bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–05–24
73 papers selected by
Cédric Chaveroux, CNRS
  1. Diverse stresses differentially regulate rRNA biogenesis and mRNA translation.
  2. Ribosomal RNA processing undergoes surveillance by the mRNA guard protein Npl3.
  3. Stress granules and RNA modifications in blood development and erythroid regeneration.
  4. SIRT2 mediates integrated stress response by deacetylating and stabilizing 4E-BP1 to suppress translation.
  5. Unexpected ribosome turnover during prolonged translation inhibition.
  6. The Rare RNA Methylations m²G, Cm, m⁵U and ms²i⁶A: Roles in Disease Pathogenesis and Emerging Therapeutic Implications.
  7. Role of RNA 5‑methylcytosine modification in cancer: Insights from coding and non‑coding RNAs (Review).
  8. Reh1 is Required for Nonfunctional 25S RNA Decay.
  9. Identification of a conserved receptor for degrading ribosomes through autophagy.
  10. The Integrated Stress Response Protein, eIF2α, Modulates UPRmt Signaling and Cell Death in Doxorubicin Treated Human Cardiac Cells.
  11. The role of the nucleus in the control of mitochondrial precursor proteins in yeast.
  12. The Pseudomonas aeruginosa ribonuclease Ribocin cleaves eukaryotic ribosomes at helix 69 to inhibit host translation.
  13. Growth-dependent tRNA Reprogramming and Codon Bias Link Translation to Metabolic State in Enterococcus faecalis.
  14. Proteomic Identification of Small-Subunit Ribosome Assembly Factors in Trypanosoma brucei.
  15. The Role of N6-Methyladenosine Modification in Health and Disease.
  16. Analysisoftheinvolvementof RNA-bindingproteinsintau-dependentneurodegeneration.
  17. The m6A reader IGF2BP3 promotes triple-negative breast cancer metastasis through HOXB9-IL15RA pathway.
  18. Systematic Quantification of Protein O-GlcNAcylation Reveals Common and Cell-Type-Specific Responses to N-Glycosylation Inhibition in Human Cells.
  19. RanBP2-dependent SUMOylation of G3BP2 inhibits formation, and promotes disassembly, of stress granules.
  20. Human SRD5A1 as a case of gene expression indel-resistance in triple-coding region.
  21. FuNGI: Fungal Nucleolar Genomic Inventory-a comprehensive database of fungal proteins with predicted nucleolar localization signals.
  22. m6A RNA methylation in sepsis-induced cardiomyopathy: direct cardiac mechanisms, emerging therapeutic targets, and translational gaps.
  23. Inhibition of the mitochondrial pyruvate carrier attenuates the integrated stress response activation in a cellular model of Huntington's disease.
  24. Genome-wide identification and expression analysis of YTH domain-containing RNA-binding protein family in maize reveals their potential role under abiotic stresses.
  25. Mechanistic Insights Into the Oxidative Reactivity of 2-Selenouridine in tRNA.
  26. A Phosphorylation Switch Modulates Configurational Codes in the Oncofetal IGF2BP RNA Binding Paralogs.
  27. RBM15B-mediated m6A modification of FOXM1 activates the AURKA/TPX2 axis to promote epithelial-mesenchymal transition-driven endometrial cancer progression.
  28. RNA Modifications as Drug Targets: Unlocking the Therapeutic Potential of the Epitranscriptome.
  29. Elucidating structure-function relationships in the mammalian nucleolus.
  30. Interaction between Rsp5-dependent ubiquitination and trehalose production during Cryptococcus neoformans temperature stress adaptation.
  31. Probing RNA-protein interactions in the early mouse embryo.
  32. ER-phagy drives resistance to mitochondria-targeted therapy in breast cancer.
  33. Oxidative stress and endoplasmic reticulum stress in acute kidney injury: mechanistic crosstalk and therapeutic modulation.
  34. Impact of Prematurity on Nutrient Signaling and Protein Synthesis in Skeletal Muscle.
  35. m6A modification in skeletal system diseases (Review).
  36. Ribo-Tweezer: Rapid removal of ribosomal proteins reveals additional layers of post-transcriptional gene regulation.
  37. Increased mRNA translation delays tumour initiation and exposes a therapeutic vulnerability in lung cancer.
  38. Mapping of in vivo cleavage sites uncovers a major role for yeast RNase III in regulating protein-coding genes.
  39. Heat Shock Proteins as Cancer Biomarkers: From Mechanism to Clinical Application.
  40. Heme oxygenase-1 does not affect formation of stress granules.
  41. A mechanism for substrate quality control in outer membrane protein assembly.
  42. Synergy of RNA Concentration, RNA Binding Proteins, and RNA Palindrome Drives clustering of oskar mRNA in vivo.
  43. eIF5A coordinates the transcription and translation of its target genes.
  44. Proximity chemistries to study RNA biology at the subcellular scale.
  45. Stress-Responsive Protein IFRD1 Protects Assembled Ribosomes via a Ribosome-Salvaging Mechanism.
  46. Unlocking translational control of specialized metabolism in plants through 5'UTR structure.
  47. YTHDF1-Mediated m6A Modification of NREP Promotes Corneal Fibrosis via TGF-β-Smad Signaling.
  48. Reengineering Protease Inhibitors to Disrupt Hsp70 Chaperone Function.
  49. Dynamic sumoylation is essential in yeast for suppressing stress-induced gene expression in non-stress conditions.
  50. RNA duplex formation and competing endogenous RNA, proposed as mechanisms in regulating expression of natural antisense transcripts- from hypotheses to potential therapeutic applications.
  51. Identification and exploration of potential N6-methylation related mRNAs in endometriosis.
  52. Genome comparison of the bacteria in Mycobacterium avium complex (MAC) reveals the role of translational selection in shaping codon usage patterns.
  53. Long-read transcriptomic profiling of a glioma cell line following m6A regulator perturbations.
  54. circHIPK3 Sustains Ribosome Biogenesis and Protects Against Cardiac Aging by Stabilizing Ncl mRNA and Supporting its LLPS.
  55. The use of Benzonase to produce ribosome footprints simplifies translational levels quantification by Ribo-seq.
  56. Dynamics of synthetic transcriptional condensates emerge from RNA synthesis and degradation.
  57. Epigenetic signatures and cellular stress response pathways in metabolic dysfunction-associated steatotic liver disease: a personalized medicine perspective.
