. In neurons, these mechanisms are especially important because protein synthesis must be regulated across highly polarized cellular compartments. In this review, we summarize evidence from diverse model systems showing that tightly regulated translation elongation supports cellular function and viability, whereas disrupted elongation contributes to dysfunction and disease throughout the nervous system.
    Keywords:  FMRP; GCN2; eEF1; eEF2; eIF5A; tRNA
    DOI:  https://doi.org/10.1016/j.tins.2026.07.004
  7. Open Biol. 2026 Aug 12. pii: 260021. [Epub ahead of print]16(8):
    The p97 adaptor p47/NSFL1C is necessary for stress granule dissolution after heat stress.
    Michelle A Johnson, Richa Khanna, Sirisha Mukkavalli, Ly Nguyen, Malavika Raman.
      Stress granules form in response to diverse cellular perturbations to sequester translation components until the stress is resolved. Stress granules are composed of RNA-protein assemblies in membrane-delimited structures and must be rapidly disassembled to release components to allow translation to resume. Disassembly of stress granules formed in response to heat stress is dependent on ubiquitylation of stress granule components such as G3BP1. Ubiquitylation of stress granule proteins recruits the AAA-ATPase p97 (also known as VCP) to enable ubiquitin-dependent disassembly of these structures. Loss of p97 activity leads to the persistence of stress granules and is implicated in several age-related neurodegenerative diseases. Here, we show that p97 recruitment to stress granules is dependent on its ubiquitin-binding co-factor p47. p47 translocates to stress granules in response to a variety of cellular stressors and is required for the recruitment of p97 to stress granules. Loss of p47 leads to an inhibition in stress granule disassembly. We further show that p47 associates with G3BP1 in response to heat stress in a ubiquitin-dependent manner. Taken together, our data add to the growing list of p97 adaptors that are implicated in the recruitment of p97 for the dissolution of stress granules.
    Keywords:  VCP; degradation; phase separation; stress granule; ubiquitin
    DOI:  https://doi.org/10.1098/rsob.260021
  8. Genes Dev. 2026 Aug 10.
    mTOR inactivation governs adaptive survival to ribosome biogenesis deficiency.
    Wenjun Fan, Hester Liu, Liling Yang, Niladri Sinha, Marco Catipovic, Daoyuan Dong, Hariharan Easawaran, Rachel Green, Marikki Laiho.
      Ribosome biogenesis is a resource-consuming process that facilitates rapid growth and feeds uncontrolled, cancerous traits. Constraining ribosome biogenesis and protein translation has become a tenable therapeutic strategy for cancer. Yet, we do not know how cells that rely on high metabolic activity adapt and sustain their growth when deprived of their translational capacity. Conversely, stem cells and treatment-resistant cells persist under low metabolic states challenging their eradication. These are critical questions in cancer therapies. To delineate survival mechanisms that allow cancer cells to adapt to ribosome biogenesis defects, we conducted functional genomics screens during inhibition of RNA polymerase I. We identified that inactivation of mTOR enabled cell survival despite severe translational suppression. This was paradoxical as activation of mTOR is considered oncogenic by boosting ribosome biogenesis and cellular translational programs. We show that mTORC1 inhibition does neither restore rRNA synthesis nor ribosome biogenesis, but redistributes limited ribosomes from highly translated 5'TOP mRNAs to survival-essential transcripts. This mTOR inactivation-mediated prioritization of translational resources represents a minimal requirement for cell survival when translational capacity is compromised, which we term "translational fitness." Our findings redefine the role of mTOR in cell survival and highlight the need for strategic targeting of translation regulation in cancer therapy.
    Keywords:  adaptive survival; cancer cell survival; mTORC1 signaling; ribosome biogenesis; therapy resistance; translational control; translational fitness
    DOI:  https://doi.org/10.1101/gad.353708.126
  9. PLoS Biol. 2026 Aug 14. 24(8): e3003363
    Stress granules formed during infections with RNA viruses have significant virus-specific differences in generation and composition.
    Reto M Lang, Silvio Steiner, Jenna Kelly, Anne-Christine Uldry, Pratik Dave, Sophie Braga-Lagache, Jeffrey Chao, Manfred Heller, G Tuba Barut, Volker Thiel.
      Eukaryotic cells evolved a cellular stress response to cope with extrinsic and intrinsic stress stimuli including virus infections. The major result of this response is the shutdown of bulk translation to prevent damage and allow the reprogramming of translation towards stress-resolving pathways. The resulting translationally stalled mRNA and associated proteins are accumulated in membrane-less cytosolic condensates called stress granules (SG). While the inhibitory effect of translation arrest on virus growth is well established, the role of SGs in the cellular defense against viruses is still unclear. The observation of specific interference with SG formation during various virus infections led to the hypothesis that SGs could serve as antiviral signaling platforms. In this study, we used mouse hepatitis virus (MHV) to characterize SGs formed during coronavirus infection. By applying APEX2-mediated proximity labeling in combination with quantitative proteomics, we dissected the proteome of MHV-induced granules and compared it to canonical SGs formed during oxidative stress. Our data revealed substantial differences in protein abundance and composition, indicating stressor-specific SG characteristics. To assess if the observed differences are a general feature of virus-induced SGs or rather virus-specific, we extended our investigations to the Semliki Forest virus (SFV), a member of the alphavirus family known to induce SGs. An initial comparison of SG formation kinetics by live-cell imaging showed distinct time points of SG induction between both viruses. A comprehensive comparison of the SG protein compositions revealed profound differences in the SG proteome between SFV and MHV. A further subcellular localization of SG components by microscopy not only confirmed a reduced abundance of several translation initiation factors in MHV-induced granules, but surprisingly, revealed the presence of SFV RNA and the absence of MHV RNA in virus-induced SGs. The reduced connection to canonical SG themes observed for MHV-induced granules compared to SFV- and oxidative stress-induced ones indicates a different impact of these condensates on MHV replication and further raises the question whether they should be considered SGs. The surprising plasticity of SGs concerning induction kinetics, protein composition and abundance, and inclusion or exclusion of viral RNA provide a base for future investigations of the role(s) of SGs in the context of viral infection and how they may impact virus replication.
    DOI:  https://doi.org/10.1371/journal.pbio.3003363
  10. Nucleic Acids Res. 2026 Aug 10. pii: gkag761. [Epub ahead of print]54(15):
    Sparsomycin inhibits translation through a conserved mechanism across all domains of life.
    Madhura N Paranjpe, Elodie C Leroy, Egor A Syroegin, Laurin Flemmich, Julia Thaler, Mélanie Gillard, Anthony Bougas, Georgia Kournoutou, George P Dinos, Thibaud T Renault, Ronald Micura, C Axel Innis, Yury S Polikanov.
      Sparsomycin (SPA) is a broad-spectrum inhibitor of protein synthesis with activity across all three domains of life. Although SPA has long been known to target the ribosomal peptidyl transferase center (PTC), previous structural studies suggested that SPA binds differently to bacterial ribosomes compared to their archaeal and eukaryotic counterparts-an unexpected conclusion given the high evolutionary conservation of the ribosomal catalytic center. Here, we show that SPA inhibits a majority of elongation-competent bacterial ribosomal complexes and present X-ray crystal structures of Thermus thermophilus 70S ribosomes stalled by SPA at the initiation and early elongation stages of translation. These structures reveal that SPA binds to the bacterial ribosome in a manner essentially identical to that observed in archaeal and eukaryotic ribosomes, establishing a unified structural mechanism of SPA action across all domains of life. In this conserved binding mode, SPA occupies the A-site cleft of the PTC and forms an extensive network of interactions with universally conserved ribosomal RNA nucleotides and the CCA-end of the P-site transfer RNA (tRNA), thereby stabilizing the peptidyl-tRNA substrate while sterically blocking accommodation of an incoming aminoacyl-tRNA. By clarifying the mode of action of SPA on the bacterial ribosome, our work provides a structural framework for the rational design of SPA derivatives with improved potency and bacterial specificity.
    DOI:  https://doi.org/10.1093/nar/gkag761
  11. J Mol Biol. 2026 Aug 13. pii: S0022-2836(26)00363-3. [Epub ahead of print] 169990
    The GCN2-ATF4 signaling axis orchestrates the hepatic transcriptional stress response to short-term sulfur amino acid deprivation.
    Valérie Carraro, Maëlle Cherpaz, Lucie Longechamp, Cécile Coudy-Gandilhon, Laurent Parry, Guillaume Voyard, Anne-Catherine Maurin, Céline Jousse, Julien Averous, Lydie Combaret, Isabelle Papet, Alain Bruhat.
      Mammals rely on the integrated stress response (ISR) to maintain essential amino acid (EAA) homeostasis. The kinase GCN2 is a key ISR sensor that is rapidly activated by uncharged tRNAs during EAA deprivation, leading to eIF2α phosphorylation and selective translation of ATF4. ATF4 subsequently orchestrates a transcriptional program regulating amino acid metabolism, redox balance, and autophagy. In this study, we investigated the role of GCN2 in the early hepatic transcriptional response to dietary sulfur amino acids (SAA; methionine and cysteine) deprivation. Using ATF4-luciferase reporter mice, we demonstrate that short-term SAA deprivation rapidly activates the eIF2α-ATF4 pathway within 3 hours, with activation primarily localized to the liver. Complementary in vivo and ex vivo approaches revealed that genetic deletion or pharmacological inhibition of GCN2 abolishes early eIF2α phosphorylation and induction of ATF4 target gene, while PERK is dispensable for this response. Furthermore, GCN2 controls the induction of multiple adaptive transcriptional programs involved in amino acid transport, aminoacyl-tRNA synthesis, autophagy, serine biosynthesis, one-carbon metabolism and glutathione degradation highlighting a coordinated adaptive response to acute SAA deprivation. These findings establish GCN2 as a major sensor mediating the early hepatic response to SAA deprivation, and define a transcriptional program essential for maintaining amino acid homeostasis. In contrast, Fgf21 induction occurs independently of GCN2, indicating the existence of parallel adaptive mechanisms. Collectively, this work provides new insight into the early dynamics and molecular specificity of ISR activation in response to acute dietary SAA deprivation.
    Keywords:  ATF4 signaling; GCN2 kinase; Integrated Stress Response; liver transcriptional response; short-termsulfur amino acid deprivation
    DOI:  https://doi.org/10.1016/j.jmb.2026.169990
  12. Cells. 2026 Jul 29. pii: 1365. [Epub ahead of print]15(15):
    The Interactions of Tau, RNA, and Stress Granules in Neurodegenerative Disease: A Comprehensive Review.
    Tristyn N Garza, Jose F Abisambra.
      The discovery of RNA in the late 19th century revolutionized the understanding of cell biology. Subsequent discoveries over the next six decades revealed a key role for RNA in protein synthesis. Nevertheless, today, the mechanisms driving RNA metabolism remain enigmatic. Given its fundamental cellular role, RNA alterations are strongly linked to disease, including devastating neurodegenerative disorders pathologically defined by the accumulation of RNA-binding proteins. For example, the mislocalization of TDP-43, an RNA-binding protein, is a pathological feature of amyotrophic lateral sclerosis and frontotemporal dementia TDP-43. Another group of more than 20 neurodegenerative disorders, called tauopathies, is characterized by the aberrant accumulation of the protein tau. Similarly, the emerging concept that tau binds RNA, facilitating the formation of pathological structures, highlights the importance of RNA stability in tauopathies. However, the dynamics and consequences of RNA-tau interactions remain unclear. This review comprehensively catalogs key findings linking tau, RNA, and stress granules. These findings are important because they could offer novel opportunities to design therapeutic strategies.
    Keywords:  RNA; neurodegeneration; neurodegenerative disease; stress granules; tau
    DOI:  https://doi.org/10.3390/cells15151365
  13. J Clin Invest. 2026 Aug 06. pii: e204312. [Epub ahead of print]
    METTL1-mediated m7G modification of valine tRNAs drives metabolic adaptation in pancreatic ductal adenocarcinoma.
    Jiabei Zhu, Qi Zhang, Douglas Evans, Rui Su, Qiuhui Pan, Ajay Goel.
      Transfer RNA (tRNA) modifications play a critical role in regulating codon-specific mRNA translation and enabling tumor cell adaptation. The RNA methyltransferase METTL1 installs N7-methylguanosine (m⁷G) modifications on tRNAs, thereby shaping codon usage and translational output. However, the function and mechanistic contribution of the METTL1-tRNA axis in pancreatic ductal adenocarcinoma (PDAC) remain poorly defined. Here, we show that METTL1 is overexpressed in PDAC tissues and that elevated METTL1 expression is associated with poor patient survival. Genetic ablation of METTL1 markedly suppresses PDAC cell proliferation, migration, and tumor growth in vitro and in vivo. Mechanistically, METTL1 loss selectively reduces m⁷G-modified valine tRNAs - particularly, Val-AAC, Val-CAC, and Val-TAC - leading to impaired translation of valine-enriched oxidative phosphorylation transcripts. As a consequence, METTL1 deficiency disrupts mitochondrial respiration and energy production in PDAC cells. Consistent with this model, valine tRNA levels are elevated in PDAC tissues, and their selective depletion phenocopies METTL1 loss by impairing mitochondrial bioenergetics and tumor cell fitness. Thus, the METTL1-valine tRNA axis promotes PDAC progression through codon-dependent translational control of mitochondrial electron transport chain and oxidative metabolism. Together, our findings identify a METTL1-tRNA-mitochondrial signaling axis as a previously unrecognized metabolic vulnerability and a promising therapeutic target in pancreatic cancer.
    Keywords:  Gastroenterology; Mitochondria; Noncoding RNAs; Oncology; RNA processing
    DOI:  https://doi.org/10.1172/JCI204312
  14. J Biol Chem. 2026 Aug 12. pii: S0021-9258(26)02308-2. [Epub ahead of print] 113436
    PUF family RNA-binding proteins Puf1 and Puf2 promote transcript degradation in Toxoplasma gondii.
    Chitti Raju Khandavalli, Rajkumar Gurupwar, Abhijit S Deshmukh.
      Toxoplasma gondii, a highly successful apicomplexan parasite, primarily relies on post-transcriptional mechanisms to regulate mRNA stability and translation during rapid life-cycle stage transitions and to adapt to diverse host environments. While RNA-binding proteins (RBPs) are crucial for these regulatory processes, their specific roles in mRNA translation, storage, and degradation during life-stage transitions and under physiological stress in Toxoplasma remain poorly understood. Here, we identified the PUF family of RBPs and characterized two conserved members, TgPuf1 and TgPuf2. We examined their expression, localization, RNA-binding activity, essentiality during asexual stages in cell culture and mouse host, responses to stress conditions, and roles in transcript regulation. Gene-knockout studies in cell-culture showed that TgPuf1 modestly supports parasite fitness under both normal and stress conditions, while TgPuf2 appears largely dispensable. Mice infected with Puf1-deleted tachyzoites showed delayed mortality compared with wild-type, whereas neither Puf1 nor Puf2 deletion affected bradyzoite development. Both TgPuf proteins bind to a conserved RNA sequence known as PUF Recognition Elements (PREs), associate with ribonucleoprotein complexes, and interact with the deadenylase enzyme TgPop2. Using synthetic RNA reporter systems, we demonstrated that, upon interaction with TgPop2, TgPuf proteins stimulate the removal of the poly(A) tail from RNA targets, thereby promoting RNA degradation. The inability to generate the double knockout is adequately addressed using TgPuf1-mAID in the delta TgPuf2 background, indicating that individual Puf proteins are dispensable; however, the lack of both results in severe growth defects. Overall, these findings suggest that PUF proteins regulate transcript levels in Toxoplasma through a deadenylation-dependent mechanism.
    Keywords:  Apicomplexan; Deadenylase; PUF; RNA degradation; RNA-binding protein; Toxoplasma gondii
    DOI:  https://doi.org/10.1016/j.jbc.2026.113436
  15. RNA. 2026 Aug 10. pii: rna.081149.126. [Epub ahead of print]
    Sense-Antisense RNA duplexes mediate stress-responsive translational control in Plasmodium falciparum.
    Rashim Malhotra, Kushankur Pandit, Pawan Malhotra, Krishanpal Karmodiya.