  58. Stress-Activated Pathways Mediate PFAS Effects on Human Placental Syncytiotrophoblast Cells.
  59. RNA methylation in autoimmune rheumatic diseases: mechanisms and therapeutic potential.
  60. A Multidimensional View of Biomolecular Condensates in Plant Biology.
  61. Nuclear Speckles Regulate Splicing During Muscle Stem Cell Activation and Aging.
  62. Multi-omics analysis reveals LARP1 as a key integrator of translation and metabolism in AML.
  63. METTL16 Promotes Head and Neck Squamous Cell Carcinoma Progression via m6A-Mediated Stabilization of SREBP2 mRNA and Enhanced Cholesterol Biosynthesis.
  64. Diverse mechanisms of translation arrest by a Clostridia ribosome stalling peptide CliM.
  65. IRES-TrAPPr reveals novel insights into viral and cellular mRNA translation.
  66. A universal Fab targeting a conserved U1A-RNA epitope for RNA structure determination by cryo-EM.
  67. OptoRibo-seq for spatiotemporally resolved mapping of the local protein translatome.
  68. Decoding the genetic basis of demyelination: Prediction of potential pathogenic coding and regulatory noncoding MBP SNPs in multiple sclerosis.
  69. High-resolution mapping of CCR4-NOT recruitment elements reveals transcriptome-wide drivers of mRNA decay.
  70. Impact of IGF2BP2 genetic variants and expression levels with the progression of endometrial cancer.
  71. Discovery of Fosigotifator, a Potent eIF2B Activator with Desired Properties for Human Studies.
  72. PRMT3 in cancer: arginine methylation as a driver of tumor metabolism, immune evasion, and therapeutic resistance.
  73. Twenty-Five Years of the Environmental Stress Response and the Enduring Power of Yeast in Stress Biology.
  1. Nucleic Acids Res. 2026 May 05. pii: gkag499. [Epub ahead of print]54(9):
    Diverse stresses differentially regulate rRNA biogenesis and mRNA translation.
    Anne Aldrich, Rachael Thomas, Michael Blower, Shawn M Lyons.
      Ribosome synthesis is one of the most energy-intensive processes in a growing cell, consuming >60% of cellular energy reserves. As such, ribosome biogenesis is highly sensitive to stress to prevent costly expenditures under adverse conditions. Moreover, successful assembly requires precise stoichiometric balance between ribosomal proteins and ribosomal RNAs (rRNA). Here, we define novel regulatory mechanisms of ribosome biogenesis under stress that reveal previously unrecognized aspects of rRNA maturation. We demonstrate that early pre-rRNA processing is particularly sensitive to stress induced by environmentally relevant heavy metals. Surprisingly, our analysis shows that 5' and 3' end processing can be uncoupled in human cells, with 3' end cleavage occurring independently of 5' end processing. We further show that classical inducers of endoplasmic reticulum stress suppress ribosomal protein synthesis without inhibiting rRNA transcription, leading to an imbalance between these essential components of ribosome assembly. This imbalance may exacerbate cellular stress and compromise proteostasis. Together, our findings uncover stress-specific checkpoints in ribosome biogenesis that link environmental exposures to disrupted nucleolar function and highlight new layers of regulation in human rRNA maturation.
    DOI:  https://doi.org/10.1093/nar/gkag499
  2. Cell Mol Life Sci. 2026 May 19. pii: 209. [Epub ahead of print]83(1):
    Ribosomal RNA processing undergoes surveillance by the mRNA guard protein Npl3.
    Anne-Sophie Lindemann, Fei Yu, Yawen Duan, Ivo Coban, Ulla-Maria Schneider, Jan-Philipp Lamping, Ali Khreiss, Katherine E Bohnsack, Heike Krebber.
      Ribosome production is an essential, but highly energy-demanding and complex cellular process. High-fidelity ribosome assembly is critical to ensure integrity of the proteome, and during their biogenesis, the pre-ribosomal subunits undergo surveillance so that defective complexes are removed. Currently, knowledge on the mechanisms of pre-ribosome quality control lag behind understanding of other RNA surveillance pathways. Interestingly, a family of "guard proteins" has been shown to monitor mRNA maturation in S. cerevisiae and act as maturation switches by either licensing ongoing biogenesis or, in case assembly defects are detected, recruiting components of the RNA degradation machinery. Here, we reveal association of the mRNA guard protein Npl3 with RNA polymerase I, the ribosomal DNA (rDNA) locus and early pre-ribosomal particles. Consistent with this, our data show that Npl3 is required for recruitment of a subset of ribosome assembly factors to the nascent pre-rRNA transcript, and we demonstrate a role for Npl3 in the turn-over of aberrant precursor ribosomal RNA (pre-rRNA). Aberrant pre-rRNAs polyadenylated by Trf5 are bound by Npl3, which in turn interacts with Air1 to recruit the RNA exosome for degradation. Thus, Npl3 is a multifunctional RNA surveillance factor, recognizing different types of aberrant pre-RNAs and promoting recruitment of the RNA degradation machinery to clear these transcripts.
    Keywords:  23S rRNA; ETS1; RDNA; RNA degradation; RNA exosome; RNA polymerase I; RNA quality control; RRNA maturation; RRNA processing; Ribosome biogenesis; TRAMP complex
    DOI:  https://doi.org/10.1007/s00018-026-06246-6
  3. Curr Opin Hematol. 2026 May 18.
    Stress granules and RNA modifications in blood development and erythroid regeneration.
    Rajesh Gunage.
       PURPOSE OF REVIEW: Stress granules (SGs) are RNA and protein assemblies that form rapidly in the cytoplasm in response to cellular or environmental stress. SGs, traditionally recognized as transient repressors of translation, are now understood as versatile regulatory centers that shape RNA metabolism, signaling, proteostasis, and cell fate. In this review, we collate recent findings showing SGs' role in steady-state and regenerative stress in erythropoiesis.
    RECENT FINDINGS: Blood loss, anemia caused by ribosomal mutations, has been reported to alter the SG axis and protein translation. During regeneration stress, SGs selectively capture lineage-defining RNAs to regulate their translation during recovery phases. This process ensures that blood progenitors and differentiating cells retain essential transcripts, supporting proper fate decisions and regeneration. Pathological SG accumulation disrupts RNA metabolism and translational reprogramming, key to blood cell regeneration.
    SUMMARY: SGs regulate the transcriptome to endure stress via translational control mechanisms during erythropoiesis. SG deregulation can undermine these adaptive processes. Therapies modulating SG formation, dissolving pathological SGs, or influencing RNA sorting via genetics or targeted small molecules promise new directions to restore blood health, treat anemia, and regeneration in a range of blood disorders.
    Keywords:  ATXN2; DBA; RNA modification; stress granules; translation
    DOI:  https://doi.org/10.1097/MOH.0000000000000930
  4. EMBO Rep. 2026 May 18.
    SIRT2 mediates integrated stress response by deacetylating and stabilizing 4E-BP1 to suppress translation.
    Yanlin Zi, Jiaqi Zhao, Miao Wang, Dan Hou, Richard A Cerione, Hening Lin.
      The ability to adapt to nutrient stress, such as amino acid limitation, is crucial for cell survival. The mTORC1 complex and integrated stress response (ISR) are two mechanisms that sense the availability of amino acids and regulate protein synthesis. Here, we reveal a new SIRT2-mediated pathway, downstream of the ISR, that is activated under amino acids limitation to suppress global translation. Under amino acid deprivation, SIRT2 protein level is upregulated translationally by its upstream open reading frame (uORF). SIRT2 in turn suppresses translation, which helps cells to survive amino acid limitation. We identify eukaryotic translation initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), which binds to eIF4E and inhibits translation, as a substrate of SIRT2. SIRT2 deacetylates 4E-BP1 at lysine 69 and stabilizes 4E-BP1 by protecting it from proteasomal degradation, leading to suppression of global translation. Our study uncovers a role for SIRT2 in regulating translation and identifies a new regulatory mechanism of 4E-BP1 in cells.
    DOI:  https://doi.org/10.1038/s44319-026-00803-7
  5. bioRxiv. 2026 May 13. pii: 2026.05.06.723260. [Epub ahead of print]
    Unexpected ribosome turnover during prolonged translation inhibition.
    Paul J Russell, Caleb A Clark, Mia Ashriem, Michael G Kearse.
      Eukaryotes use several distinct quality control pathways to resolve aberrant ribosomes and mRNAs. For example, the no-go decay mRNA pathway is stimulated after ribosome collisions caused by stalled ribosomes translating damaged or truncated mRNAs. Separate decay pathways for non-functional 40S and 60S subunits containing rRNA mutations affecting decoding and peptidyl transferase activity, respectively, have also been elucidated. To our knowledge, whether eukaryotes have evolved a quality control pathway to sense and process globally stalled ribosomes is unclear; however, such a pathway would be advantageous to eukaryotes during exposure to natural elongation inhibitors such as ricin and diphtheria toxin. Here, we test how prolonged robust inhibition of elongation using a high dose of cycloheximide (CHX) affects ribosome turnover. Despite no decrease in cell viability and that mammalian ribosomes have been classically characterized of having a half-life of 3-5 days, a single 24 hr high dose of CHX resulted in drastically shortened half-lives (<24 hr) of 28S and 18S rRNA in A549 cells. A ~2-fold reduction in nearly all ribosome species was observed by polysome analysis in HeLa and A549 cells after prolonged CHX treatment. Depletion of ribosomes was also evident when assessing ribosomal proteins from both the 40S and 60S subunits by Western blot. Literature supports that ribosomes can be degraded by autophagy and the ubiquitin (Ub)-proteasome system. Upon testing inhibitors of both pathways, only proteasome inhibitors (i.e., MG132 and bortezomib) rescued both rRNA and ribosomal protein levels. Proteasome inhibitors also rescued ribosome levels in polysome profiling experiments. Remarkably, rRNA levels were not rescued during CHX treatment when co-treated with the Ub activating enzyme E1 inhibitor, TAK243. Polysome analysis also showed that the high prolonged dose of CHX did not cause robust accumulation of collided ribosomes compared to control treatments. Proteasome-dependent turnover of rRNA was also observed with high doses of other elongation inhibitors, namely anisomycin, homoharringtonine, and lactimidomycin. The recognition capabilities of the pathway were further expanded as we observed that 80S ribosomes not trapped on the mRNA were also targeted for degradation by the proteasome. Together, our findings define the framework of a regulatory pathway in mammalian cells that degrades both ribosomal subunits in response to prolonged periods of robust elongation inhibition.
    DOI:  https://doi.org/10.64898/2026.05.06.723260
  6. Int J Med Sci. 2026 ;23(6): 1966-1981
    The Rare RNA Methylations m²G, Cm, m⁵U and ms²i⁶A: Roles in Disease Pathogenesis and Emerging Therapeutic Implications.
    Keyu Wan, Tiantian Nie, Qin Zhang, Ying Huang, Jing Bian, Jia Min.
      RNA methylation modifications play a central and multifaceted role in various physiological processes by precisely regulating key steps in the RNA life cycle, including nuclear processing, nuclear export, splicing, and cytoplasmic translation. These modifications, which occur on the four nucleotides that constitute RNA strands, are tightly regulated by specific proteins known as "writers," "readers," and "erasers." Advances in high-throughput sequencing and mass spectrometry technologies have progressively unveiled the biological functions of common RNA methylation marks such as N6-methyladenosine (m6A), N1-methyladenosine (m1A), and 5-methylcytosine (m5C). However, our understanding of how RNA modifications influence various cellular processes remains limited, and research focusing on the biological significance of rare RNA methylation modifications is particularly scarce. This review shifts the research focus toward several relatively understudied and less widely recognized RNA methylation modifications, providing an in-depth analysis of four specific modifications: N2-methylguanosine (m2G), 2'-O-methylcytidine (Cm), 5-methyluridine (m5U), and 2-methylthio-N6-isopentenyladenosine (ms2i6A). It comprehensively elucidates their molecular mechanisms, biological functions, and associations with disease. In addition, this article summarizes the current methodologies available for detecting RNA modifications and discusses the potential applications of these RNA methylation modifications in disease therapy.
    Keywords:  2-methylthio-N6-isopentenyladenosine (ms2i6A); 2′-O-methylcytidine (Cm); 5-methyluridine (m5U); N2-methylguanosine (m2G); RNA modification; detection methods; diseases
    DOI:  https://doi.org/10.7150/ijms.125197
  7. Mol Med Rep. 2026 Jul;pii: 199. [Epub ahead of print]34(1):
    Role of RNA 5‑methylcytosine modification in cancer: Insights from coding and non‑coding RNAs (Review).
    Qin Jiang, Yi Gong, Mimi Zhai, Tenglong Tang, Sushun Liu.