      Plasmodium falciparum, the primary cause of human malaria, relies on tightly coordinated gene-expression programs to adapt to host-derived stress despite possessing a limited repertoire of canonical transcription factors. Antisense long noncoding RNAs have emerged as important regulators of parasite biology, including virulence gene regulation and sexual commitment; however, their prevalence, origin, and broader functional significance remain poorly understood. Here, we demonstrate that antisense transcription is a widespread, reproducible, and regulated feature of the P. falciparum transcriptome rather than a byproduct of pervasive euchromatic transcription. Environmental stress, including febrile temperature exposure and artemisinin treatment, extensively remodelled antisense transcription, particularly at loci associated with virulence and stress adaptation, promoting widespread sense-antisense RNA duplex formation. Functional analyses of two stress-responsive chromatin regulators, PfGCN5 and PfHDAC1, identified as antisense-expressing loci, revealed that increased antisense expression elevated steady-state mRNA abundance while reducing cognate protein levels. Mechanistically, sense-antisense RNA duplex formation stabilized complementary transcripts but suppressed translation. Integrated transcriptomic, RNA-RNA duplex profiling, ribosome sequencing, and proteomic analyses further showed that duplex-enriched transcripts exhibit reduced ribosome occupancy and reduced protein abundance, accompanied by localized antisense enrichment near transcription end sites and altered ribosome distribution consistent with impaired translational engagement. Collectively, our findings identify an antisense RNA-ribosome regulatory axis that couples RNA duplex formation to adaptive translational control, providing a previously unrecognized mechanism underlying stress adaptation and post-transcriptional gene regulation in P. falciparum.
    Keywords:  Antisense RNA; Malaria; Plasmodium falciparum; Transcription regulation
    DOI:  https://doi.org/10.1261/rna.081149.126
  16. Biochim Biophys Acta Mol Cell Res. 2026 Aug 12. pii: S0167-4889(26)00106-0. [Epub ahead of print] 120207
    Mitochondrial RNA polyadenylation: Defining RNA fate through 3' end regulation.
    Linden Muellner-Wong, William Carter, Christoph Freyer, Anna Wredenberg.
      Polyadenylation is a conserved post-transcriptional RNA modification with fundamentally different consequences for RNA fate across biological systems. In bacteria, chloroplasts, and plant mitochondria, adenylation is generally associated with RNA turnover and degradation, whereas its role in metazoan mitochondria remains incompletely understood. In metazoa, polyadenylation is best known for generating complete UAA stop codons in a subset of mitochondrial mRNAs. However, this explanation does not fully account for the evolutionary conservation of the modification, its diverse RNA substrates, or the broad phenotypic consequences of disrupted polyadenylation. In this review, we re-examine RNA adenylation and propose that, in metazoan mitochondria, polyadenylation primarily establishes a permissive 3' end state that governs RNA maturation, stability, translational competence, and decay. This perspective provides a unifying explanation for the diverse functions attributed to mitochondrial polyadenylation.
    Keywords:  Gene expression; Mitochondria; Polyadenylation; RNA homeostasis; mtPAP
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120207
  17. Biology (Basel). 2026 Jul 30. pii: 1253. [Epub ahead of print]15(15):
    Dynamic Cellular Regulation of Proteasome Translocation and Phase Transition.
    Conner Butcher, Jianhui Li.
      Proteasome dysfunction has been implicated in the pathogenesis of many human diseases, and the proteasome system has emerged as a major therapeutic target for cancer treatment. Besides proteasome activity, the dynamics of proteasome localization provide another tier of mechanism for regulating proteasome function and cellular protein homeostasis. While proteasomes are highly enriched in the nucleus, they can dynamically reshuffle across cellular compartments in response to metabolic cues. This localization shift is coupled with autophagy as a major mechanism for cell survival under stress. Under certain metabolic stress, proteasomes can reorganize into distinct membraneless condensates, termed proteasome condensates. While the current understanding of the biological significance of proteasome condensates is limited, they may provide proteolytic control to meet metabolic needs under stress. This review highlights how distinct metabolic cues, such as carbon starvation, amino acid deficiency, and senescence, regulate divergent proteasome fates including proteasome subcellular translocation, autophagic degradation of proteasomes, and proteasome condensate formation. A better understanding of proteasome regulation in a spatiotemporal manner will help identify new therapeutic targets for diseases affected by proteasome dysfunction.
    Keywords:  autophagy; liquid–liquid phase separation; metabolic stress; nucleocytoplasmic translocation; proteasome condensates; proteasome translocation dynamics; proteostasis; ubiquitin–proteasome system
    DOI:  https://doi.org/10.3390/biology15151253
  18. Genes Dev. 2026 Aug 11.
    rRNA 5'ETS processing contributes to nucleolar organization and nuclear architecture.
    Maria Saraí Mendoza-Figueroa, Ellen Lavorando, Yulia Gonskikh, Heidi Elashal, Anthony Yulin Chen, Dawn Carone, Kathy Fange Liu.
      The eukaryotic nucleolus is a highly organized, multilayered structure essential for ribosomal RNA (rRNA) processing and ribosome assembly. While rRNA transcription is known to drive nucleolar assembly, the contribution of downstream processing steps to nucleolar organization remains less well defined. Here, we show that disruption of endonucleolytic cleavage of the 5' external transcribed spacer (5'ETS), a key early step mediated by the SSU processome, leads to pronounced changes in nucleolar structure and organization. These altered nucleoli display reduced dynamic exchange behavior consistent with altered material properties and exhibit changes in the NPM1-associated nucleolar interactome. In parallel, we observe redistribution of heterochromatin markers, indicating broader effects on nuclear organization. Together, our findings support a model in which progression of pre-rRNA processing contributes to maintaining nucleolar compartmentalization and links early steps of ribosome biogenesis to nuclear organization. The nucleolus is a defining feature of eukaryotic cells, yet the principles that maintain its multilayered organization remain incompletely understood. While rRNA transcription is known to initiate nucleolar assembly, we show that a specific downstream processing step, the cleavage of the 5' external transcribed spacer (5'ETS), plays a key role in maintaining nucleolar organization. By functionally uncoupling rRNA transcription from processing, we demonstrate that defects in 5'ETS maturation are associated with alteration of the NPM1-associated interactome and changes in nucleolar dynamics. These findings support a model in which the progression of rRNA processing contributes to the material organization of the nucleolus, linking enzymatic steps in ribosome biogenesis to nuclear architecture.
    Keywords:  biogenesis; enzymes; nucleolus; rRNA; ribosome
    DOI:  https://doi.org/10.1101/gad.353963.126
  19. J Mol Biol. 2026 Aug 04. pii: S0022-2836(26)00341-4. [Epub ahead of print] 169968
    Genome-Wide Impact of Human DBR1 Depletion on RNA Processing Networks Reveal a Connection Between Pre-mRNA Splicing, mRNA Surveillance and Stress Granule Dynamics.
    Tiffany Barwell, Caleb M Embree, Robert Reid, Guramrit Singh, Kausik Chakrabarti.
      The RNA lariat debranching enzyme DBR1 is essential for intron turnover and RNA metabolism, yet its broader impact on transcriptome regulation remains incompletely defined. To elucidate the consequences of DBR1 depletion, we performed transcriptome-wide RNA sequencing of DBR1-knockdown and wild-type HEK293 cells. Differential expression analysis revealed widespread perturbations in pathways linked to RNA splicing, mRNA surveillance, translational control, and stress-granule biology. Many of the most significantly altered transcripts encode splicing factors and RNA quality-control components, underscoring DBR1's influence on post-transcriptional regulation. Alternative splicing analysis showed changes across multiple event types, with exon skipping accounting for >50% of events, followed by mutually exclusive exons, alternative 5' and 3' splice sites, and retained introns, indicating that DBR1 depletion induces pervasive splicing defects. Direct spliceosome inhibition using isoginkgetin (blocks tri-snRNP recruitment) and pladienolide B (targets SF3B1) reproduced the DBR1-KD mis-splicing patterns of cell signaling genes and factors involved in RNA metabolism, supporting a functional link between DBR1 activity and alternative splicing. Notably, DBR1 knockdown revealed a subset of transcripts that are both NMD-sensitive and enriched within stress granules. Consistent with this observation, G3BP1 immunopurification and confocal microscopy further support a role for DBR1 and UPF1 in stress-granule dynamics, suggesting that these factors may participate at distinct stages to influence mRNA fate under stress conditions. Together, these findings indicate that DBR1 functions beyond lariat RNA turnover as a common regulator of RNA processing, transcriptome stability, and stress granule homeostasis, revealing intricate crosstalk between RNA splicing and RNA quality control pathways in human cells.
    Keywords:  DBR1; RNA splicing; differential gene expression; mRNA surveillance; siRNA knockdown; stress granules; transcriptomic profiling
    DOI:  https://doi.org/10.1016/j.jmb.2026.169968
  20. Genetics. 2026 Aug 11. pii: iyag214. [Epub ahead of print]
    Inhibiting Ribosomal RNA Synthesis in C. elegans Protects Against Reductive Stress During de novo Fatty Acid Synthesis Deficiency.
    Jen F Rotti, Fasih Ahsan, Nicole L Stuhr, Sinclair Emans, Alexander Soukas, Armen Yerevanian.
      Reductive stress has remained underappreciated as a significant disrupter of redox homeostasis. Recent studies have begun to link the accumulation of NADH and NADPH to the development and progression of metabolic diseases such as cancer, cardiac disease, and diabetes. In this study we use the nematode Caenorhabditis elegans to examine the phenomenon of catastrophic reductive-death caused by combined biguanide treatment and fasn-1 deficiency. This process of synergistic biguanide-induced reductive stress correlates with the activation of hypodermal stress response genes and aberrant alternations in the nucleolar morphology of hypodermal cells. Interestingly, we find that loss-of-function and RNAi-based knockdown of the catalytic RNA exosome subunit crn-3 significantly protects against reductive death. RNAi knockdown of multiple other genes involved in rRNA synthesis recapitulate this phenotype. We postulate that this reversal of reductive death can be attributed to impaired ribosomal RNA biogenesis that promotes tolerance of accumulated reducing equivalents NADPH and NADH while also preventing the accumulation of GSH by potentially activating downstream signaling pathways. Notably, we identify a downstream nuclear RNAi pathway that is activated by phenformin in a fasn-1 dependent manner and is also activated upon disruption of rRNA processing. Overall, we identify a novel mechanism by which pathologic states of reductive stress-related diseases could be ameliorated.
    Keywords:   C. elegans ; WormBase; biguanides; longevity; nucleolar stress; reductive stress; ribosomal RNA (rRNA)
    DOI:  https://doi.org/10.1093/genetics/iyag214
  21. Plants (Basel). 2026 Jul 25. pii: 2278. [Epub ahead of print]15(15):
    FERONIA Modulates Translational Buffering Capacity of Ribosome-Associated Gene Module in Salt-Stressed Tomato Roots.
    Junyu Bai, Yanfen Fan, Ruolin Yang, Jingquan Yu.
      Salt stress limits tomato productivity, yet how translational regulation contributes to root salt adaptation remains poorly understood. We integrated RNA-seq and ribosome profiling in wild-type (WT) and FERONIA (FER) mutant (fer) tomato roots under control and 150 mM NaCl conditions. In WT roots, the salt response was predominantly transcript-driven, but a 29-gene ribosome-associated module showed reduced RNA abundance alongside increased translational efficiency, indicating selective translational buffering. FER loss-of-function disrupted this balance, constitutively elevating ribosome occupancy of ribosome-associated genes while reducing basal expression of stress- and ion-transport-related genes; under salt treatment, fer also showed stronger ion-transport transcriptional responses but weaker translational efficiency responses of this module. WT salt stress further shifted ribosome allocation from the 5' untranslated region (UTR) toward the coding sequence (CDS), an effect attenuated in fer, alongside positive coupling between uORF and CDS translational efficiency. Feature modeling identified sequence and structural predictors of uORF translation, including weaker local RNA folding near the start codon and specific amino acid and stop codon preferences. Together, these results reveal FER-associated changes in ribosome-associated translational buffering during tomato root salt responses.
    Keywords:  FERONIA; ribosome profiling; salt stress; tomato roots; translational buffering; translational efficiency; translatome; upstream open reading frame
    DOI:  https://doi.org/10.3390/plants15152278
  22. Nucleic Acids Res. 2026 Aug 10. pii: gkag800. [Epub ahead of print]54(15):
    23S rRNA modifications stimulate catalytic activity and prevent the formation of alternative structures.
    Daniel S D Larsson, Aivar Liiv, Rya Ero, Jaanus Remme, Maria Selmer.
      Ribosomal RNA (rRNA) modifications cluster around the peptidyl transferase centre (PTC), the catalytic centre of the ribosome, yet their collective functional roles remain unclear. Here we analyse Escherichia coli ribosomes lacking 11 or 12 modifications near the PTC. Using kinetic assays, we show these hypo-modified ribosomes catalyse peptide bond formation at rates twofold to threefold lower than wild-type and exhibit reduced thermal stability. Cryo-electron microscopy of hypo-modified ribosomes reveals multiple alternative conformations of the PTC and exit tunnel regions, disrupting native stacking and hydrogen bonding critical for positioning of transfer RNA substrates. These findings indicate that rRNA modifications stabilize the native PTC structure, preventing formation of alternative, nonfunctional conformations and thereby enhancing catalytic efficiency. Our study provides insight into how rRNA modifications fine-tune ribosome function by maintaining structural integrity essential for efficient translation.
    DOI:  https://doi.org/10.1093/nar/gkag800
  23. Mol Biol Cell. 2026 Aug 12. mbcE26040176
    In vivo clustering of oskar mRNA is driven by RNA concentration, RNA binding proteins, and an RNA palindrome.
    Ziqing Ye, Siran Tian, Ayse Ecer, Tatjana Trcek.
      mRNA organization into clusters is observed in many cellular contexts, yet the features that govern this process in vivo remain poorly understood. Using super-resolution microscopy, single-mRNA imaging, and genetic perturbations, we investigated how mRNA concentration, the double-stranded RNA-binding protein Staufen, and intermolecular base-pairing driven by an RNA palindrome influence clustering of oskar mRNA in Drosophila embryos. We find that these factors collectively optimize oskar clustering by promoting its dimerization and subsequent oligomerization. Both processes depend on all three factors, although oligomerization is much more sensitive to their perturbation, indicating that the driving force for oskar oligomerization is partially distinct from that governing dimerization. Moreover, oskar palindrome is a potent driver of heterotypic mRNA clustering, further supporting its in vivo role in mediating intermolecular base pairing. Finally, computational analyses identified a subset of candidate mRNAs in the early embryo that are predicted to harbor oskar-like palindromes. Among these, eIF3a mRNA emerged as a potential candidate whose clustering may likewise be driven by intermolecular base pairing. These preliminary observations raise the possibility that mRNA clustering driven by palindrome-mediated intermolecular base pairing may be more widespread than previously appreciated and may represent an important mechanism for controlling mRNA spatial organization during Drosophila development.
    DOI:  https://doi.org/10.1091/mbc.E26-04-0176
  24. Cell Signal. 2026 Aug 10. pii: S0898-6568(26)00471-7. [Epub ahead of print] 112813
    MYC-driven BYSL overexpression promotes hepatocellular carcinoma by suppressing nucleolar stress and inactivating the RPL5/RPL11-MDM2-p53 pathway.
    Heyuan Zhao, Huiying Liu, Xia Liu, Liangmei He, Shuping Jiang, Haijian Zhong, Vladimir L Katanaev, Yumei Li.
      BYSL gene encodes the bystin-like (BYSL) protein, a nucleolar protein involved in eukaryotic ribosome biogenesis and essential for 40S ribosomal subunit synthesis. Although BYSL upregulation has been implicated in hepatocellular carcinoma, its mechanistic contribution to tumor progression remains undefined. We observed that BYSL is consistently upregulated across multiple cancer types and is associated with adverse clinicopathological features and poor prognosis, with the strongest clinical relevance observed in hepatocellular carcinoma through the integrative transcriptomic and proteomic analyses. BYSL-knockout suppresses malignant phenotypes, including proliferation, migration, and invasion, and induced G1/S arrest and apoptosis. Mechanistically, loss of BYSL disrupts nucleolar homeostasis and reduces global protein synthesis, thereby activating the RPL5/RPL11-MDM2-p53 axis, leading to p53 stabilization and tumor suppression. Importantly, MYC directly bound to the BYSL promoter and transcriptionally activated its expression, whereas co-targeting BYSL and MYC produced more synergistic antitumor effects than either intervention alone. Collectively, our study reveals that BYSL acts as a pivotal downstream mediator of MYC-regulated ribosome biogenesis and promotes hepatocellular carcinoma progression. Our findings suggest that BYSL may represent a potential therapeutic target for hepatocellular carcinoma; nevertheless, additional in vivo preclinical studies are warranted to validate its translational prospects.