      RNA modifications serve notable roles in various biological processes, with >170 identified modifications. These modifications increase the complexity of RNA species by influencing their tertiary structure, biogenesis, localization and function. The combination of high‑throughput detection technologies and corresponding analytical workflows provides a precise 5‑methylcytosine (m5C) landscape, helping to elucidate its biological functions. The m5C methylation occurs in coding and non‑coding RNAs and is dynamically regulated by related enzymes, including methyltransferases (writers), demethylases (erasers) and binding proteins (readers). m5C is involved in various physiological functions and regulates the progression of numerous types of tumors. Aberrant m5C RNA modifications contribute to the proliferation, migration and drug resistance of cancer cells, suggesting that targeting aberrant posttranscriptional modifications in cancer cells may hold promise as an efficient therapy for tumors. The present review systematically outlines the regulatory components of m5C modification, emphasizing their dynamic regulatory roles in RNA metabolism and function. The mechanisms by which m5C modification promotes tumor progression through the regulation of cancer cell proliferation, migration and drug resistance are summarized. The present review proposes that targeting abnormal m5C modifications could serve as a novel strategy for cancer treatment, offering new research directions in oncology.
    Keywords:  5‑methylcytosine; RNA modification; cancer; mRNA; non‑coding RNA
    DOI:  https://doi.org/10.3892/mmr.2026.13909
  8. bioRxiv. 2026 May 07. pii: 2026.05.05.723076. [Epub ahead of print]
    Reh1 is Required for Nonfunctional 25S RNA Decay.
    Caroline Wang, Sham Sunder, Arlen W Johnson.
      25S nonfunctional RNA decay (NRD) eliminates 60S ribosomal subunits carrying inactivating mutations in the RNA. However, how cells identify defective subunits has not been described. We recently showed that the zinc-finger protein Reh1 is the last assembly factor to be released from a nascent 60S subunit. We now show that in yeast Reh1 is required for the degradation of 25S NRD substrates. 25S rRNAs carrying mutations in the catalytic center, A2820G or U2954A (A2451 and U2585, respectively in E coli numbering), are unstable in wildtype cells but are fully stabilized when REH1 is deleted. However, not all 25S rRNA mutations are recognized by Reh1. Ribosomes with a truncated L1 stalk engage in translation but cannot support viability. These ribosomes display a half-life indistinguishable from wild-type rRNA, suggesting that yeast does not have a robust surveillance system for such mutant ribosomes. Deletion of REH1 also has no impact on the levels of defective 18S rRNA. These results indicate that Reh1 and 25S NRD are specific for mutations in or near the catalytic center of the ribosome.
    DOI:  https://doi.org/10.64898/2026.05.05.723076
  9. Autophagy. 2026 Jun;22(6): 1149-1150
    Identification of a conserved receptor for degrading ribosomes through autophagy.
    Chhabi K Govind, Daniel J Klionsky.
      Ribosomes consist of approximately 80 distinct ribosomal proteins and rRNA. The genes encoding these ribosomal components are among the most highly expressed in growing cells. Changes in ribosome composition, such as those induced by oxidative stress, may compromise ribosome function. Such ribosomes are subsequently targeted for degradation. Additionally, under stress, both protein synthesis and ribosome biogenesis are downregulated. Under starvation stress, excess ribosomes are degraded through a process called ribophagy, a selective form of macroautophagy/autophagy that utilizes the autophagy pathway. While receptors for several selective autophagy pathways are known, the evolutionarily conserved ribophagy receptor was not identified until recently. In a recent publication, the authors identify Rpl12 and its homologs as receptors that promotes ribophagy from yeast to humans. They also demonstrate that ribophagy enhances lifespan and facilitates the clearance of pathogenic bacteria.Abbreviations: AIM: Atg8-family interacting motif; ATG: autophagy related; LIR: LC3-interacting region; NUFIP1: nuclear FMR1 interacting protein 1.
    Keywords:  Autophagy; Rpl12A; ribophagy; ribosomes; starvation
    DOI:  https://doi.org/10.1080/15548627.2026.2624242
  10. Cardiovasc Toxicol. 2026 May 20. pii: 53. [Epub ahead of print]26(6):
    The Integrated Stress Response Protein, eIF2α, Modulates UPRmt Signaling and Cell Death in Doxorubicin Treated Human Cardiac Cells.
    Kienan P O'Dwyer, Perry E Bauer, Subhankhi Pal, Kathleen Brundage, Sundararajan Venkatesh.
      Doxorubicin (DOX), is an indispensable first-line chemotherapeutic. Despite this first-line indication, clinical use of DOX is limited by severe, off-target, and often irreversible cardiotoxicity. DOX induces cytotoxicity in rapidly dividing cancer cells via inhibition of Topoisomerase IIα. However, the underlying mechanisms by which DOX causes cell death in non-replicative, terminally differentiated cardiomyocytes remain poorly understood. Emerging evidence suggests that mitochondrial uptake of DOX is contributory to cardiotoxicity. Whether mitochondrial stress pathways, including the mitochondrial unfolded protein response (UPRmt), are activated and critical for mediating DOX cardiotoxicity is poorly understood. Moreover, whether phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), a mediator of the Integrated Stress Response, regulates potential UPRmt signaling during DOX treatment is also unknown. Here, using human AC-16 cardiac cells, we examined the role of eIF2α phosphorylation during DOX treatment. Our data suggest that DOX triggers a transient increase in eIF2α phosphorylation, followed by a progressive decline. Further, knockdown of eIF2α decreased key transcriptional regulators of UPRmt signaling such as C/EBP Homologous Protein and ATF5, blunted the induction of UPRmt genes (AFG3L2, CLPP, HSPA9, HSPD1, LONP1, SPG7), and aggravated DOX induced cytotoxicity. Together, these findings identify eIF2α as a critical upstream regulator of UPRmt signaling, and suggest that activation of the UPRmt may confer cardio-protection against DOX-induced mitochondrial stress in human cardiac cells.
    Keywords:  ATF5; CHOP; Cardiomyocytes; Cardiotoxicity; Doxorubicin; Mitochondria; UPRmt ; eIF2α
    DOI:  https://doi.org/10.1007/s12012-026-10124-9
  11. Protein Sci. 2026 Jun;35(6): e70622
    The role of the nucleus in the control of mitochondrial precursor proteins in yeast.
    Kira Ritzenhofen, Stefano Rossi, Axel Mogk, Fabian den Brave.
      Mitochondria are essential organelles of eukaryotic cells, with vital roles in energy production, biosynthesis of macromolecules, and intracellular signaling. Their function depends on a complex proteome with proteins targeted to different mitochondrial sub-compartments. Synthesis of precursors of mitochondrial proteins (mitoPREs) mostly occurs in the cytosol followed by post-translational import. Delay or block of mitochondrial import leads to mitoPRE accumulation in the cytosol, where they interact with cytosolic protein quality control (PQC) factors and might get re-routed to other cellular organelles, including the nucleus. Recent research implies the nucleus as a central hub in cellular PQC. Here, not only nuclear but also proteins from other organelles, including mitochondria or the cytosol, are handled by intra-nuclear PQC factors. In addition, the nucleus controls the expression of mitochondrial proteins and PQC components involved in handling mitoPREs and surveilling the integrity of mitochondrial import channels. In this review, we discuss recent insights from yeast on the dual function of the nucleus in controlling the biogenesis of mitoPREs and as a compartment for quality control of non-imported mitoPREs. We additionally describe how mitochondrial dysfunction and defects in mitochondrial import trigger compensatory stress responses inside the nucleus. Here, nuclear targeting of non-imported mitoPREs may serve as a direct signal to adjust stress response pathways to the status of mitochondrial import.
    Keywords:  chaperones; mitochondria; nucleus; protein quality control; protein sorting; stress response; ubiquitin‐proteasome system
    DOI:  https://doi.org/10.1002/pro.70622
  12. PLoS Biol. 2026 May;24(5): e3003790
    The Pseudomonas aeruginosa ribonuclease Ribocin cleaves eukaryotic ribosomes at helix 69 to inhibit host translation.
    Alejandro Vasquez-Rifo, Denis Susorov, Emily H Sholi, Gabriel Demo, Yasaman Jami, Jihui Sha, James A Wohlschlegel, Andrei Korostelev, Victor Ambros.
      Pseudomonas aeruginosa employs host translation inhibition as a virulence-enhancing strategy. We previously showed that the bacterium induces cleavage of Caenorhabditis elegans large ribosomal RNA at helix 69 (H69), part of a central intersubunit bridge and the ribosomal decoding center. In this study, we demonstrate that a previously uncharacterized ribonuclease, Ribocin, is necessary and sufficient for H69 cleavage. Recombinant Ribocin cuts H69 in worm and mammalian ribosomes, indicating that H69 cleavage by P. aeruginosa is phylogenetically conserved. In worms, mammalian cells, and rabbit reticulocyte lysates, H69 cleavage results in translation inhibition. Furthermore, Ribocin contributes to bacterial virulence toward C. elegans, triggers a major host response to translation inhibition, and operates in parallel with Exotoxin A-mediated translation inhibition. These findings unveil the first known nuclease that cleaves eukaryotic ribosomes at H69 and expand the understanding of host translation-inhibition by establishing targeted rRNA cleavage as a mechanism of host attack.
    DOI:  https://doi.org/10.1371/journal.pbio.3003790
  13. bioRxiv. 2026 May 09. pii: 2026.05.07.723122. [Epub ahead of print]
    Growth-dependent tRNA Reprogramming and Codon Bias Link Translation to Metabolic State in Enterococcus faecalis.
    Michelle M Mitchener, Caleb M Anderson, Mark Veleba, Kayla Teo, Mélanie Roch, Ruixi Chen, Yifeng Yuan, Isaiah Han, Agnieszka Dziergowska, Kevin Pethe, Thomas J Begley, Kimberly A Kline, Peter C Dedon.
      Enterococcus faecalis is a Gram-positive commensal bacterium of the human gut microbiome and an opportunistic pathogen responsible for many hospital-acquired infections. Despite the clinical importance of E. faecalis , how gene and protein expression are coordinated with growth remains poorly defined. Here, we profiled transcript, protein, and tRNA pool dynamics across distinct phases of E. faecalis growth. Differences in protein abundance and corresponding mRNA levels suggested growth phase-dependent posttranscriptional regulation. Growth-associated genes exhibited biased synonymous codon usage, with ribosomal and glycolytic proteins enriched in low-abundance codons read by queuosine-modifiable tRNAs. Analysis of tRNA modification and tRNA isoacceptor abundance revealed growth phase-dependent changes, particularly in anticodon stem loop modifications that influence synonymous codon translation. Changes in queuosine levels preceded shifts in ribosomal proteins, suggesting a contribution to codon-biased translation. Collectively, these findings reveal growth phase-associated remodeling of the E. faecalis tRNA pool and support a model in which queuosine-dependent translational reprogramming shapes protein expression during bacterial growth.
    IMPORTANCE: Enterococcus faecalis is a common cause of hospital-acquired infections. Despite its clinical importance, a comprehensive understanding of the organism's physiology and adaptation to environmental changes remains incomplete. Here, we characterized protein, transcript, and tRNA dynamics across bacterial growth phases, uncovering a role for post-transcriptional regulation marked by tRNA reprogramming and biased synonymous codon usage. These findings enhance our understanding of E. faecalis growth and support a model of translational reprogramming therein.
    DOI:  https://doi.org/10.64898/2026.05.07.723122
  14. J Proteome Res. 2026 May 18.
    Proteomic Identification of Small-Subunit Ribosome Assembly Factors in Trypanosoma brucei.
    Gustavo Guadagnini Perez, Priscila Mazzocchi Hiraiwa, Verônica Santana da Silva, Nilson Ivo Tonin Zanchin, Beatriz Gomes Guimarães.
      Trypanosomatid ribosomes display distinctive features, including extensive ribosomal RNA (rRNA) expansions and additional insertions in ribosomal proteins. Moreover, the region corresponding to the human 28S rRNA is fragmented into six molecules in these organisms with a duplication of the 3' fragment (ε) inLeishmania. Although these differences suggest that ribosome biogenesis in trypanosomatids may involve unique processing events, the molecular mechanisms underlying this process are still poorly characterized. In this study, we investigated the protein composition of pre-small-subunit (pre-SSU) complexes in Trypanosoma brucei. We generated cell lines expressing tagged versions of UTP6 and PNO1, two conserved ribosome biogenesis factors that provide complementary access to complexes of early SSU processome intermediates and later pre-40S maturation stages. Affinity purification followed by mass spectrometry identified numerous conserved ribosome biogenesis factors alongside a substantial set of trypanosomatid-specific proteins with no assigned function. Structural analyses revealed that many of these uncharacterized proteins contain predicted RNA-binding motifs or protein-protein interaction domains, and have been previously localized to the nucleolus, supporting potential roles in ribosome synthesis. Our findings expand the repertoire of candidate SSU assembly factors in kinetoplastids and highlight species-specific adaptations in ribosome biogenesis, providing a foundation for future functional studies targeting these unique components.
    Keywords:  Trypanosoma brucei; affinity purification; proteomic analysis; ribosome biogenesis; ribosome small-subunit
    DOI:  https://doi.org/10.1021/acs.jproteome.6c00066
  15. MedComm (2020). 2026 Jun;7 e70767
    The Role of N6-Methyladenosine Modification in Health and Disease.
    Linghuan Li, Yuanhai Sun, Wanfang Zheng, Lingqin Li, Yaqian Feng, Minyou Qi, Hanbing Li.