    Keywords:  BYSL; Hepatocellular carcinoma; MYC transcriptional target; RPL5/11-MDM2-P53 axis; Ribosome biogenesis
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112813
  25. Int J Mol Sci. 2026 Jul 24. pii: 6588. [Epub ahead of print]27(15):
    Differential Effects of PERK and IRE1α Silencing on Expression of Apoptosis and Autophagy Markers in T-Lymphoblastic Leukemia MOLT-3 Cells.
    Ekaterina Sergeevna Prokopenko, Tatyana Vladimirovna Sokolova, Olga Vladimirovna Nadei, Anastasia Dmitrievna Trubnikova, Natalia Ivanovna Agalakova.
      Cancer cells are able to survive under conditions of high endoplasmic reticulum (ER) stress by activating the adaptive unfolded protein response (UPR), which is closely linked with autophagy. On the other hand, excessive and prolonged ER stress leads to apoptosis. However, the relationships between different UPR branches and apoptosis or autophagy vary in cancer cells of different origins and depend on the extent and nature of the stress signal. This study was designed to establish the role of ER stress sensors protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1 (IRE1α) in apoptosis or autophagy signaling in T-lymphoblastic leukemia MOLT-3 cells via the RNA interference method. The cells were transfected with small interfering RNAs (si-PERK, si-IRE1α, or si-Cont) for 6 h and further cultured under normal conditions for 72 h to provide an insight into chronic effects of the gene silencing. The expression of apoptosis and autophagy effectors at the mRNA and protein levels was compared using RT-PCR and Western blot assays, respectively. Transfection of the cells with PERK siRNA led to a significant decrease in PERK protein and gene expression, and decreased phosphorylation of its downstream effector eukaryotic initiation factor 2α (eIF2α). PERK silencing was accompanied by activation of apoptosis-related genes and proteins-BCL2-associated X (Bax), caspase-3, C/EBP homologous protein (CHOP), while the levels of autophagy markers (Unc-51 like autophagy activating kinase 1 (ULK1), Beclin-1, and microtubule-associated proteins 1A/1B light chain 3 (LC3A/B)) remained stable. In contrast, treatment of the cells with si-IRE1α reduced the content of IRE1α, X-box-binding protein 1 (sXBP1), and glucose-regulated protein 78 (GRP78) proteins, but increased ERN1 gene expression. IRE1α RNA interference did not affect the levels of the pro-apoptotic marker Bax, but suppressed caspase-3, CHOP, c-Jun N-terminal kinase (JNK), and autophagy signaling molecules (ULK1, Beclin-1, LC3A/B) at both the transcriptional and translational levels. These results indicate that the PERK pathway is an important contributor to the survival of MOLT-3 cells under basal ER stress, while PERK depletion compromises the resistance of cells to UPR-mediated apoptosis. The IRE1α UPR branch is directly linked with autophagy-dependent signaling, although IRE1α knockdown exerted a more complicated influence on the cells, probably via activation of multiple pro-death and compensatory pro-survival regulatory mechanisms.
    Keywords:  IRE1α; PERK; RNA interference; T-lymphoblastic leukemia MOLT-3 cells; apoptosis; autophagy
    DOI:  https://doi.org/10.3390/ijms27156588
  26. Trends Mol Med. 2026 Aug 14. pii: S1471-4914(26)00175-9. [Epub ahead of print]
    RNA translational control in skeletal development, homeostasis, and disease.
    Denghao Huang, Siyuan Hu, Qiwen Li, Quan Yuan.
      Skeletal development, maintenance, and repair require precise control of protein production, yet mRNA levels often correlate poorly with protein abundance. Translation is the process through which mRNA is converted into protein, but its role in skeletal biology remains much less understood than that of transcriptional regulation. Recent advances in translatomics have begun to reveal how translational regulation contributes to skeletal development, homeostasis, and repair. Here, we summarize translational control across skeletal lineages, developmental stages, and disease settings. We also discuss emerging approaches for studying mRNA translation and potential therapeutic opportunities that target translational pathways. Understanding how translational regulation shapes skeletal health and disease will open new avenues for precise interventions for skeletal defects.
    Keywords:  RNA translation; bone development; bone diseases; protein synthesis
    DOI:  https://doi.org/10.1016/j.molmed.2026.07.005
  27. Int J Mol Sci. 2026 Aug 04. pii: 6992. [Epub ahead of print]27(15):
    Targeting IGF2BP3 in Cancer: From Molecular Structure and Biology to Early Drug Discovery.
    Elisa Uliassi, Maria Laura Bolognesi, Katia Scotlandi, Caterina Mancarella.
      RNA-binding proteins (RBPs) remain underexplored as small-molecule targets, although their dysregulation contributes to numerous human diseases, including cancer. RBPs are key regulators of post-transcriptional gene expression, controlling multiple stages of RNA metabolism. Among them, insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is an oncofetal RBP that is highly expressed during embryonic development, largely absent in adult tissues, and re-expressed in multiple malignancies. A growing body of evidence supports IGF2BP3 as a diagnostic and prognostic biomarker and a potent oncogenic driver across tumor types, underscoring its potential as a therapeutic target. However, the development of effective IGF2BP3-targeting compounds remains in its early stages. In this review, we first describe the structural organization of IGF2BP3, the molecular basis of RNA recognition, and the mechanisms underlying its dysregulation across human cancers. We then discuss emerging therapeutic approaches, including direct inhibition of IGF2BP3-RNA interactions and indirect strategies that rewire IGF2BP3 expression or activity through epigenetic, epitranscriptomic, and signaling pathways. By critically highlighting the opportunities and limitations of these approaches and their impact on cancer progression, we provide an integrated perspective combining structural biology, medicinal chemistry, and cancer biology to support the development of next-generation IGF2BP3-targeted therapies.
    Keywords:  BET modulators; IGF2BP3; IGF2BP–RNA small molecule inhibitors; RNA dynamics; RNA-binding proteins; epitranscriptomics; natural compounds; rigosertib; trabectedin
    DOI:  https://doi.org/10.3390/ijms27156992
  28. Nucleic Acids Res. 2026 Aug 10. pii: gkag792. [Epub ahead of print]54(15):
    Crystal structures of type T archaeal ribonuclease P Rpp30, Rpp30/Pop5, and L7Ae provide insights into a reduced RNase P.
    Clarence W Chan, Alfonso Mondragón.
      RNase P is primarily responsible for processing the 5' end of precursor transfer RNA (tRNA). Although there are protein-only RNase P enzymes, the most widely distributed RNase Ps form ribonucleoprotein complexes where the number of protein components varies across evolutionary domains. Ribonucleoprotein RNase P enzymes universally contain a single RNA component. Pyrobaculum, a genus of archaeal hyperthermophiles, possess a minimal RNase P composed of a small RNA subunit and four small proteins. To understand the structure of this minimal RNase P, high-resolution structures of three protein components from Pyrobaculum were determined. These structures reveal that the proteins closely resemble their larger homologs, although entire secondary structure elements are absent in some instances. Modeling of the RNA subunit suggests a structure closely related to the RNA components of other RNase P complexes, but with a minimal S-domain containing only a single T-loop. The modeling further supports the formation of an RNase P complex that retains all the elements needed for tRNA recognition and processing. Finally, RNA composition analysis by size exclusion chromatography indicates that the L7Ae protein component may assist in the folding and structural stabilization of the RNA subunit.
    DOI:  https://doi.org/10.1093/nar/gkag792
  29. Int J Mol Sci. 2026 Jul 24. pii: 6587. [Epub ahead of print]27(15):
    Heat Shock Proteins and Exercise in Skeletal Muscle Insulin Resistance: Protective Mechanisms and Therapeutic Potential.
    Mariam A Othman, Joo Hyun Kim, Khaled Y Kamal, John M Lawler.
      Heat shock proteins (HSPs) are a family of conserved molecular chaperons present in both prokaryotic and eukaryotic species, playing a crucial role in maintaining cellular proteostasis and enhancing stress resilience. HSPs have a multitude of roles in regulating cell signaling transduction, antioxidant defenses, apoptosis, and protein folding, thereby contributing to overall cellular homeostasis. Insulin resistance is characterized by elevated oxidative stress, dysregulated pro-inflammatory signaling, and impaired cellular stress response, ultimately leading to deficient glucose uptake in skeletal muscle. Many studies have illustrated the benefits of exercise in improving insulin resistance and reducing the risk of metabolic disorders, such as type 2 diabetes. Habitual exercise and lifestyle modifications have been shown to activate heat shock response, enhancing HSP70 expression and promoting cellular adaptations that protect against metabolic dysfunction. However, the link between HSPs, particularly HSP70, and skeletal muscle insulin resistance remains complex and not fully elucidated. In this review, we discuss the mechanistic pathways by which HSP70 modulates insulin resistance, mitochondrial function, and inflammatory responses in skeletal muscle. Additionally, we discuss the protective effects of exercise-induced HSP70 expression and its potential as a therapeutic target for improving insulin sensitivity and metabolic health.
    Keywords:  exercise; heat shock proteins; insulin resistance; molecular pathways; skeletal muscles
    DOI:  https://doi.org/10.3390/ijms27156587
  30. FASEB Bioadv. 2026 Aug;8(8): e70135
    Exploring the BICC1 Interactome in HEK293T Cells: Insights Into RNA-Mediated Protein Networks and Biomolecular Condensates.
    Heloísa Monteiro do Amaral-Prado, Gabriela Alves Moreira, Cristiane Santos, Fernando Henrique Bosso, Felipe Eduardo Ciamponi, Guilherme Oliveira Barbosa, Mario Henrique Bengtson, Katlin Brauer Massirer.
      Bicaudal C Homolog 1 (BICC1) is a conserved RNA-binding protein that, in mammals, has been primarily associated with polycystic kidney disease and renal organogenesis. However, its role in other disease contexts, including cancer, remains poorly understood. In this study, we characterized the BICC1 interactome, with emphasis on its dependence on RNA and the sterile alpha motif (SAM) domain, to identify novel biological processes associated with BICC1 function. Protein complexes were purified from HEK293T cells by co-immunoprecipitation and analyzed by mass spectrometry. Notably, co-immunoprecipitations performed in the presence of RNA yielded a larger number of interacting proteins, with 31 of 71 proteins (~43%) uniquely identified under RNA-preserved conditions, highlighting the critical role of RNA in mediating BICC1 protein-protein interactions. Enriched proteins were predominantly associated with mRNA splicing, the PRMT5 methylosome complex, and membraneless organelles, such as biomolecular condensates. Consistent with these findings, immunofluorescence assays performed on stressed cells revealed the co-localization of BICC1 with stress granule markers. Moreover, BICC1 interactions with PRMT5, STK38, PARP1, and IGF2BP1 were confirmed by immunoblotting.
    Keywords:  PRMT5 methylosome; RNA‐binding proteins; membraneless organelles; splicing; stress granules
    DOI:  https://doi.org/10.1096/fba.2026-00035
  31. Mol Cell Biochem. 2026 Aug 10.
    Heat shock protein family D member 1 (HSPD1) modulates ribosome-related pathways and protein synthesis in lung adenocarcinoma.
    Keerakarn Somsuan, Artitaya Rongjumnong, Wararat Chiangjong, Jatuporn Ngoenkam, Atthapan Morchang, Papawarin Karamart, Jirawan Panachan, Patcharin Kaewboonruang, Wariya Mongkolwat, Somchai Chutipongtanate, Sutatip Pongcharoen, Wim Vanden Berghe, Siripat Aluksanasuwan.
      Lung adenocarcinoma (LUAD) is the most prevalent histological subtype of lung cancer. Heat shock protein family D member 1 (HSPD1 or HSP60), a multifunctional chaperone, has been implicated in promoting lung cancer progression by regulating tumor cell growth, cancer-associated fibroblast activation, and angiogenesis. Despite these roles, the molecular mechanisms underlying its oncogenic activity remain incompletely understood. In this study, we conducted a proteomic analysis and functional investigations on HSPD1-knockdown and control A549 cells. Knockdown of HSPD1 suppressed cell proliferation, disrupted cell-cycle progression, and had no significant effect on apoptosis. Additionally, HSPD1-knockdown cells exhibited reduced colony formation, wound closure, and invasion capabilities. Sequential Window Acquisition of All Theoretical fragment ions (SWATH)-targeted proteomics revealed 21 significantly altered proteins, primarily involved in ribosome-related functions and associated with overall survival in LUAD patients. Reduced levels of ribosomal proteins and translational capacity were further examined by Western blot and protein synthesis assays. A decrease in ribosome abundance was confirmed by immunofluorescence staining of ribosomal protein S3 (RPS3) and by direct visualization under transmission electron microscopy. Quantitative real-time PCR demonstrated downregulation of MTOR in HSPD1-knockdown cells. Moreover, HSPD1 knockdown sensitized cells to homoharringtonine, a chemotherapeutic drug targeting ribosomal activity. These effects on cell proliferation, ribosomal protein levels, and drug sensitivity were validated in an independent LUAD cell line, H1975. Collectively, these findings indicate that HSPD1 acts as an oncogenic driver in LUAD by modulating ribosome-related pathways and protein synthesis.
    Keywords:  HSP60; HSPD1; LUAD; Quantitative proteomics; Ribosome; Translational regulation; shRNA knockdown
    DOI:  https://doi.org/10.1007/s11010-026-05693-w
  32. Int Urol Nephrol. 2026 Aug 12.
    Epigenetic regulation of tubular epithelial cell dysfunction in diabetic kidney disease.
    Hanxue Li, Mengmeng Ma, Qiuyue Ren, Zhihai Feng.
      Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease. Recent studies have shown that tubular epithelial cells (TECs) are not merely passive targets of injury, but rather key drivers throughout the initiation and progression of DKD. Under persistent hyperglycemia and metabolic stress, TECs undergo metabolic reprogramming, continuous inflammatory activation, and aberrant cell fate transitions, which ultimately promote the progression of tubulointerstitial fibrosis. Emerging studies further suggest that epigenetic regulation plays a central role in maintaining these pathological alterations and may represent a key molecular basis for the "metabolic memory" of DKD. In this review, we systematically summarize the epigenetic mechanisms associated with TEC dysfunction in DKD, including DNA methylation, histone modifications, non-coding RNAs, and RNA modifications. In addition, we comprehensively discuss recent therapeutic strategies targeting epigenetic abnormalities and discuss their translational potential and current challenges. In general, epigenetic regulation provides a new conceptual framework for understanding TEC dysfunction in DKD and provides a potential direction for the development of precision therapeutic strategies.
    Keywords:  Diabetic kidney disease; Epigenetic regulation; Metabolic memory; Renal tubular Epithelial cell; Treatment
    DOI:  https://doi.org/10.1007/s11255-026-05334-7
  33. Nucleic Acids Res. 2026 Aug 10. pii: gkag778. [Epub ahead of print]54(15):
    Structural characterization of ribosome recycling and fusidic acid inhibition in Staphylococcus aureus.
    Adrián González-López, Maria Selmer.
      During bacterial ribosome recycling, 70S ribosomes are split into subunits by ribosome recycling factor (RRF) and elongation factor G (EF-G). The antibiotic fusidic acid (FA) inhibits elongation and ribosome recycling by locking EF-G to the ribosome. Yet, no functional ribosome recycling FA complex has been successfully captured. Here, we used single-particle cryo-electron microscopy to resolve multiple FA-stalled intermediates of Staphylococcus aureus ribosomes, including a 70S intermediate with RRF and EF-G in a previously unobserved conformation. Our structures reveal how RRF and EF-G jointly disrupt inter-subunit bridges, promote back-rotation of the small subunit, and move the transfer RNA toward the E site to facilitate ribosome splitting. We further show that FA predominantly inhibits recycling by trapping EF-G on the post-termination complex in the absence of RRF, preventing formation of the active RRF•EF-G complex. These insights advance understanding of the molecular mechanism of bacterial ribosome recycling and the mode of action of FA as an antibiotic.
    DOI:  https://doi.org/10.1093/nar/gkag778
  34. Cell Rep. 2026 Aug 14. pii: S2211-1247(26)00910-1. [Epub ahead of print]45(8): 117832
    ATF4 activates a transcriptional program that chronically suppresses mTOR activity and promotes neurodegeneration in Parkinson disease models.