      Emerging evidence highlights that N6-methyladenosine (m6A), the most prevalent internal RNA modification in eukaryotes, serves as a critical epitranscriptomic regulator of RNA metabolism. This posttranscriptional modification modulates alternative splicing, nuclear export, stability, and translation, thereby regulating various physiological processes. Notably, dysregulation of m6A-associated modifiers (writers/erasers/readers) is implicated in a variety of diseases, such as metabolic disorders and cancer. Despite the rapid progress of m6A-mediated emerging therapeutic strategies, there remains an imperative to bridge the gap between basic epitranscriptomics and clinical application. This review systematically depicts recent advances in understanding m6A-mediated epitranscriptomic regulation, with particular focus on its dual role in maintaining cellular homeostasis and driving disease progression upon dysregulation, provides a dedicated exploration of m6A-regulated mitochondrial remodeling, and outlines cutting-edge technologies for m6A mapping and inhibitors targeting m6A modifiers. Furthermore, we conduct an in-depth exploration of the existing limitations and therapeutic potential associated with targeting m6A modification. Acting as a pivotal link between epitranscriptomics and medicine, m6A modification provides novel perspectives for developing precision interventions in complex human diseases.
    Keywords:  N6‐methyladenosine; diseases; molecular mechanisms; therapy
    DOI:  https://doi.org/10.1002/mco2.70767
  16. Neurobiol Dis. 2026 May 20. pii: S0969-9961(26)00199-3. [Epub ahead of print] 107454
    Analysisoftheinvolvementof RNA-bindingproteinsintau-dependentneurodegeneration.
    Ignacio Silva-Llanes, Pablo Baceiredo-Macho, Isabel Lastres-Becker.
      TAU-dependent neurodegeneration encompasses a group of disorders, collectively known as tauopathies, characterized by the pathological accumulation of the TAU protein. TAU is a microtubule-associated protein that stabilizes neuronal microtubules, but emerging evidence indicates it also plays a role in RNA metabolism through interactions with RNA-binding proteins (RBPs). RBPs are essential for the regulation of mRNA transport, translation, and the formation of stress granules (SGs), which are critical for synaptic function and maintenance. We hypothesize that TAU pathology induces dysregulation of RBPs involved in RNA transport, the translation preinitiation complex (PIC), and SG formation, contributing to neurodegeneration. We observed that the expression of RBPs involved in RNA transport, PIC, and SG formation is increased in the hippocampus of both an adeno-associated virus AAV-TAUP301L mouse model and 8 months old transgenic TAUP301S mice, as well as in samples from patients with Alzheimer's disease (AD). This change in expression is evident at both mRNA and protein levels and, in some cases, is accompanied by alterations in their subcellular localization. Our results suggest that RBP dysregulation is a common mechanism in various tauopathies and may be related to impaired TAU functionality. Furthermore, the upregulation of RBPs may represent a compensatory mechanism in response to deficits in synaptic translation.
    Keywords:  ATAXIN-2; PABP; RNA-binding proteins (RBP); STAUFEN; TAU; TIA1
    DOI:  https://doi.org/10.1016/j.nbd.2026.107454
  17. Funct Integr Genomics. 2026 May 22. pii: 107. [Epub ahead of print]26(1):
    The m6A reader IGF2BP3 promotes triple-negative breast cancer metastasis through HOXB9-IL15RA pathway.
    Xinhao Zhang, Yehao Wang, Na Wang, Ting Wang, Tongtong Jiang.
      Triple-negative breast cancer (TNBC) is among the most life-threatening women malignancies with largely uncharacterized pathogenic mechanisms. While N6-methyladenosine (m6A) methylation has been documented to impact carcinogenesis through extensively altering the gene expression profile, its precise role in TNBC remains poorly understood. Here, we found that insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) promotes TNBC progression in an m6A modification-dependent way. Mechanistically, IGF2BP3 binds to and stabilizes the mRNA of a transcription factor, HOXB9, which subsequently licenses the expression of interleukin 15 receptor α subunit (IL-15RA). The IL-15/IL15RA signaling thus potentiates the migration and invasion of neoplastic cells and contributes to in vivo metastasis of TNBC. These observations provide novel insights into the role of RNA modification in the occurrence of TNBC, and demonstrate the applicability of targeting the m6A machinery especially specific reader proteins in the clinical treatment of advanced TNBC.
    Keywords:  HOXB9; IGF2BP3; IL15RA; Metastasis; Triple-negative breast cancer; m6A
    DOI:  https://doi.org/10.1007/s10142-026-01881-5
  18. Anal Chem. 2026 May 19.
    Systematic Quantification of Protein O-GlcNAcylation Reveals Common and Cell-Type-Specific Responses to N-Glycosylation Inhibition in Human Cells.
    Longping Fu, Kejun Yin, Xing Xu, Ronghu Wu.
      Both protein O-GlcNAcylation and N-glycosylation are extremely important in human cells and regulate many cellular events. While O-GlcNAcylation is known to act as a stress sensor, its changes in human cells with N-glycosylation perturbations remain to be explored. In this study, we comprehensively and site-specifically studied common and cell-type-specific responses of protein O-GlcNAcylation under N-glycosylation inhibition in three types of human cells (HEK293T, HepG2, and Jurkat cells) by integrating metabolic labeling, bio-orthogonal chemistry, and multiplexed proteomics. In total, more than 1000 O-GlcNAcylated proteins were identified and quantified, and the results demonstrate that under the inhibition of protein N-glycosylation, O-GlcNAcylated proteins related to stress response and translation are commonly changed in different types of cells. Furthermore, O-GlcNAcylation changes are cell-type-specific, and O-GlcNAcylated proteins related to leukocyte proliferation and T-cell activation were upregulated in Jurkat cells, while in HEK293T cells, those associated with ribonucleotide metabolism and ribosome biogenesis were upregulated. Site-specific analysis revealed that O-GlcNAcylation sites in structured regions exhibited larger abundance changes compared with those in intrinsically disordered regions. This study provides valuable insights into the regulation of protein O-GlcNAcylation in human cells under N-glycosylation inhibition, advancing our understanding of protein glycosylation.
    DOI:  https://doi.org/10.1021/acs.analchem.6c00972
  19. Mol Biol Cell. 2026 May 20. mbcE25030135
    RanBP2-dependent SUMOylation of G3BP2 inhibits formation, and promotes disassembly, of stress granules.
    Yifan E Wang, Javid Guliyev, Sean S J Ihn, Gaelen Moore, Fermisk Saleh, Hyun O Lee, Alexander F Palazzo.