    Matthew D Demmings, Erica A Kane, Elizabeth C Tennyson, Kate Hurley, Joy Zhao, Nicholas A Cruickshanks, Victoria Ciz, Jordan M Krupa, Stephen H Pasternak, Sean P Cregan.
      The integrated stress response (ISR) enables cells to adapt to diverse cellular stresses, but during chronic or unresolved stress it becomes maladaptive and is implicated in neurodegenerative diseases, including Parkinson disease (PD). The mechanisms underlying maladaptive ISR-driven neurodegeneration, however, remain poorly defined. Here, we find a critical pathway by which chronic ISR activation promotes neurodegeneration in neurotoxin and α synucleinopathy models of PD in vitro and in vivo. We show that sustained activation of ATF4, the central ISR transcription factor, induces the coordinated transcriptional upregulation of SESN2, DDIT4, and Trib3, which cooperate to suppress both mTORC1 and mTORC2 activity. This ATF4-dependent inhibition of mTOR signaling promotes dopaminergic neuron death by facilitating activation of the pro apoptotic BCL 2 family protein PUMA. Together, these findings define a maladaptive ISR/ATF4-mTOR pathway with potential therapeutic relevance for neurodegenerative disorders characterized by chronic ISR activation.
    Keywords:  ATF4; CP: molecular biology; CP: neuroscience; ISR; PUMA; dopaminergic neurons; integrated stress response; mTOR; neurodegeneration; α-synuclein
    DOI:  https://doi.org/10.1016/j.celrep.2026.117832
  35. Cell Rep. 2026 Aug 12. pii: S2211-1247(26)00909-5. [Epub ahead of print]45(8): 117831
    Quantitative single-base m6A profiling reveals dynamic reprogramming, evolutionary conservation and transcriptional regulation in bacteria.
    Youyue Li, Letong Xu, Na Liu, Xiangkai You, Jiadai Huang, Yue Sun, Beifang Lu, Chunyan Yao, Xin Deng.
      N6-methyladenosine (m6A) is a widespread RNA modification that regulates RNA metabolism in eukaryotes, but its distribution and function in bacteria remain poorly defined. Here, we apply GLORI sequencing to generate single-base resolution transcriptome-wide m6A maps in seven bacterial species. We identify 2,845 m6A sites during exponential growth and find extensive condition-dependent methylation dynamics in three strains. In Pseudomonas syringae, m6A remodeling is associated with virulence-related pathways. Comparative analyses reveal 455 conserved m6A site pairs enriched in genes required for growth, energy metabolism, and transmembrane transport. Integrating methylation, transcript abundance, and RNA stability analyses shows that m6A is associated with reduced mRNA abundance and increased RNA stability. We further identify the rRNA methyltransferases RlmF and RlmJ as bacterial mRNA m6A writers. Together, these findings provide a quantitative atlas of bacterial m6A and establish a foundation for understanding its regulatory and evolutionary roles.
    Keywords:  CP: Microbiology; N(6)-methyladenosine; RNA methylation; bacteria; bacterial epitranscriptomics; epigenetic; m(6)A; single-base resolution
    DOI:  https://doi.org/10.1016/j.celrep.2026.117831
  36. Naunyn Schmiedebergs Arch Pharmacol. 2026 Aug 11.
    The role of m6A RNA methylation in skeletal muscle pathophysiology and its targeted therapeutic prospects.
    Jie Wang, Haiyan Jiang, Jiacheng Sun, Hualin Sun, Lei Qi.
      N6-methyladenosine (m6A) is the most abundant internal epitranscriptomic modification in eukaryotic mRNA. It dynamically regulates RNA splicing, transport, stability, and translation efficiency through the "Writers-Erasers-Readers" system, thereby playing a broad role in gene expression regulation. Skeletal muscle, a key metabolic and locomotor organ, undergoes precise m6A-mediated regulation during development, regeneration, homeostasis, and aging. In this review, we systematically summarize the composition and function of the m6A modification system, with a focus on its critical roles in skeletal muscle physiology, including satellite cell fate determination, myofiber differentiation and fusion, and energy homeostasis. Furthermore, we dissect the molecular mechanisms by which m6A network dysregulation contributes to skeletal muscle diseases such as sarcopenia, muscular dystrophy, muscle atrophy, metabolic myopathies, and fibrosis. The therapeutic potential of small-molecule drugs and intervention strategies targeting the m6A pathway is also discussed. This work provides a new epitranscriptomic perspective for the precise diagnosis and targeted therapy of skeletal muscle diseases.
    Keywords:  Epitranscriptomic regulation; M6A RNA methylation; Satellite cells; Skeletal muscle; Targeted therapy
    DOI:  https://doi.org/10.1007/s00210-026-05802-y
  37. Methods Mol Biol. 2026 ;3069 127-133
    Multicolor Live-Cell mRNA Imaging Using RNA-Regulated Destabilization Domains.
    Tien G Pham, Omoyemi Ajayi, Jiahui Wu.
      mRNA molecules are critical for relaying genetic information from the genome into functional proteins for maintaining cellular function. Real-time imaging of mRNA in living cells reveals the spatiotemporal dynamics of RNA and offers insights into RNA-mediated regulation of gene expression and cellular function. Here, we describe a method of using RNA-regulated destabilization domains to simultaneously image multiple mRNAs in living cells. In this method, three mRNAs of interest are engineered to contain three distinct RNA imaging tags. Each tag specifically binds to and stabilizes its cognate RNA-regulated destabilization domain fused to fluorescent proteins, resulting in selective activation of fluorescence on the corresponding mRNA for imaging.
    Keywords:  Fluorescence microscopy; Fluorogenic proteins; Live-cell RNA imaging; Mammalian cells; RNA imaging tags; RNA-regulated destabilization domains
    DOI:  https://doi.org/10.1007/978-1-0716-5508-5_8
  38. Front Immunol. 2026 ;17 1890839
    Photothermal therapy triggering organelle stress and metabolic reprogramming to potentiate antitumor immunity.
    Lin Chen, Hanyu Zhang, Yunlong Wang, Xianhu Feng, Yi Hou, Qiang Su.
      Metabolic reprogramming is a hallmark of malignant tumors, providing tumor cells with energy and promoting immune escape through changes in glucose, lipid, and amino acid metabolism. Photothermal therapy (PTT) not only eliminates tumor cells through localized hyperthermia but also disrupts metabolic networks. However, the mechanisms by which PTT-induced metabolic perturbation engages antitumor immunity remain a considerable challenge. This review proposes that PTT interferes with tumor metabolism through organelle stress and synergizes with exogenous drugs to enhance metabolic perturbation, thereby eliciting a potent antitumor immune response. We first detail how hyperthermia and ROS induced by PTT damage organelles, leading to organelle stress, including mitochondrial depolarization, endoplasmic reticulum (ER) proteotoxicity, cytosolic enzyme denaturation, and nucleolar stress. Critically, stressed organelles release immunogenic signals, activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway to trigger innate immune recognition, and regulating the functions of CD8+ T cells and macrophages through metabolites in the tumor microenvironment (TME). We also discuss how tumor cells activate adaptive responses, such as heat shock protein (HSP) upregulation and metabolic switching, to resist sublethal thermal stress, and evaluate synergistic strategies designed to amplify organelle stress and overcome thermotolerance. Finally, we focus on the latest advancements in overcoming tumor heterogeneity and advancing the clinical translation of targeted organelle PTT nanoplatforms. It is expected to elucidate the mechanism by which organelle stress in PTT causes metabolic perturbation, the tumor adaptive response, and its impact on tumor immunity, providing innovative ideas and references for the development of metabolic and tumor combined treatment strategies based on PTT.
    Keywords:  immunometabolism; metabolic reprogramming; organelle stress; photothermal therapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1890839
  39. Nucleic Acids Res. 2026 Aug 10. pii: gkag799. [Epub ahead of print]54(15):
    Cross-species R-DeeP profiling reveals a conserved core of RNA-dependent proteins in yeast.
    Nadine Bianca Wäber, Johanna Franziska Seidler, Fabienne Thelen, Palina Kot, Silke Schreiner, Thomas Timm, Günter Lochnit, Katja Sträßer, Cornelia Kilchert.
      Delineating the constituents and structural composition of RNA-associated protein complexes is essential to mapping the molecular machinery driving RNA metabolism and its impact on cellular function. Here, we present a comprehensive dataset of RNA-dependent proteins and complexes in the phylogenetically distant yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe. Using R-DeeP-a density gradient-based method that uses quantitative mass spectrometry to profile protein sedimentation in the presence and absence of RNA-we introduce an RNA dependence index (RDI) as a descriptive framework for RNA dependence, enabling the robust comparative analysis of RNA dependence across proteins in both species and relative to existing data from their human counterparts. This identifies a conserved core of RNA-dependent proteins shared across both yeasts, alongside distinct, organism-specific adaptations in complex behaviour. The data further support the analysis of co-sedimentation behaviour of protein complexes with known RNA-directed functions. For instance, we find that the five subunits of the S. cerevisiae THO complex only co-sediment in the absence of RNA, pointing to an underappreciated structural modularity of the well-characterized pentameric complex. The two datasets, available at https://yeast-r-deep.computational.bio/, provide a resource for hypothesis-driven research in RNA biology and establish R-DeeP as a broadly applicable tool for comparative analysis of RNA-protein interactions.
    DOI:  https://doi.org/10.1093/nar/gkag799
  40. EMBO J. 2026 Aug 12.
    Principles of ribosome-associated protein quality control during the synthesis of CFTR.
    Tom Joshua Oldfield, Raquel Gonçalves Torres, Romy Enrica Baier, Robin Renn, Débora Broch Trentini.
      Prolonged translational arrests caused by defective mRNAs activate the ribosome-associated protein quality control (RQC) pathway, which marks harmful incomplete proteins for degradation. Multipass transmembrane proteins have increased propensity to be targeted by the RQC, raising the question of whether problems in transmembrane domain insertion and assembly can also cause RQC-eliciting translational arrests. Here, we investigated RQC-mediated quality control of CFTR, a large transmembrane protein mutated in cystic fibrosis. Reporter assays showed that although a fraction of nascent CFTR expressed in HEK293 cells arrested during translation and activated the RQC, multiple interventions compromising CFTR folding and membrane insertion did not exacerbate this response. CFTR translation abortion was also largely unaffected by regulators of translation kinetics such as codon usage, the ribosome collision sensor GCN1, and the SRP ER targeting complex. We propose that the RQC can be triggered by the inherent difficulties in synthesizing transmembrane segments, resulting from their inappropriate interaction with the protein synthesis machinery. Our study uncovers and characterizes a novel physiological role for the RQC in dealing with elongation-arrested transmembrane proteins.
    DOI:  https://doi.org/10.1038/s44318-026-00883-0
  41. Int J Mol Sci. 2026 Aug 02. pii: 6937. [Epub ahead of print]27(15):
    Transfer RNA Modifications in the Immune System Participate in Disease Pathogenesis.
    Xinke Ma, Hejia Gu, Yi Zhang, Hanru Jia, Peiying Li, Yingjia Wang, Jiahui Wu, Aiwei Wu, Jing Wu.
      The human immune system executes immune defense against foreign antigens, immune surveillance against mutant cells, and immune homeostasis to maintain bodily physiological equilibrium. Transfer RNA (tRNA) is an important part of gene expression regulation. Recent studies have found that aberrant tRNA modifications can disturb the function of the immune system by altering translation efficiency, including regulating immune recognition and signal transduction, as well as influencing apoptosis and autophagy. tRNA modifications are also closely related to the development and occurrence of immune-related disorders such as infections, tumors, and autoimmune diseases. By integrating current research on immune-related tRNA modifications, this review systematically summarizes the mechanisms of tRNA modifications involved in three major immune functions and their relationship with related diseases, encompassing the direct regulation of immune cells and the indirect immune effects mediated through tissue or tumor cells. In addition, some tRNA modifications can also modulate immune responses by affecting tRNA cleavage and the consequent generation of tRNA-derived small RNAs (tsRNAs). Accordingly, this review outlines promising intervention targets and unresolved research bottlenecks, facilitating follow-up investigations into tRNA modification-dependent immune regulation and translational therapeutic research.
    Keywords:  immune defense; immune homeostasis; immune surveillance; immune-related diseases; intervention; tRNA modification
    DOI:  https://doi.org/10.3390/ijms27156937
  42. J Vis Exp. 2026 Jul 24.
    Stabilizing Protein and Protein-RNA Condensates in Low-Melting Agarose Hydrogels for Quantitative Biophysical Measurements.
    Nina C Kathe, Leonidas Emmanouilidis, Mihajlo Novakovic, Frédéric H-T Allain.
      Biomolecular condensates formed by liquid-liquid phase separation are increasingly recognized as fundamental organizational units of the cell, with roles ranging from RNA processing to stress granule assembly. In vitro reconstitution of such condensates using purified proteins and RNA provides model systems, yet liquid droplets coarsen, sediment, and spread on surfaces over time, introducing significant variability into quantitative measurements over experimental timeframes. Embedding these condensates within a sparse, optically transparent, and chemically inert hydrogel-here prepared from low-melting agarose (LMA) at 0.3-1.0% w/v-stabilizes droplets in three dimensions, enabling the use of methodologies with longer measurement times or experimental setups with repeated measurements. This paper presents a detailed, step-by-step protocol for LMA stock preparation, droplet formation, and embedding, and provides examples of specific downstream biophysical readouts. We also show that specific droplet properties, such as molecular diffusion, are preserved after LMA embedding in the representative systems tested. Since the method is compatible with confocal, widefield, or super-resolution microscopy, fluorescence recovery after photobleaching, or nuclear magnetic resonance spectroscopy, among others, it can support quantitative characterization of biomolecular condensates relevant in health and disease.
    DOI:  https://doi.org/10.3791/72146
  43. Int J Mol Sci. 2026 Aug 01. pii: 6886. [Epub ahead of print]27(15):
    Adaptation of the Transcriptome and miRNAome in Response to Hepatocellular Hypoxia.
    Jenica H Kakadia, Cristiana Iosef, Ilka U Heinemann, Victor K M Han.
      Inadequate supply of oxygen causing hypoxic cellular stress drives metabolic reprograming across diverse physiological conditions, including cancer. The activation of hypoxia-inducible factors (HIFs) to facilitate adaptation to low oxygen environments is well-characterized; however, post-transcriptional regulation by microRNAs (miRNAs) is poorly understood. Here, we investigated the mRNA and miRNA response in hypoxia-mediating reduced growth and cellular metabolism. Next-generation sequencing revealed the impact of hypoxia in cultured human hepatocellular carcinoma cells and identified over 400 mRNAs and 140 miRNAs that were differentially expressed. Hypoxia upregulated mRNA transcripts associated with glycolysis, DNA replication and the PI3K (phosphoinositide 3-kinase)-Akt pathway, which promote anaerobic metabolism for energy production, decreased cell proliferation and genomic instability, respectively. Upregulated miRNAs included miR-197-3p and miR-766-3p, targeting genes involved in lipid biosynthesis and metabolism. Downregulated miRNAs included miR-33a-5p and miR-15a-5p, targeting genes involved in glycolysis and lactate metabolism. Notably, miR-6834 emerged as a potential regulator of mechanistic target of rapamycin (mTOR) signaling and insulin-like growth factor binding protein-1 (IGFBP-1) signaling; miR-6834 overexpression altered 4E-BP1 phosphorylation levels and IGFBP-1 secretion. These findings provide critical insights into miRNA-mRNA regulation of metabolic adaptation and highlight miRNAs as potential targets for interventions with relevance to tumor biology and other hypoxia-associated conditions.
    Keywords:  cell proliferation; glycolysis; hypoxia; microRNAs
    DOI:  https://doi.org/10.3390/ijms27156886
  44. Adv Sci (Weinh). 2026 Aug 13. e77155
    BOULE is Essential for the Dynamic Disassembly of Heat Shock Granules in Male Germ Cells.
    Xin Li, Nana Zhang, Zexin Bian, Baobao Geng, Liyun Cao, Peipei Liu, Zengming Li, Yan Zhao, Jun Tan.