      Stress granules and processing bodies (P-bodies) are dynamic cytoplasmic ribonucleoprotein (RNP) condensates that coordinate translation inhibition, mRNA storage, and decay during cellular stress. Emerging evidence suggests that SUMOylation contributes to the regulation of these RNP granules in human cells, though the underlying mechanisms remain largely unexplored. Here, we identify RanBP2-dependent SUMOylation as a key regulator of stress granule and P-body dynamics. Cells that lack RanBP2-mediated SUMOylation show enhanced stress granule assembly and delayed disassembly in response to oxidative stress. We further demonstrate that G3BP2, a core component of stress granules, is SUMOylated in a RanBP2-dependent manner at lysine 281, and that this modification limits spontaneous stress granule formation and promotes efficient disassembly. In addition, the loss of RanBP2-mediated SUMOylation reduces P-body abundance and promotes the merging of a subset of P-bodies with stress granules during stress. Together, our findings suggest that SUMOylation may regulate RNP granules by increasing G3BP solubility, thereby limiting stress granule formation, and by maintaining the balance and segregation of stress granules and P-bodies.
    DOI:  https://doi.org/10.1091/mbc.E25-03-0135
  20. Genome Biol. 2026 May 18.
    Human SRD5A1 as a case of gene expression indel-resistance in triple-coding region.
    Martina M Yordanova, Jack A S Tierney, Kyle A Meiklejohn, Conor Slattery, Michał I Świrski, Mirriam Baranova-Gurvich, Manon Engels, Oscar Ting, Ananth Prakash, Håkon Tjeldnes, Jonathan M Mudge, Gary Loughran, Juan Antonio Vizcaíno, Dmitry E Andreev, Pavel V Baranov.
       BACKGROUND: Nucleotide sequence can be translated in three reading frames producing distinct protein products. Many examples of RNA translation in two reading frames (dual coding) have been identified so far.
    RESULTS: We report translation of mRNA transcripts derived from SRD5A1 locus in all three reading frames that result in the synthesis of long polypeptides. This occurs due to initiation at three nearby AUG codons occurring in all three reading frames. Only one of the three proteoforms contains the conserved catalytical domain of SRD5A1 produced either from the second or the third AUG codon depending on the transcript. Paradoxically, ribosome profiling data and expression reporters indicate that the most efficient translation would produce catalytically inactive polypeptide. While phylogenetic analysis suggests that the long triple decoding region is specific to primates, occurrence of nearby AUGs in all three reading frames is ancestral to placental mammals. This suggests that their evolutionary significance belongs to regulation of translation rather than biological role of their products. By analysing multiple publicly available ribosome profiling data and with gene expression assays carried out in different cellular environments, we show that relative expression of these proteoforms is mutually dependent and varies across environments supporting this conjecture. We show that a remarkable feature of triple decoding is its resistance to frameshift causing variants with apparent implications to clinical interpretation of genomic sequence variants.
    CONCLUSIONS: We argue for the importance of identification, characterisation and annotation of productive RNA translation irrespective of the presumed biological roles of its products.
    Keywords:  Gene annotation; Overlapping genes; Protein synthesis; Ribosome decision graphs; SRD5A1; Translation control; Translation initiation; Translon; uORF
    DOI:  https://doi.org/10.1186/s13059-026-04106-x
  21. Database (Oxford). 2026 Jan 15. pii: baag023. [Epub ahead of print]2026
    FuNGI: Fungal Nucleolar Genomic Inventory-a comprehensive database of fungal proteins with predicted nucleolar localization signals.
    Gnanendra Shanmugam, Chaewon Kim, Surajit De Mandal, Minji Kim, Song Hee Lee, Jaeyoung Choi, Junhyun Jeon.
      The nucleolus is a well-characterized sub-nuclear compartment primarily responsible for ribosomal RNA (rRNA) synthesis and ribosome biogenesis. In addition to these canonical functions, it plays roles in a variety of other cellular processes. Despite its importance, the contributions of the nucleolus to fungal development and pathogenicity remain poorly understood, especially in filamentous fungi. The structure and function of the nucleolus are regulated by numerous proteins that either reside within it or shuttle between the nucleolus and nucleoplasm, often guided by short amino acid motifs known as nucleolar localization signals (NoLSs). However, comprehensive resources cataloguing nucleolar proteins and their localization signals in fungi are currently lacking, hindering systematic investigations of nucleolar function across species. To address this gap, we developed FuNGI (Fungal Nucleolar Genomic Inventory), a web-based interactive database for the exploration of fungal proteins containing predicted nucleolar localization signals. The current version of FuNGI includes proteins containing predicted nucleolar localization signals and their associated NoLSs across 769 fungal proteomes spanning eight phyla. The database offers a user-friendly interface that enables browsing, retrieval, and comparison of NoLS-containing proteins across multiple species. Each entry integrates sequence-based predictions and functional annotations to support comparative and functional analyses. To our knowledge, FuNGI is the first comprehensive and interactive database dedicated to fungal proteins containing predicted nucleolar localization signals. By enabling systematic and cross-species analyses, FuNGI provides a valuable resource for advancing our understanding of fungal nucleoli and their roles in fungal biology and pathogenicity.
    DOI:  https://doi.org/10.1093/database/baag023
  22. Front Med (Lausanne). 2026 ;13 1826751
    m6A RNA methylation in sepsis-induced cardiomyopathy: direct cardiac mechanisms, emerging therapeutic targets, and translational gaps.
    Fengmei Zhang, Lijun Zhang, Yuhan Wang.
      Sepsis-induced cardiomyopathy (SICM) develops in up to 60% of patients with sepsis, substantially increases mortality, and currently lacks specific pharmacotherapy. N6-methyladenosine (m6A), the most prevalent internal modification on eukaryotic mRNA, dynamically regulates transcript fate through coordinated actions of methyltransferases (writers), demethylases (erasers), and binding proteins (readers). Direct cardiac studies have now implicated multiple m6A regulators in several key cellular processes relevant to SICM, including inflammatory injury, apoptosis, pyroptosis, ferroptosis, and adaptive mitophagy. Current evidence highlights pronounced context dependence: the eraser FTO shows the most consistent cardioprotective profile across inflammation, ferroptosis, and mitophagy, whereas the other eraser ALKBH5 paradoxically promotes pyroptotic injury, and the writer METTL3 predominantly drives damage through distinct transcript-reader axes. Notably, several independent m6A pathways converge on the SLC7A11/GPX4/NRF2 antioxidant network, suggesting that ferroptosis-centered m6A regulation may represent the most coherent translational entry point identified thus far. This review synthesizes the direct cardiac evidence using a process-oriented framework, distinguishes injury-associated pathways from adaptive mitochondrial quality control, and identifies critical translational gaps-including heavy reliance on lipopolysaccharide-based models, limited use of primary cardiomyocytes and cardiac-specific genetic tools, and the absence of human validation-that must be addressed before m6A-targeted strategies can advance toward clinical application.