      Heat shock triggers stress granule (SG) formation, yet their dynamics in mammalian germ cells remain unclear. Through systematic analysis, we uncovered distinct heat shock granule (HSG) composition and stage-specific assembly/disassembly in the mouse testis. Ribosome profiling revealed that germ cells selectively sustain translation of spermatogenic genes during heat shock. We identified that the germ cell-specific RNA-binding protein BOULE is essential for HSG clearance. BOULE deficiency under heat shock impairs HSG disassembly, with increased germ cell apoptosis and a disrupted ubiquitinome. Mechanistically, BOULE orchestrates HSG clearance through a two-pronged mechanism. It post-transcriptionally maintains the expression of the disassembly factors G3BP1 and FAF2. Additionally, BOULE promotes heat-shock-induced ubiquitination of G3BP1 by regulating the E3 ligase TRIM27, thereby recruiting the VCP/FAF2 complex. Our findings establish BOULE as a key regulator of proteostasis that coordinates HSG disassembly in germ cells, providing mechanistic insight into heat shock-induced germ cell damage that may contribute to male infertility.
    Keywords:  BOULE; G3BP1; germ cell; heat shock; stress granule
    DOI:  https://doi.org/10.1002/advs.77155
  45. Protein Sci. 2026 Sep;35(9): e70763
    Adaptation of OXPHOS biogenesis to cellular requirements.
    Sven Dennerlein, Peter Rehling.
      Metabolic cues regulate the formation of the mitochondrial OXPHOS machinery. These regulatory processes are tightly linked to mitochondrial translation, proteolytic degradation of unassembled subunits, and the formation of supercomplexes, creating checkpoints at which nutrient availability, oxygen tension, and signaling pathways remodel OXPHOS content and activity. In particular, the cytochrome c oxidase (COX) assembly pathway is regulated at multiple steps of its biogenesis in response to cellular demands. COX consists of mitochondrially encoded catalytic core subunits and nuclear-encoded accessory subunits whose coordinated expression, cofactor insertion, and incorporation into the COX enzyme result in optimized electron transport capacity. Consequently, COX assembly depends on numerous dedicated factors and protein isoforms, many of which are expressed in a tissue-specific manner. Through these metabolically regulated processes, cells tune oxidative phosphorylation efficiency, limit reactive oxygen species production, and support context-specific metabolic programs in development, adaptation, and disease.
    Keywords:  Cytochrome c Oxidase; OXPHOS; mitochondria
    DOI:  https://doi.org/10.1002/pro.70763
  46. Front Immunol. 2026 ;17 1878552
    Targeting the unfolded protein response in cancer: mechanisms, small-molecule inhibitors, and translational challenges.
    Meizhen Lin, Zhijie Li.
      Endoplasmic reticulum (ER) stress, triggered by the accumulation of misfolded proteins, activates the unfolded protein response (UPR) to restore protein homeostasis. Dysregulated ER stress responses have emerged as critical modulators of cancer progression and immune escape, influencing the initiation, development and maintenance of antitumor immunity. The UPR is mediated by three principal sensors-PERK, IRE1α, and ATF6-each operating at distinct regulatory levels to coordinate translational reprogramming, RNA processing, and transcriptional reprogramming. Through these mechanisms, ER stress promotes malignant progression, tumor growth, and metastasis, while excessive activation can instead trigger cell death. Given this context-dependent duality, pharmacological targeting of the UPR has emerged as a promising anticancer strategy. For instance, IRE1α inhibitors block XBP1 splicing and RIDD-mediated immune escape, PERK inhibitors and ISR modulators reverse chemoresistance, ATF6-targeted strategies modulate ATF6-dependent tumor growth and treatment responses, and chemical chaperones exhibit both cytoprotective and antitumor effects depending on tumor context. This review integrates recent mechanistic insights into UPR-driven tumor progression, including pathway crosstalk, immune regulation, and immunotherapy resistance, with advances in small-molecule inhibitors, while critically evaluating their therapeutic potential and translational challenges in cancer treatment.
    Keywords:  ATF6; IRE1α; PERK; cancer therapy; chemical chaperones; unfolded protein response
    DOI:  https://doi.org/10.3389/fimmu.2026.1878552
  47. Oncogene. 2026 Aug 10.
    CSTF2-mediated 3'UTR shortening drives oncogenic activation of GPC3 in hepatocellular carcinoma.
    Soyoung Jeon, Eunbi Shin, Jin Woong Ha, Min Jeong Na, Sang Yean Kim, Suk Woo Nam.
      Alternative polyadenylation (APA) generates mRNA isoforms with distinct 3' untranslated regions (3'UTRs), thereby influencing transcript stability and translation. In cancer, 3'UTR shortening can activate oncogenes by escaping microRNA (miRNA)-mediated repression, but its role in hepatocellular carcinoma (HCC) remains poorly defined. Here, we profiled mRNA length alterations in multistage human HCC transcriptome datasets and investigated their functional consequences. Approximately 77% of mRNAs with altered length exhibited 3'UTR shortening. Glypican-3 (GPC3) was the most prominently upregulated shortened transcript, and high GPC3 expression was associated with poor prognosis in HCC. GPC3 knockdown reduced proliferation and induced apoptosis, whereas GPC3 overexpression promoted cell growth. Among APA regulators, Cleavage Stimulation Factor 2 (CSTF2) was upregulated in HCC, correlated positively with GPC3 expression, and predicted adverse clinical outcomes. Modulation of CSTF2 expression altered GPC3 3'UTR length, with CSTF2 overexpression promoting GPC3 3'UTR shortening, increasing GPC3 protein expression, enhancing proliferation, and suppressing apoptosis. Further analysis revealed that GPC3 3'UTR shortening removed binding sites for miR-96-5p and miR-140-5p, relieving miRNA-mediated translational repression. These findings identify CSTF2-driven APA as a mechanism of oncogenic GPC3 activation in HCC and suggest the CSTF2-GPC3 axis as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41388-026-03937-z
  48. J Extracell Vesicles. 2026 Aug;15(8): e70339
    Tumour-Derived Extracellular Vesicles Containing dsRNA Induce Degradation of Ribosomal Protein mRNA in Platelets.
    Gaoge Sun, Yuhuan Tao, Zihan Liu, Kaixiang Zhang, Shuai Zuo, Shanwen Chen, Shufang Ning, Tianyi Zhang, Pengyuan Wang, Ying Zhang, Zhi John Lu, Hang Hubert Yin.
      Extracellular vesicles (EVs) mediate intercellular communication within the tumour microenvironment by carrying cargoes from paracrine parent cells. EVs have attracted great research interest for their ability to carry nucleic acids into recipient cells and modulate cellular functions. However, previous studies have largely focused on RNA sequence information rather than RNA structure features. Here, we observed that EVs derived from colorectal cancer cells are enriched with endogenous double‑stranded RNA (dsRNA), a danger‑associated molecular pattern (DAMP) that leads to the activation of dsRNA‑sensing pathways in recipient cells. Crucially, we investigated the specific crosstalk between tumour-derived EVs and circulating platelets. As anucleate cells, platelets are uniquely suited models for isolating the effects of exogenous nucleic acids. Our analysis reveals that endogenous dsRNA from tumour EVs activates the platelet OAS-RNASEL innate immune ribonuclease cascade and the RNASEL/ABCE1/PELO axis, resulting in the decay of ribosomal protein mRNAs. This study, spanning from clinical observation to mechanistic validation, uncovers a novel pathway of tumour-platelet communication. We identify EV-enriched endogenous dsRNA as a functional mediator that enables tumour cells to directly reprogram platelet transcriptomes, revealing a new dimension of tumour-immune modulation.
    Keywords:  double‐stranded RNA; extracellular vesicles; platelets; ribosomal protein mrna
    DOI:  https://doi.org/10.1002/jev2.70339
  49. Biology (Basel). 2026 Jul 23. pii: 1230. [Epub ahead of print]15(15):
    Pre-Existing Heterogeneity Predicts Rare Proteostasis-Stress Programs Across Diverse Perturbations.
    Zongnan Lyu, Chunxue Shao, Renyu Yang, Qi Yu, Guang Yang, Ziheng Wang.
      Stress-associated transcriptional programs are common in single-cell perturbation data, but they are often treated as technical or experimental nuisance signals. Whether rare high-stress populations arise stochastically after perturbation or reflect outcomes associated with pre-existing cellular heterogeneity remains unclear. Herein, we build a cross-dataset stress-program prediction framework spanning 146,321 single cells and 926 perturbation-cell-line tasks. Untreated baseline heterogeneity, together with perturbation identity, predicted future rare integrated-stress burden across held-out cell-line-drug pairs (R2=0.742, Pearson r=0.862). Single-cell stress-program prediction generalized across leave-task-out, leave-cell-line-out and leave-perturbation-out splits; retained signal in leave-dataset-out evaluation; and collapsed to near-null performance under within-task label permutation. Independent validation datasets provided external support for the inferred stress axes: tunicamycin and thapsigargin activated unfolded protein response/integrated stress response (UPR/ISR) modules in bulk RNA sequencing (RNA-seq), thapsigargin expanded populations with high X-box binding protein 1 (XBP1) UPR or activating transcription factor 4 (ATF4) ISR activity in donor-paired single-cell data, and an independent protocol-stress dataset indicated heat shock/proteostasis structure beyond cell type and quality control (QC). The resulting resource summarizes perturbation responses as activator protein 1 (AP1) immediate, UPR/ATF4, heat shock, replication-coupled and low/mixed dominant stress-program patterns. These findings suggest that stress variation should not be viewed solely as a nuisance covariate but may represent a predictable and biologically structured dimension of perturbation response space.
    Keywords:  baseline heterogeneity; heat shock response; integrated stress response; predictability across perturbations; proteostasis stress; rare high-stress populations; single-cell perturbation; stress-program prediction; unfolded protein response
    DOI:  https://doi.org/10.3390/biology15151230
  50. Oncogene. 2026 Aug 10.
    Complementary intra- and extracellular AGR2 activities support epithelial ovarian cancer cell aggressiveness.
    Marianne Guilbard, Saïd Taouji, Marc Aubry, Jacques Robert, Raphael Pineau, Valérie Velasco, Romane Florent, Louis-Bastien Weiswald, Cecile Hartog, Coriolan Lebreton, Alix Coulon, Sabrina Croce, Guillaume Babin, Cédric Chaveroux, Stéphanie Beq, Eric Chevet, Delphine Fessart, Frédéric Delom.
      Anterior Gradient 2 (AGR2) is an endoplasmic reticulum (ER)-resident protein that belongs to the protein disulphide isomerase (PDI) family, and whose expression and secretion are induced by stress. Extracellular (secreted) AGR2 has been proposed as a marker of ER stress-related proteostasis alterations. Cancer cells frequently overexpress intracellular AGR2 (iAGR2) and secrete extracellular AGR2 (eAGR2). These features are associated with tumour progression and may serve as potential biomarkers in epithelial ovarian cancer (EOC). To investigate the roles of both iAGR2 and eAGR2 in EOC, we first generated EOC cells overexpressing iAGR2 and secreting eAGR2. Antibodies blocking eAGR2 reduced the proliferation and migration of these overexpressing cells. Concurrently, supplementation of parental cells with recombinant eAGR2 partially rescued these properties, further supporting a functional extracellular role for AGR2 in EOC. Quantitative proteomics, complemented by analysis of the TCGA database, revealed that eAGR2 modulated the expression of proteins involved in autophagy. This suggests that eAGR2-induced signalling may enhance catabolic activity under stress conditions, thereby increasing nutrient availability and, in turn, facilitating protein synthesis. This was reflected in the increased translational activity observed in AGR2-overexpressing and eAGR2-stimulated cells. Our results highlight two distinct, compartmentalised roles for AGR2. Specifically, iAGR2 acts as an ER-resident PDI, enhancing protein folding and ER quality control. In a complementary manner, eAGR2 functions as a metabolic regulator that may relieve constraints on tumour cell aggressiveness by maintaining autophagic flux and promoting protein synthesis. Overall, these findings support a dual-compartment model in which iAGR2 couples ER proteostasis with the metabolic and translational stimulation mediated by eAGR2.
    DOI:  https://doi.org/10.1038/s41388-026-03938-y
  51. Curr Res Microb Sci. 2026 ;11 100653
    Stress-induced remodeling of membrane-bound organelles in budding yeast.
    Peng Sheng, Mengna Sun, Xinyue Wang, Lizhe Bai, Hong Cao, Dan Li.
      Membrane-bound organelles undergo extensive remodeling during environmental stress, yet systematic side-by-side comparisons of organelle responses in budding yeast remain limited. Here, a panel of fluorescent markers was used to examine multiple organelles in Saccharomyces cerevisiae exposed to heat, hydrogen peroxide, acetic acid, or ethanol. Across all conditions, mitochondria consistently shifted from tubular networks to fragmented puncta, representing a common stress response. Quantitative scoring showed that heat stress induced mitochondrial fragmentation in more than 90% of cells within 20 min, and GFP-HDEL redistribution was detected in a substantial fraction of cells under all four stress conditions, with the strongest effect under heat stress. In contrast, overall endoplasmic reticulum (ER) morphology remained largely preserved, although redistribution of GFP-HDEL indicated altered ER retention and/or endomembrane homeostasis. Heat and oxidative stress also induced Ire1 puncta. Several nuclear proteins exhibited stress-dependent redistribution from the nucleus, indicating dynamic remodeling of nuclear protein localization. Vacuoles generally appeared enlarged and fused, whereas acetic acid induced a distinct phenotype with Ybh3 enrichment at the vacuolar membrane and redistribution of Prc1 and Pep4 to cytoplasmic puncta. Markers of the early and late Golgi and the late endosome showed stress-specific loss, clustering, or relocalization. Lipid droplets, peroxisomes, and autophagy-related structures were also altered. Additionally, Yca1, Aif1, and Mmi1 formed puncta under heat and ethanol stress. Together, these findings provide a comparative imaging framework defining shared and stress-specific features of organelle remodeling in budding yeast.
    Keywords:  Budding yeast; Endoplasmic reticulum; Environmental stress; Fluorescence imaging; Mitochondria; Organelle remodeling
    DOI:  https://doi.org/10.1016/j.crmicr.2026.100653
  52. Molecules. 2026 Aug 06. pii: 2728. [Epub ahead of print]31(15):
    Cross-Family Mechanistic Analysis of Plant Alkaloids Against Neglected Arboviruses and Related RNA Viruses.
    Marcia Régis, Mario Fernando Sanchez Moreno, Hugo Germain, Natacha Mérindol, Isabel Desgagné-Penix.
      Neglected arboviruses dengue (DENV), Zika (ZIKV), yellow fever (YFV), Japanese encephalitis (JEV), and chikungunya collectively affect hundreds of millions of people annually, yet no specific antiviral drug has been approved for any of them. Alkaloids, nitrogen-containing specialized metabolites produced by diverse plant families, have emerged as a promising source of broad-spectrum antiviral scaffolds. This review compiles and critically analyzes over 100 alkaloid-virus pairs across several RNA virus families, providing a comparative mechanistic analysis. Lycorine, narciclasine, emetine, and berbamine, among others, exhibit potent activity against phylogenetically distant viruses, with the most potent activities reported against flaviviruses (narciclasine: EC50 0.02 µM against DENV, ZIKV, YFV, and JEV; pancratistatine: 0.0063 µM against ZIKV). Structure-activity analysis of multiple alkaloid classes identifies key pharmacophoric features, including the phenanthridine nucleus (lycorine derivatives) and the bis-benzylisoquinoline scaffold (tetrandrine, berbamine), as determinants of antiviral potency, selectivity, and broad-spectrum activity. Genetic resistance data in West Nile virus challenge the widely accepted model of lycorine as a direct nucleoside inhibitor, instead pointing toward the involvement of the membrane-associated NS4A-2K-NS4B replication complex, though direct validation remains limited for other flaviviruses. Converging structural, biochemical, and transcriptomic evidence suggests that ribosome-mediated translational stress may represent an additional host-directed antiviral mechanism for isoquinoline-type alkaloids, though the causal chain from ribosome binding to activation of the integrated stress response and to antiviral effect has not been established. The present analysis highlights that in vivo validation remains limited to a few alkaloid-virus pairs. Unbiased target deconvolution and formal testing of the ribosome/integrated stress response hypothesis stand out as essential research priorities.
    Keywords:  broad-spectrum antivirals; flavivirus; integrated stress response; mechanism of action; neglected tropical diseases; ribosome; structure-activity relationships
    DOI:  https://doi.org/10.3390/molecules31152728
  53. J Mol Biol. 2026 Aug 11. pii: S0022-2836(26)00361-X. [Epub ahead of print] 169988
    In trans RNA replication of a defective self-amplifying RNA lowers RNA replication but enhances protein translation.
    David Silverio Moreno Gutierrez, Ana Luisa Duran Meza, William M Gelbart.
      RNA replication is fundamental to the life cycle of the large majority of viruses and has attracted increasing interest due to its potential to enhance mRNA expression for vaccines and gene therapy. This process relies on RNA-dependent RNA polymerase (RdRp) genes that, once translated, recognize their cognate mRNAs and replicate them. Self-amplifying RNAs (saRNAs) - "replicons" - can be engineered by incorporating the RdRp gene, a gene of interest (GOI), and the required cis-acting sequence elements for replication. Compared to non-replicating RNAs, saRNAs typically achieve up to two orders of magnitude higher gene expression in target cells. However, this enhanced replication is often associated with high cytotoxicity. Developing strategies to control or modulate RNA replication is therefore critical for the therapeutic application of saRNAs. Here, we report the effects of combining replication-competent and replication-deficient replicons on RNA replication and GOI translation. We quantify the extent to which the competent replicon rescues replication of the deficient replicon in trans, leading to reduced overall RNA replication but to increased total GOI translation. These findings highlight the delicate balance between RNA replication and protein synthesis in the context of cellular cytotoxity and metabolic burden, factors to be considered when designing strategies of saRNA-based therapeutics.
    Keywords:  Nodaviruses; Self-amplifying RNA; in trans RNA replication
    DOI:  https://doi.org/10.1016/j.jmb.2026.169988
  54. J Am Soc Nephrol. 2026 Aug 11.
    Nonhistone Post-translational Modifications as Integrative Signaling Networks in Podocyte Injury and Glomerular Disease.
    Zhuoying He, Hanzhi Jiang, Shaoguo Tao, Yannic Becker, Patricia Schroder, Jie Xiao, Hermann Haller, Guibao Ke.
      Podocytes are key structural components of the glomerular filtration barrier and are essential for maintaining selective protein filtration. Podocyte dysfunction is closely associated with proteinuria and the progression of glomerulosclerosis, constituting the common pathological basis of various chronic kidney diseases such as diabetic nephropathy and focal segmental glomerulosclerosis. While histone post-translational modifications have been extensively studied in podocyte biology, recent attention has shifted toward the regulatory roles of nonhistone post-translational modifications. By modulating protein stability, activity, localization, and interactions, these modifications participate in core biological processes such as apoptosis, cytoskeletal remodeling, inflammatory signaling, and metabolic reprogramming. Nevertheless, the strength of evidence is not uniform across post-translational modification categories. While some mechanisms have been directly demonstrated in podocytes, others are inferred mainly from broader kidney injury models or from studies in non-podocyte cell types. Accordingly, not all reported post-translational modification changes should be interpreted as equally well-established causal drivers of podocyte injury. This review focuses on the molecular regulatory networks and pathophysiological significance of major nonhistone post-translational modifications, including acetylation, phosphorylation, methylation, lactylation, ubiquitination, and SUMOylation. We further propose a hypothesis-generating and integrative conceptual model of podocyte deterioration, linking initiating pathological stimuli to stress transduction and downstream effector decompensation that may culminate in structural collapse. Importantly, this proposed cascade is not intended to represent a universally validated linear sequence or a definitive disease mechanism. Rather, it provides an organizing framework to generate testable hypotheses. We further highlight the therapeutic promise of targeting nonhistone post-translational modification pathways while acknowledging the considerable translational challenges that remain. By synthesizing the mechanistic landscape of nonhistone post-translational modifications, this review provides an integrated framework for advancing our understanding of podocytopathy pathogenesis and fostering the development of precision-targeted therapies.
    DOI:  https://doi.org/10.1681/ASN.0000001242
  55. Mol Neurobiol. 2026 Aug 10. pii: 827. [Epub ahead of print]63(1):
    The Amino Acid-Neurodegeneration Axis: Excitotoxicity and Oxidative Stress as Context-Dependent Amplifiers of Metabolic Dysfunction.
    Precious Adeoye Oyedokun, Joshua Oluwasola Gbadero, David Ishola Ajao, Mayowa Damilola Olorunsesan, Ayanfeoluwa Isaac Oyesiji, Gideon Opeyemi Ayilara, Marvellous Kehinde Ogunsina, Blessing Stephany Justus, Fatimoh Motunrayo Ademola, Elizabeth Adebusola Adetunji, Precious Sunday Okodio, Nathaniel Ohiemi Amedu.
      Homeostasis of amino acids is essential for the integrity of the CNS, and is maintained by a tightly regulated transport and metabolic circuit that ensures efficient neurotransmission, mitochondrial bioenergetics and redox homeostasis. Disruption of this equilibrium is associated with the pathogenesis of the major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Excessive glutamatergic stimulation and impaired glycine or homocysteine metabolism result in pathological Ca2⁺ influx, loss of mitochondrial membrane potential and production of reactive oxygen species, which are hallmarks of these disorders. It also limits cysteine availability and causes glutathione depletion, which affects antioxidant defence, and disrupts tryptophan-kynurenine metabolism, further affecting neurotoxic and neuroprotective signalling. Though there are disease-specific molecular triggers, the convergent pathogenesis of metabolic disruption makes neurons susceptible to disease. The convergent pathways link amino acid dysregulation to the reinforcement of each other's mechanisms of excitotoxicity, oxidative stress, mitochondrial dysfunction, and protein aggregation. Correcting the amino acid balance has clear translational potential for developing new therapies, such as glutathione augmentation, modulation of NMDA receptors, targeting of transporters, and regulation of metabolic enzymes. In addition, the use of metabolic biomarkers alongside neuroprotective endpoints in clinical trials could improve detection rates, patient stratification, and therapeutic precision. The concept of amino acid metabolism as a mechanism of neurodegeneration, therefore, provides a systems-level perspective and targets potential areas for continued neuroprotection and disease modification.
    Keywords:  Amino acid; Amino acid metabolism; Excitotoxicity; Metabolic dysregulation; Mitochondrial dysfunction; Neurodegeneration
    DOI:  https://doi.org/10.1007/s12035-026-06121-2
  56. Nucleic Acids Res. 2026 Aug 10. pii: gkag805. [Epub ahead of print]54(15):
    The pseudouridine synthase PUSL1 modifies U39 of mitochondrial tRNAs and is linked to human neurological phenotypes.
    Pedro Rebelo-Guiomar, Nadav Kra-Oz, Christopher Powell, Guillaume Jouret, Morgane Plutino, Veronique Paquis-Flucklinger, Schraga Schwartz, Aldema Sas-Chen, Michal Minczuk.
      Variants in the mitochondrial and nuclear genomes are linked to a wide range of human disorders marked by impaired mitochondrial function. Among these disorders, there is a growing number of patients with variants affecting mitochondrial RNA biology. Mitochondrial transcripts are pseudouridylated, and some enzymes responsible for this modification-pseudouridine synthases (PUS)-have been identified. Although known as the 'fifth nucleotide' owing to its high abundance in transcripts, the exact cellular role of pseudouridine is still unclear. Here, we expand the group of mitochondrial PUS enzymes by demonstrating that the protein encoded by PUSL1 is an active pseudouridine synthase with mitochondrial localization. Nucleotide-resolution pseudouridine mapping (mito-Ψ-Seq) followed by primer extension analysis showed that PUSL1 selectively modifies universal position 39 of all mitochondrial transfer RNAs (tRNAs) with a uridine residue in this position. Two newly described clinical PUSL1 variants, c.704G > A (p.Arg235Gln) and c.634del, p.Glu212Argfs*26, were functionally studied, presenting defects in pseudouridylation of mt-tRNA position 39 in patient-derived material, corroborating the association of this enzyme with human pathology. Our data show that PUSL1 regulates mitochondrial RNA post-transcriptional processing and its dysfunction and could be associated with neurological phenotypes.
    DOI:  https://doi.org/10.1093/nar/gkag805
  57. G3 (Bethesda). 2026 Aug 13. pii: jkag203. [Epub ahead of print]
    Transcriptomic profiles of the maternal-to-zygotic transition for Drosophila embryos exposed to acute and chronic heat stress.
    Faizan Rashid, Natalie Biel, Jenny Drnevich, Anna Marie Sokac.
      Heat stress challenges embryo survival, but the molecular reasons for this are unclear. We investigated how heat stress alters the maternal-to-zygotic transition (MZT) during Drosophila melanogaster development. Using RNA sequencing, we characterized the MZT under nonstress, acute, and chronic heat stress conditions. MZT genes were defined as those differentially expressed between the minor and major waves of zygotic genome activation. MZT genes were associated with multiple processes, including transcription, splicing, translation, and development. Under acute stress, the MZT deviated little from nonstressed embryos except that heat shock protein (HSP) genes were activated, and maternal transcript clearance was minimally misregulated. Under chronic stress, a core MZT persisted; but stress-related gene expression was obvious, maternal transcripts were strongly misregulated, and embryos showed poor survival. Overall, the MZT is robust, but increasingly falters with more severe stress. We present our dataset as a resource to aid molecular understanding of embryo resilience and vulnerability to environmental stressors.
    Keywords:   Drosophila ; RNA sequencing (RNA-seq); embryo; heat shock response (HSR); maternal-to-zygotic transition (MZT); zygotic genome activation
    DOI:  https://doi.org/10.1093/g3journal/jkag203
  58. J Adv Res. 2026 Aug 08. pii: S2090-1232(26)00634-X. [Epub ahead of print]
    DACH1 SUMOylation protects against diabetic cardiomyopathy by suppressing endoplasmic reticulum stress.
    Jie Lin, Na Liu, Bo Li, Yi Wang, Congye Li, Yue Yin, Heng Ma, Lu Yu, Jie Zhou.
       INTRODUCTION: Endoplasmic reticulum (ER) stress is a key driver of diabetic cardiomyopathy (DCM), but its upstream regulators are incompletely defined. The transcription factor DACH1 is genetically linked to diabetes and cardiovascular risk, yet its role in the diabetic heart is unknown.
    OBJECTIVES: This study aimed to elucidate the function and post-translational regulation of DACH1 in DCM, focusing on its interplay with ER stress.
    METHODS: Cardiac function, ER stress, and apoptosis were assessed in db/db mice and high glucose-treated cardiomyocytes. AAV9 was used for cardiac-specific DACH1 overexpression in vivo. SUMOylation and ubiquitination of DACH1 were analyzed via co-immunoprecipitation, mutagenesis, and proteasome inhibition assays.
    RESULTS: Myocardial DACH1 protein, but not its mRNA, was significantly reduced in experimental DCM. Restoring cardiac DACH1 alleviated dysfunction, ER stress, apoptosis, and fibrosis in diabetic mice. DACH1 stability was associated with SUMOylation at lysines K348, K599, and K631, and TRIM28 facilitated this modification in our experimental system. This modification was reduced under diabetic conditions and was associated with increased ubiquitin-proteasome degradation of DACH1. Enhancing SUMO1 increased DACH1 stability, helped preserve DACH1 nuclear retention, and protected cardiomyocytes from high glucose-induced ER stress and apoptosis.
    CONCLUSION: Impaired SUMOylation may contribute to DACH1 depletion in the diabetic heart. SUMOylation-dependent stabilization of DACH1 represents a potential cardioprotective pathway that mitigates diabetic myocardial injury by suppressing ER stress.
    Keywords:  DACH1; Diabetic cardiomyopathy; ER stress; SUMOylation; Ubiquitination
    DOI:  https://doi.org/10.1016/j.jare.2026.08.026
  59. Int J Oncol. 2026 Oct;pii: 111. [Epub ahead of print]69(4):
    piR‑164552 promotes malignant progression in head and neck squamous cell carcinoma via the RBM4/EIF4E2 signaling axis: Insights from multi‑omics and functional analyses.
    Shan Yang, Zhen Shang, Shunxian Xia, Hongbo Liu, Yanhan Dong, Xiaomin Wang, Wenhua Xu, Haijun Lu.
      Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy with limited options for early diagnosis and poor clinical outcomes. In the present study, PIWI‑interacting RNA (piR)‑164552 was identified as a novel oncogenic regulator in HNSCC. piR‑164552 was found to be markedly upregulated in tumor tissues and serum exosomes and its expression promoted the proliferation, migration, invasion and tumorigenicity of HNSCC cells both in vitro and in vivo. Mechanistic analyses revealed that piR‑164552 interacted with RNA‑binding motif protein 4 (RBM4) and positively regulated RBM4 protein levels, which in turn enhanced the expression of eukaryotic initiation factor 4E‑like 2 (EIF4E2), forming a piR‑164552/RBM4/EIF4E2 axis. Integrated transcriptomic and translatomic profiling further demonstrated that this axis orchestrated extensive reprogramming of mRNA metabolism, ribosome biogenesis and cancer‑associated signaling pathways, underscoring its multilayered role in tumor progression. The present findings highlighted the diagnostic potential of piR‑164552 and uncovered its key contribution to the molecular network driving HNSCC, providing new insights into biomarker development and therapeutic strategies.
    Keywords:  PIWI‑interacting RNAs; RNA‑binding motif protein 4; eukaryotic initiation factor 4E‑like 2; head and neck squamous cell carcinoma; transcription; translation
    DOI:  https://doi.org/10.3892/ijo.2026.5924
  60. Molecules. 2026 Jul 24. pii: 2588. [Epub ahead of print]31(15):
    Chemical Modification Strategies for Therapeutic Oligonucleotides: Mechanism Compatibility, Design Trade-Offs, and Translational Barriers.
    Kameron Burton, Kristen Dellinger.
      Oligonucleotide therapeutics represent an expanding class of medicines that can regulate gene expression, RNA processing, protein translation, immune signaling, and biomolecular recognition through sequence-specific or structure-dependent mechanisms. Despite clinical progress, their application remains constrained by nuclease degradation, rapid clearance, inefficient tissue and cellular delivery, endosomal sequestration, off-target activity, immune recognition, and mechanism-specific requirements for target engagement. Chemical modification is central to oligonucleotide therapeutic development because it can mitigate some of these limitations while influencing target affinity, protein binding, pharmacokinetics, and intracellular activity. This review examines chemical modification strategies to improve the biological stability and functional performance of therapeutic oligonucleotides and is organized around major classes of chemical modification, including phosphate and backbone-linkage modifications, sugar and conformational modifications, backbone-replacement analogs, and conjugation-based approaches. Rather than presenting these chemistries as uniformly beneficial, this review emphasizes that the same modification can be enabling in one therapeutic mechanism and disruptive in another, so its value cannot be judged apart from the modality and molecular architecture in which it is placed. Clinically successful oligonucleotide designs are likely to rely on combinations of chemical features, including modified backbones, modified sugars, stereochemical control, terminal stabilization, and ligand- or formulation-based delivery strategies. Understanding how these features interact is essential to develop more predictable and mechanism-appropriate oligonucleotide therapeutics.
    Keywords:  antisense oligonucleotides; chemical modification; drug delivery; medicinal chemistry; nuclease resistance; nucleic acid chemistry; oligonucleotide therapeutics; small interfering RNA
    DOI:  https://doi.org/10.3390/molecules31152588
  61. Genome Biol Evol. 2026 Aug 10. pii: evag199. [Epub ahead of print]
    Lineage-specific retention of the plastid tilS-trnI(CAU) module and its variable relationship with codon usage evolution in green algae.
    Nam Ju Lee, Jeongha So, Jehyun Jeon, Young Wook Ko, Hyunsik Chae, Sanghee Kim, Sung Mi Cho.
      Plastid genomes retain a reduced but essential translation system inherited from cyanobacterial ancestors, but the evolutionary constraints shaping their diversification remain poorly resolved. One key component ensuring translational fidelity is the tRNAIle-lysidine system, mediated by tRNAIle-lysidine synthetase (TilS), which enables accurate decoding of the AUA isoleucine codon. Here, we characterized the complete plastid genome of the Antarctic green alga Micractinium simplicissimum and investigated the evolutionary distribution of the tilS-trnI(CAU) module across green algal plastomes. Phylogenomic analyses of 35 plastomes revealed consistent retention of this module in Chlorellales, whereas partial loss or structural fragmentation occurred in core Trebouxiophyceae lineages. Comparative analyses of codon usage showed that AUA frequencies varied widely among major green algal lineages but were not tightly associated with tilS retention, suggesting partial evolutionary decoupling between tRNA modification systems and synonymous codon usage. Structural comparisons further revealed lineage-specific insertions and domain rearrangements in plastid TilS proteins relative to their cyanobacterial homologs. Candidate nuclear-encoded TilS homologs were additionally identified in several plastid tilS-lacking taxa, suggesting possible intracellular relocation of decoding functions. Together, these findings suggest that plastid decoding systems evolve through modular, lineage-specific trajectories that allow structural plasticity while maintaining translational fidelity. This study provides new insights into the evolutionary dynamics of gene expression systems in endosymbiotic organelles.
    Keywords:  Chlorellales; Plastid genome evolution; codon usage bias; tRNA modification; tRNAIle–lysidine synthetase (TilS); translational fidelity
    DOI:  https://doi.org/10.1093/gbe/evag199
  62. Plants (Basel). 2026 Jul 23. pii: 2256. [Epub ahead of print]15(15):
    Ubiquitination-Mediated Regulation of Brassinosteroid Signaling.
    Yonghong Xie, Qin Zhang, Juansheng Ren.
      Brassinosteroids (BRs) are essential steroid hormones that coordinate plant growth, development and adaptation to changing environments. Although BR signaling has long been viewed primarily as a phosphorylation-dependent pathway, increasing evidence shows that ubiquitination provides an additional regulatory layer that shapes the abundance, activity, subcellular distribution and turnover of key signaling components. Ubiquitin-mediated regulation operates at multiple points in the BR pathway, including receptor homeostasis at the plasma membrane, turnover of GSK3-like kinases, and stability control of the transcription factors BES1/BZR1. These processes determine not only the strength and duration of BR signaling but also its coordination with other hormonal and stress-response pathways. In this review, we discuss recent advances in ubiquitin-mediated regulation of BR signaling, focusing on receptor-level control, proteolytic regulation of core signaling components, and modulation of transcriptional outputs. We also highlight emerging links between ubiquitination, selective autophagy, deubiquitination and BR-associated stress responses and outline key questions concerning ubiquitin chain specificity, substrate recognition and conservation of these regulatory modules in crops. Defining how ubiquitination fine-tunes BR signaling will deepen our understanding of plant steroid hormone regulation and may provide new strategies for optimizing crop architecture, productivity, and stress resilience.
    Keywords:  brassinosteroids; plant hormones; protein degradation; signal transduction; ubiquitination
    DOI:  https://doi.org/10.3390/plants15152256
  63. Nat Rev Mol Cell Biol. 2026 Aug 14.
    Regulation and roles of mammalian mitophagy.
    Sascha Martens, Ian G Ganley.
      Mitochondria are essential metabolic and signalling hubs exposed to stress, and mitochondrial damage is highly detrimental to the cell. Mitophagy - the autophagy of mitochondria - is a key mechanism that maintains both mitochondrial integrity and metabolic flexibility. Mitophagy occurs via multiple pathways that either involve activation of PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin-protein ligase Parkin, or are independent of PINK1 and Parkin. Recessive mutations in PINK1 and PKRN (the gene that encodes Parkin) cause early-onset Parkinson's disease and have provided key mechanistic insights into mitophagy. However, emerging findings indicate that mitophagy is also executed by other molecular routes. Despite these molecular advances in mitophagy characterization, the physiological roles of these pathways in mammals and the specific contexts or conditions in which they operate remain poorly defined. This Review summarizes current understanding of PINK1-Parkin-dependent and independent mitophagy pathways, highlighting mechanistic distinctions and coordinated regulation. We also examine physiological and pathological triggers of mitophagy, as well as the expanding therapeutic potential of targeting mitophagy in disease.
    DOI:  https://doi.org/10.1038/s41580-026-01012-9
  64. Amyloid. 2026 Aug 12. 1-8
    Selective cellular vulnerability and resilience in amyloidosis: insights from the 2025 International Society of Amyloidosis Workshop.
    Giampaolo Merlini.
       BACKGROUND: Amyloidosis is characterized by hierarchical organ-specific targeting related to the nature and amino acid sequence of the precursor protein. However, several crucial aspects of tissue vulnerability and resilience to amyloid deposition and toxicity remain poorly defined.
    RESULTS: The amino acid sequence of the amyloid protein is a primary determinant of organ targeting. Cryo-electron microscopy reveals common fibril architectures across organs, indicating interactions with shared tissue constituents. The interaction with the microenvironment, comprising glycosaminoglycans, collagen, endoproteases, and tissue cells, may underlie tissue vulnerability. Cellular interactions involve internalization of amyloid precursors, leading to lysosomal dysfunction, mitochondrial impairment, reactive oxygen species production, and proteotoxicity, particularly in cardiomyocytes and mesangial cells. Increased structural dynamics in amyloidogenic light chains promote improper interactions with cell constituents. Tissue-specific proteostasis capacity declines with age, contributing to tissue vulnerability in elderly patients. Parallels with neurodegenerative diseases underscore selective cellular susceptibility due to proteostatic overload and metabolic stress.
    CONCLUSIONS: Evidence shows that the amino acid sequence of the amyloid protein, microenvironmental factors, and cell-intrinsic and extracellular proteostatic capacity jointly determine tissue vulnerability and resilience in amyloidosis, with relative contributions varying by amyloid protein. Identifying key determinants provides actionable targets for improving the care of systemic and localized amyloidosis.
    Keywords:  AL amyloidosis; ATTR amyloidosis; Meeting report; microenvironment; neurodegenerative diseases; organ targeting; proteostasis
    DOI:  https://doi.org/10.1080/13506129.2026.2714521
  65. Int J Mol Sci. 2026 Jul 29. pii: 6789. [Epub ahead of print]27(15):
    Regulation of Translation by PKA Signaling Pathway.
    Lele Yang, Kun Hou, Huayu Qi.
      Extracellular stimuli, including hormones, growth factors and nutrients in the milieu of cells often initiate intracellular changes via signaling pathways, of which the cyclic 5', 3'-adnosine monophosphate (cAMP)-dependent protein kinase (PKA) signaling pathway is prototypical. Research in the past decades has demonstrated that PKA plays versatile roles during cell proliferation and differentiation, mainly through phosphorylating a plethora of protein substrates by its protein kinase activity. Studies using model systems including yeast, neurons and mammalian germ cells indicate that PKA functionality is regulated by not only the cell-type-specific expression of its regulatory and catalytic subunits, but also the spatiotemporal distribution of its binding proteins and secondary messengers. How PKA elicits its functional specificity in a spatiotemporal manner constitutes fundamental mechanisms that regulate development, aging and regeneration. In this review, we first summarize basic aspects that drive the functional diversity of PKA and then focus on the less studied regulatory roles of PKA during synthesis of cellular proteins, the functional units of the cell. Direct links between PKA signaling and protein synthesis machinery are yet to be fully characterized. We anticipate that research in this area, combining model systems and newly developed methodologies, will continue to deepen our understanding of animal development and the etiology of human diseases.
    Keywords:  AKAP; PKA; protein synthesis; regulatory subunit; spermatogenesis
    DOI:  https://doi.org/10.3390/ijms27156789
  66. J Physiol. 2026 Aug 11.
    Development of a protein synthesis network at the sarco/endoplasmic reticulum in adult cardiac myocytes.
    Christoph Sandmann, Sören Brandenburg, Dennis Uhlenkamp, Bianca Meyer, Clara Sandmann, Nicole Herzog, Julia Groß, Charlotta Funaya, Hugo A Katus, Stephan E Lehnart, Christopher C Glembotski, Mirko Völkers, Shirin Doroudgar.
      The endoplasmic reticulum (ER) is the primary site for the synthesis and folding of membrane and secretory proteins, which together comprise a large fraction of the total protein output in mammalian cells. Striated muscle cells contain a specialized membrane system, the sarcoplasmic reticulum (SR), which regulates calcium homeostasis and contraction. However, the biochemical and physiological relationship between the ER and SR, as well as the extent to which both compartments contribute to protein synthesis, remain incompletely understood. Quantification of ER- and SR-associated proteins in isolated ventricular cardiac myocytes revealed that the relative abundance of ER/SR-resident protein quality control components and ribosomes decreased during postnatal maturation, whereas SR-associated Ca2 +-handling proteins increased. Immunocytochemistry revealed that the membrane compartment prominent in early postnatal stages exhibits predominantly ER characteristics and diminishes during postnatal development. In adult cardiac myocytes, the SR becomes the dominant membrane network throughout the cell, while ER markers remain enriched in the perinuclear region. Immunocytochemistry further indicated that the ER and SR perform overlapping yet distinct specialized functions, with excitation-contraction coupling localized to the SR, and initiation of secretion concentrated within the ER. In adult ventricular cardiac myocytes, ribosomes and mRNA localize adjacent to both the ER and SR, indicating their roles as direct sites of localized protein synthesis and homeostasis. These findings demonstrate that molecular differentiation and structural organization of the ER/SR during cardiac muscle development culminate in a specialized protein synthesis network within the sarco/endoplasmic reticulum of adult myocytes. KEY POINTS: Although the sarcoplasmic reticulum (SR) is the established centre for calcium regulation in striated muscle, its role in membrane and secreted protein synthesis has remained unknown. It has remained unclear whether the endoplasmic reticulum (ER) and SR coexist as distinct membrane networks in cardiac myocytes or whether they form a single system that fulfills both calcium-handling and protein synthesis functions. We found that postnatal cardiac maturation involves a major reorganization in which the centralized, ER-dominant network of neonatal myocytes is replaced by an expansive, SR-dominant network in the adult cell periphery, while ER markers become largely confined to the perinuclear region. Using stimulated emission depletion super resolution microscopy and electron microscopy, we demonstrated that active ribosomes and mRNA associate with the longitudinal SR but are spatially excluded from ryanodine receptor 2-rich junctional zones. Our results establish that the SR functions as a specialized, distributed protein synthesis network that enables adult cardiac myocytes to maintain their highly organized cellular architecture through localized translation.
    Keywords:  cardiac myocytes; endoplasmic reticulum; protein synthesis; sarcoplasmic reticulum; translation; ventricular myocyte
    DOI:  https://doi.org/10.1113/JP288658
  67. FEBS J. 2026 Aug 11.
    p62/SQSTM1: From an autophagy receptor to a condensate organizer of selective autophagy and stress signaling.
    Jun-Ichi Sakamaki, Masaaki Komatsu.
      Upon exposure to stress, cells activate a variety of stress-response and quality-control mechanisms to maintain homeostasis. Dysregulation of these processes is implicated in numerous diseases, including cancer, liver disorders, and neurodegenerative diseases. p62/Sequestosome 1 (SQSTM1) is a multifunctional protein that plays a central role in protein homeostasis and stress responses by regulating autophagy and signal transduction pathways. Through its multiple protein-interacting domains, p62 functions both as a scaffold for selective autophagic degradation and as a signaling hub. Since our previous review of p62 a decade ago, substantial progress has been made in elucidating its molecular functions and physiological roles. Notably, p62 undergoes liquid-liquid phase separation with ubiquitinated proteins to form membraneless condensates, termed p62 bodies, when cells are exposed to proteotoxic stress. By sequestering specific proteins, p62 bodies act as platforms for autophagy-dependent degradation and stress signaling. These findings have substantially revised our view of p62 function, which was previously considered primarily as a receptor simply linking ubiquitinated substrates to autophagic membranes and connecting signaling molecules. This conceptual shift from one-to-one molecular interactions to multivalent, multimolecular, higher-order assemblies has fundamentally redefined the functional landscape of p62. In this review, we highlight how p62 bodies integrate selective autophagy and stress signaling, with a particular emphasis on their emerging roles in disease pathogenesis and their potential as therapeutic targets.
    Keywords:  KEAP1‐NRF2 pathway; liquid–liquid phase separation; p62 body; p62/SQSTM1; selective autophagy; ubiquitination
    DOI:  https://doi.org/10.1111/febs.70689
  68. Nat Neurosci. 2026 Aug 13.
    Dendritic translation and neuroproteasome-mediated degradation of endogenous tau revealed by STARFISH.
    Kalin D Konrad-Vicario, Victoria Paradise, Lara Y Demir, Chi Nguyen, Christopher D Makinson, Zhao Ming, Kapil V Ramachandran.
      In Alzheimer's disease, the protein tau is thought to redistribute from axons to the somatodendritic compartment and form fibrillar aggregates. Although tau aggregation is a hallmark of Alzheimer's disease, the dynamics of its synthesis and degradation are not well characterized. Given that nascent polypeptides are particularly susceptible to misfolding, local control of tau synthesis and degradation may be essential to prevent aggregation. Here we develop STARFISH, a method for visualizing the subcellular site of endogenous mRNA translation in primary neurons and in vivo with single-molecule sensitivity and near-codon resolution, without modifying the nascent polypeptide. Using STARFISH, we show that despite the broad distribution of Mapt mRNA, tau is translated exclusively in neuronal dendrites. About one-third of newly synthesized tau is co-translationally or peri-translationally degraded in dendrites by a neuronal-specific plasma-membrane-associated proteasome, the neuroproteasome. Failure of neuroproteasome-mediated degradation leads to the protein synthesis-dependent accumulation of somatodendritically mislocalized endogenous tau aggregates. These findings define a proteostasis mechanism that counterbalances the constitutive physiological overproduction of tau. We speculate that failure of this proteostasis system contributes to tau aggregation in dendrites in Alzheimer's disease.
    DOI:  https://doi.org/10.1038/s41593-026-02398-7
  69. Int J Mol Sci. 2026 Aug 01. pii: 6911. [Epub ahead of print]27(15):
    Med9 Is a Novel eIF4E-Interacting Protein in Saccharomyces cerevisiae.
    Dora E Vélez, Zorica Ristic, Daniela Ross-Kaschitza, Michael Altmann, Angélica Montiel-Dávalos, Vincent G Osnaya, Yolanda Camacho-Villasana, Xochitl Pérez-Martínez, Greco Hernández.
      The cap-binding protein eukaryotic initiation factor (eIF) 4E is a key protein for mRNA metabolism. The biological role of eIF4E is defined by the specific protein it interacts with. Thus, eIF4E binds to a constellation of partners across eukaryotes. The best-characterized role of eIF4E is to promote mRNA translation through interaction with the translation factor eIF4G. To seek new interactors in the ascomycete Saccharomyces cerevisiae, we performed a genomic yeast two-hybrid screen using eIF4E as bait. In addition to the already reported p20 and Eap1, we identified Med9, a component of the RNA polymerase II Mediator complex. A physical interaction between eIF4E and Med9 was confirmed using recombinant proteins prepared in E. coli and further isolating the eIF4E-Med9 complex both by size-exclusion chromatography and by m7GTP-Sepharose pull-down experiments. Moreover, the in vivo interaction was also detected. Surprisingly, the eIF4E W75A mutation, which impairs binding to eIF4G, p20, and Eap1, only slightly affected the interaction with Med9 in the two-hybrid system. We further performed random mutagenesis to identify the Med9 amino acids involved in eIF4E recognition. Mutants F65A/I66A and F65A/I66A/H68N did not interact with eIF4E. Our data suggest that the eIF4E-Med9 complex may be formed in both the cytoplasm and the nucleus.
    Keywords:  Med9; carbon source; eIF4E; mRNA metabolism; translation initiation
    DOI:  https://doi.org/10.3390/ijms27156911
  70. Int J Mol Sci. 2026 Aug 04. pii: 6986. [Epub ahead of print]27(15):
    RAN Translation-Coupled Decay of the C9orf72 GGGGCC Repeat Transcript by the RNA Exosome Suppresses Dipeptide Repeat Production.
    You Wu, Li Li, Jing Tian, Leilei Liu, Kunzhao Du, Zhicheng Shao, Tianlin Cheng, Xin Cao, Tao Wang.
      The RNA exosome plays a critical role in surveilling nuclear mRNA biogenesis and regulating co-translational mRNA decay in the cytoplasm. Unlike canonical translation, repeat-associated non-AUG (RAN) translation of a GGGGCC hexanucleotide repeat expansion (HRE) within an intron of the C9orf72 locus leads to the synthesis of neurotoxic dipeptide-repeat (DPR) proteins, contributing to the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis (C9-ALS/FTD). However, it remains unclear whether aberrant RAN translation is monitored and regulated co-translationally or how C9orf72 HRE (C9-HRE) mRNA is degraded during this process. Here, we demonstrate that RAN translation triggers the rapid decay of C9-HRE mRNA. During this process, the RNA exosome engages the translating ribosome-C9-HRE mRNA complex to mediate RAN translation-coupled mRNA decay. Moreover, overexpression of EXOSC3, a key subunit of the RNA exosome cap, promotes RAN translation-coupled decay of C9-HRE mRNA and suppresses DPR production. In iPSC-derived neurons, a reduction in EXOSC3 levels blocks C9-HRE mRNA decay in a translation-dependent manner, further confirming its role in RAN translation surveillance. These findings highlight the essential function of the RNA exosome, particularly EXOSC3, in mitigating RAN translation-associated toxicity and preventing pathological DPR production. This work provides insights into potential therapeutic strategies for C9-ALS/FTD and may have broader implications for other disorders involving RAN translation.
    Keywords:  C9orf72-ALS; RAN translation; RNA exosome; co-translational regulation; mRNA stability
    DOI:  https://doi.org/10.3390/ijms27156986
  71. IEEE Trans Pattern Anal Mach Intell. 2026 Aug 11. PP
    Sensitivity Analysis in Translation Averaging.
    Lalit Manam, Venu Madhav Govindu.
      Translation averaging solves for absolute translations given a set of pairwise relative translation directions. Most of the existing literature focuses on robustness to outliers and studies the uniqueness of the solution. In this paper, we deal with a distinctly different problem of sensitivity in translation averaging under input uncertainty. We first analyze sensitivity in estimating the translation of a camera and extend it to all the cameras involved in the problem. Then, we define the conditioning of the translation averaging problem, which assesses the reliability of estimated translations based solely on the input directions. We provide a sufficient criterion to ensure that the problem is well-conditioned. Based on the criterion, we present an efficient algorithm to identify and remove combinations of directions which make the problem ill-conditioned. Applying our algorithm leads to improved conditioning of translation averaging, resulting in the reduction of absolute translation errors.
    DOI:  https://doi.org/10.1109/TPAMI.2026.3722795
  72. FEBS J. 2026 Aug 14.
    A live-cell autophagy reporter reveals reversible vacuolation in naked mole-rat skin fibroblasts under lysosomal stress.
    Fangze Tong, Mateo P Hoare, Laura J Grundy, Filomena Gallo, Karin H Müller, Ewan St John Smith, Janet R Kumita.
      Naked mole-rats (NMRs, Heterocephalus glaber) display unusual longevity and resistance to age-related decline, and accumulating evidence suggests that their autophagy-lysosome pathway (ALP) is regulated differently from that of conventional mammalian models. However, most studies in NMR cells have relied on static biochemical or ultrastructural readouts, leaving the dynamic organisation of autophagy in living cells poorly defined. Here, we establish a stable tandem fluorescent autophagy reporter in NMR skin fibroblasts using an mCherry-EGFP-LC3NMR construct to enable live-cell, single-cell resolution analysis of ALP dynamics. Under basal conditions, NMR skin fibroblasts exhibit a greater abundance of LC3-positive structures than HeLa cells, together with a mixed population of autophagosomes and autolysosomes, indicating a distinct steady-state organisation of the ALP. Chloroquine (CQ)-induced lysosomal stress caused the expected accumulation of LC3-positive structures but also triggered the formation of large cytoplasmic vacuoles in NMR skin fibroblasts. Importantly, this vacuolation was not associated with acute cytotoxicity and progressively resolved following CQ removal, accompanied by reorganisation of LC3-positive compartments and recovery of lysosomal acidity. Electron microscopy showed that CQ-induced vacuoles are membrane-bound, containing internal material and co-existing with multiple ALP-related vesicular compartments. Primary NMR skin fibroblasts display a similar vacuolation phenotype, indicating that this response is not an artefact of immortalisation or reporter expression. Together, these findings establish a live-cell platform for analysing autophagy in NMR cells and identify a distinctive, reversible vacuolation response to lysosomal stress, consistent with dynamic remodelling of the lysosomal system within NMR skin fibroblasts.
    Keywords:  LC3‐reporter; autophagy–lysosome pathway; long‐lived species; naked mole‐rats; vacuolation
    DOI:  https://doi.org/10.1111/febs.70695
  73. MedComm (2020). 2026 Aug;7(8): e70892
    Cardiovascular Diseases and Cancer: Convergent Proteostasis Networks at the Crossroads of Mechanisms and Therapeutic Opportunities.
    Jacob Eli García Torres, Norbert Frey, Ashraf Yusuf Rangrez.
      Cancer and cardiovascular diseases, the primary causes of mortality globally, are increasingly understood as biologically interconnected rather than distinct pathologies. Recent evidence indicates that protein homeostasis (proteostasis) functions as a crucial molecular link connecting tumor progression, therapeutic resistance, cardiac remodeling, and treatment-related cardiotoxicity. Proteostasis, which encompasses the cellular processes of protein synthesis, folding, quality control, and degradation, dictates tissue adaptation to chronic stress. Notably, the adaptive mechanisms that allow tumor cells to endure proteotoxic stress and resist therapy are often vital for maintaining cardiac structure and function. Thus, tumor control and cardiovascular injury may be divergent outcomes of a common stress-response framework. In this review, we propose proteostasis as a comprehensive framework for understanding the cancer-cardiovascular interface. We analyze how the ubiquitin-proteasome system, autophagy-lysosome pathway, endoplasmic reticulum stress-induced unfolded protein response signaling, and molecular chaperone networks are differentially reconfigured in cancer and cardiac tissues, influencing tumor survival, therapeutic susceptibility, and cardiovascular dysfunction. Additionally, we explore the translational implications of proteostasis dysregulation, including mechanisms of anticancer therapy-induced cardiotoxicity, emerging biomarkers, cardioprotective strategies, and opportunities for precision cardio-oncology. By conceptualizing efficacy and toxicity as interconnected outcomes of shared proteostasis biology, this review establishes a foundation for developing therapies that optimize cancer control while safeguarding cardiovascular health.
    Keywords:  CVDs; ER stress; autophagy; cancer; cardiotoxicity; cardio‐oncology; drug repurposing; proteostasis; ubiquitin–proteasome system; unfolded protein response
    DOI:  https://doi.org/10.1002/mco2.70892
  74. Cell Biochem Biophys. 2026 Aug 12.
    Metabolomic Analysis of Intracellular Amino Acid Profile Differences Between Cisplatin-Resistant and Cisplatin- Sensitive CALU-1 Lung Cancer Cells.
    Ismail Koyuncu, Mehmet Ali Tapsık, Ozgur Yuksekdag, Murat Tiken, Ebru Temiz, Hale Güler Kara.
      Lung cancer remains one of the leading causes of cancer-related mortality worldwide, and resistance to cisplatin remains a major limitation in the treatment of non-small cell lung cancer (NSCLC). Accumulating evidence indicates that cancer cells reprogram amino acid metabolism to support proliferation, stress adaptation, redox balance, and therapeutic resistance. In this context, defining the amino acid-related metabolic alterations associated with cisplatin resistance may help identify potential metabolic vulnerabilities and biomarker candidates. In this study, intracellular free amino acid profiles were compared between cisplatin-sensitive parental human lung squamous cell carcinoma cells (CALU-1) and their cisplatin-resistant counterpart (cr-CALU-1) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The analysis revealed marked differences in the intracellular amino acid profiles of cr-CALU-1 cells compared with parental CALU-1 cells. Several amino acids, including proline, glutamine, glutamate, arginine, and alanine, were detected at higher levels in parental CALU-1 cells, whereas their intracellular levels were significantly lower in cr-CALU-1 cells. In contrast, cystine and phosphoethanolamine were increased in resistant cells. Multivariate and pathway analyses indicated that arginine and proline metabolism, histidine metabolism, and glutathione metabolism were among the most prominently affected pathways. These findings suggest that cisplatin resistance in CALU-1 cells is associated with broad remodeling of intracellular amino acid homeostasis. However, because targeted LC-MS/MS provides static metabolite pool-size information, further isotope-tracing and functional validation studies are required to determine whether these alterations reflect changes in amino acid uptake, biosynthesis, catabolism, or downstream utilization.
    Keywords:  CALU-1 cells; Cisplatin resistance; Intracellular amino acid profiling; LC-MS/MS; Lung cancer; Metabolomics; cr-CALU-1 cells
    DOI:  https://doi.org/10.1007/s12013-026-02134-9
  75. Front Cell Dev Biol. 2026 ;14 1836185
    Lactylation in kidney diseases: a review of regulatory mechanisms and therapeutic prospects.
    Yuxi Feng, Jinjin Wang, Jiawei Cao, Xuan Zhang, Mengyu Liang, Yi Cai, Jiaqi Wang, Chenxi Lu, Runzhi Zhu, Qinyang Jin, Zhuanxin Chen, Qin Zhu.
      Lactylation, a novel post-translational modification (PTM) of proteins, plays a critical role in various diseases through the regulation of gene expression and metabolic reprogramming. Recent studies have increasingly highlighted its pathological and physiological relevance in kidney diseases. Lactylation exerts pleiotropic effects across diverse renal pathologies, from promoting fibrotic progression in Chronic kidney disease (CKD) to modulating immune evasion in clear cell renal cell carcinoma (ccRCC), thereby positioning it at the epicenter of metabolic-epigenetic interplay in kidney disease. This review systematically delineates the dynamic regulatory mechanisms of PTMs and their pivotal roles and current research status in kidney diseases, explores the latest advancements in lactylation research concerning CKD, acute kidney injury (AKI), and ccRCC, and discusses its potential as a therapeutic target. By synthesizing current findings, the article aims to offer new perspectives and directions for future treatments of kidney diseases and the development of targeted therapies.
    Keywords:  acute kidney injury; chronic kidney disease; lactylation; post-translational modification; renal cell carcinoma
    DOI:  https://doi.org/10.3389/fcell.2026.1836185
  76. Wiley Interdiscip Rev RNA. 2026 Jul-Aug;17(4):17(4): e70053
    Spatiotemporal Control of microRNA-Target Interactions.
    Linh T T Le.
      MicroRNA-mediated gene regulation occurs within spatially organized intracellular environments and is governed by dynamic molecular interactions that unfold across defined kinetic timescales. Although classical models emphasize sequence complementarity between microRNAs (miRNAs) and their target transcripts, growing evidence indicates that the outcomes of miRNA-target interactions vary widely across cellular contexts and cannot be explained solely by seed pairing or steady-state expression levels. These observations suggest that additional regulatory layers shape the efficiency and fate of miRNA-mediated silencing. In this Review, we examine how the spatial organization of the cell structures miRNA activity across distinct intracellular microenvironments, where the local availability of Argonaute (AGO)-containing RNA-induced silencing complexes (RISCs), target RNAs and regulatory cofactors influences the probability that RISCs encounter and productively engage their targets. We further explore the temporal dimension of miRNA regulation, including Argonaute loading and turnover, the dwell time of RISC-target interactions, miRNA stability and target transcript lifetimes. Recent advances in quantitative and high-resolution approaches for studying RNA dynamics in living cells are beginning to reveal these regulatory processes directly. Together, these observations support a spatiotemporal kinetic model of miRNA regulation, in which intracellular organization and molecular dynamics jointly determine the probability and efficiency of gene silencing. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms.
    Keywords:  RISC–target interaction kinetics; microRNA; spatiotemporal miRNA regulation; target dwell time; translational repression
    DOI:  https://doi.org/10.1002/wrna.70053
  77. J Mol Biol. 2026 Aug 13. pii: S0022-2836(26)00357-8. [Epub ahead of print] 169984
    URG7-Driven Homeostatic Adaptation Protects SH-SY5Y Cells from 6-OHDA Neurotoxicity.
    Ilaria Nigro, Rocchina Miglionico, Ludovica Lela, Luana Genovese, Giusy Pietrafesa, Luigi Milella, Faustino Bisaccia, Maria Francesca Armentano.
      Parkinson's disease (PD) is characterized by progressive dopaminergic neurodegeneration associated with oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and impaired proteostasis. In this study, we investigated the role of Up-Regulated Gene 7 (URG7), an ER-resident protein, in regulating cellular stress responses in SH-SY5Y neuroblastoma cells exposed to 6-hydroxydopamine (6-OHDA), a widely used in vitro model of PD. URG7 overexpression significantly enhanced activation of the adaptive unfolded protein response (UPR), particularly the PERK/eIF2α/ATF4 pathway, while limiting ER stress-induced damage. Moreover, URG7 promoted protein quality control mechanisms by stimulating both the ubiquitin-proteasome system and autophagy, as demonstrated by increased ubiquitination, proteasome activity, and upregulation of Beclin-1 and LC3-II. URG7 also prevented intracellular calcium overload and reduced the expression of proteins involved in the SOCE pathway, thereby preserving calcium homeostasis under oxidative stress conditions. In addition, URG7 attenuated G1 cell cycle arrest and reduced the expression of pro-apoptotic markers, including p53, p21, Bax, and cleaved PARP, while promoting pro-survival signaling pathways such as AKT and ERK1/2. Collectively, these findings identify URG7 as an important regulator of adaptive stress responses and suggest its possible involvement in neuroprotective mechanisms associated with neurodegenerative disorders characterized by oxidative stress.
    Keywords:  Apoptosis; Calcium Homeostasis; Endoplasmic Reticulum stress; Neuroprotection; Oxidative stress; Proteostasis; URG7
    DOI:  https://doi.org/10.1016/j.jmb.2026.169984
  78. Cells. 2026 Jul 23. pii: 1318. [Epub ahead of print]15(15):
    From PLP1 Misfolding to Oligodendrocyte Degeneration: A Proteostasis-Centered Framework for Pelizaeus-Merzbacher Disease.
    Tianyi Li, Hao Huang, Xiaobin Li, Runlin Leng, Binbin Liu, Guohua Yang.
      Oligodendrocytes (OLs) are the myelinating cells of the central nervous system (CNS). The PLP1 gene, predominantly expressed in OLs, encodes proteolipid protein (PLP), a major structural component of CNS myelin that also regulates oligodendrocyte precursor cell (OPC) proliferation, differentiation, and maturation. Pelizaeus-Merzbacher disease (PMD) is a rare X-linked leukodystrophy caused by PLP1 mutations and characterized by defective myelination. Clinical manifestations range from severe connatal PMD to classic PMD and the milder spastic paraplegia type 2 (SPG2), reflecting substantial phenotypic heterogeneity. Beyond disrupting myelin structure, PLP1 mutations impair oligodendrocyte development and function. Increasing evidence indicates that PMD is fundamentally a proteostasis disorder, in which misfolded PLP accumulates within the endoplasmic reticulum (ER), overwhelms ER quality control mechanisms, and triggers chronic unfolded protein response (UPR) activation. Persistent ER stress and maladaptive UPR signaling ultimately promote oligodendrocyte dysfunction and degeneration. Using PMD as a representative model, this review summarizes the relationships between PLP1 mutations and disease phenotypes and discusses the cellular mechanisms by which ER stress and UPR signaling contribute to oligodendrocyte pathology.
    Keywords:  ERO1α; PLP1; Pelizaeus–Merzbacher disease; oligodendrocyte; proteostasis; unfolded protein response
    DOI:  https://doi.org/10.3390/cells15151318
  79. Int J Mol Sci. 2026 Jul 28. pii: 6766. [Epub ahead of print]27(15):
    Liquid-Liquid Phase Separation (LLPS) in Tumor Biology: Special Focus on the Process of Transcription.
    Wei Chen, Zihan Yang, Qiaodan Zhou, Bin Cheng.
      Liquid-liquid phase separation (LLPS) has attracted considerable attention in cell biology as a potentially widespread organizing principle in the cellular environment. LLPS involving proteins and nucleic acids participates in a wide range of cellular processes, including regulation of genome activity, modulation of enzymatic activity, and control of subcellular compartmentalization. Emerging evidence supports the idea that aberrant LLPS behavior is associated with various diseases, including cancer and infectious diseases. These findings suggest that LLPS provides a new framework for understanding complex regulatory phenomena in cells. In this review, we provide a comprehensive overview of LLPS, focusing on the biophysical mechanisms underlying condensate formation, the molecular composition of biomolecular condensates, and current experimental approaches used to study this process. In particular, we highlight the role of LLPS in aberrant transcriptional regulation, with a specific focus on its regulatory functions and underlying molecular mechanisms in tumor cells. Collectively, this review provides an updated perspective on the functional and mechanistic roles of LLPS in physiological and pathological contexts, particularly in tumor biology.
    Keywords:  biomolecular condensate; liquid–liquid phase separation; transcription; tumor
    DOI:  https://doi.org/10.3390/ijms27156766
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