    Keywords:  FTO; METTL3; N6-methyladenosine; apoptosis; epitranscriptomics; ferroptosis; pyroptosis; sepsis-induced cardiomyopathy
    DOI:  https://doi.org/10.3389/fmed.2026.1826751
  23. Mol Cell Biochem. 2026 May 21.
    Inhibition of the mitochondrial pyruvate carrier attenuates the integrated stress response activation in a cellular model of Huntington's disease.
    Ângela Oliveira, Liliana M Almeida, Jorge M A Oliveira, Brígida R Pinho.
      Mitochondrial pyruvate carrier (MPC) inhibition was found protective in models of neurodegenerative diseases, such as Alzheimer's and Parkinson's. However, little is known about MPC as a potential therapeutic target in Huntington's disease (HD), a neurodegenerative disorder with dysregulation of the pro-survival pathway integrated stress response (ISR). Here, we investigate if MPC inhibition modulates the ISR and mitigates mutant huntingtin (mut-Htt) proteotoxicity in a cellular HD model. We treated cells expressing N-terminal fragments of wild-type- (wt-) or mut-Htt with two MPC inhibitors (mitoglitazone and UK5099) or solvent control. Metabolism was assessed analysing resazurin reduction, oxygen consumption, extracellular acidification, and ATP levels. ISR activation and huntingtin proteostasis were assessed using western-blot and filter-trap assays. Mut-Htt-expressing cells showed decreased resazurin reduction and ATP levels, and increased eIF2α phosphorylation, indicating metabolic stress and ISR activation. MPC inhibitors (100 µM) increased resazurin reduction and decreased respiration. The latter was rescued by the membrane-permeant methyl pyruvate, which bypasses MPC inhibition. In wt-Htt-expressing cells, MPC inhibitors increased levels of ATP and ISR markers, suggesting metabolic adaptation and ISR activation. In mut-Htt-expressing cells, MPC inhibitors preserved ATP levels and attenuated mut-Htt-induced eIF2α phosphorylation but without changing soluble or aggregated mut-Htt levels. This work showed that MPC inhibition differentially modulates the ISR: it activates ISR in control cells and attenuates overactive ISR in mut-Htt-expressing cells. However, MPC inhibition did not impact the proteostasis of N-terminal fragment mut-Htt. Further studies are essential to explore MPC inhibition in less severe full-length mut-Htt-expressing models to better understand its therapeutic potential in HD.
    Keywords:  Aggregation; Huntingtin; Huntington’s disease; Integrated stress response; Metabolism; Mitochondrial pyruvate carrier
    DOI:  https://doi.org/10.1007/s11010-026-05573-3
  24. Sci Rep. 2026 May 18.
    Genome-wide identification and expression analysis of YTH domain-containing RNA-binding protein family in maize reveals their potential role under abiotic stresses.
    Hameed Gul, Shareef Gul, Gao Jing, Rakia Manzoor, Muhammad Mudasir, Liu Qiuyi, Sumit Singh, Ali Shahzad.
      Post-transcriptional control of gene expression is one of the strategies in plants to regulate growth, development, and stress adaptation. YT521-B homology (YTH) domain-containing RNA-binding proteins are essential for this post-transcriptional control through influencing the fate of RNA molecules containing N6-methyladenosine (m6A). Here, we conducted a genome-wide identification and characterization analysis of the YTH gene family in maize (Zea mays L.) and found 22 ZmYTHs. Phylogenetic analysis showed that the ZmYTH could be divided into four groups, while the ZmYTH genes are distributed across ten chromosomes. Subcellular localization analysis suggests that most ZmYTH proteins often exhibit a nuclear localization consistent with their involvement in RNA metabolism. Duplication of genes, in particular segmental and whole-genome duplications, has driven the proliferation of this gene family, potentially endowing maize with greater capacity to regulate stress-responsive pathways. Further, we identified 31 cis-regulatory elements in the promoter regions of ZmYTH genes involved in development, stress, and hormonal regulation. Protein-protein interaction prediction and miRNA target prediction further elaborate their role in post-transcriptional modification. We profiled ZmYTH's expression pattern across development and stress conditions, confirming 10 genes differentially expressed under drought, salt, and heat stresses. ZmYTH1 and ZmYTH3 were consistently induced, ZmYTH7 was repressed under all three conditions, and the remaining genes showed condition-specific patterns. Overall, these findings highlight the key role of the ZmYTH family in stress adaptation and provide a basis for future studies on its molecular mechanisms.
    Keywords:   Zea mays ; Abiotic stress response; Genome-wide identification; YTH domain proteins; YTH gene family; m6A RNA modification
    DOI:  https://doi.org/10.1038/s41598-026-53179-y
  25. Chemistry. 2026 May 16. e71130
    Mechanistic Insights Into the Oxidative Reactivity of 2-Selenouridine in tRNA.
    Katarzyna Kulik, Ewelina Wielgus, Michelangelo Cocchioni, Hilda Kovács, Éva A Enyedy, Anna Maciaszek, Barbara Nawrot.
      Selenium-containing nucleosides, such as 2-selenouridine, represent natural transfer RNA (tRNA) modifications that influence translation fidelity and cellular stress responses. In this study, we investigated the oxidative behavior of Se2U and its derivatives, including 5-methylaminomethyl-2-selenouridine, both as free nucleosides and within a tRNA anticodon stem-loop model. Electrochemical and spectroelectrochemical analyses revealed that Se2U exhibits greater redox reactivity than its sulfur analogue, 2-thiouridine, undergoing rapid and reversible oxidation to diselenide species under anaerobic conditions. Chemical oxidation with hydrogen peroxide produced diselenides and deselenated products, while biologically relevant thiols, such as glutathione and dithiothreitol, efficiently restored the parent nucleosides. Oxidation of Se2U within RNA led to uridine and 4-pyrimidinone riboside formation, potentially altering codon recognition, and enabled nucleophilic substitution at the C2 position both by glutathione, as a biologically relevant nucleophile, and by hexafluoroisopropanol, a nucleophilic buffer component used in our experiments, underscoring the general character of this transformation. These findings suggest that oxidation proceeds via transient acidic selenium species, which act as efficient leaving groups and may facilitate additional post-transcriptional modifications under oxidative stress. Overall, this study provides mechanistic insight into Se2U oxidation and suggests that oxidative activation - mediated tRNA modifications, could influence translation and cellular stress adaptation.
    Keywords:  2‐selenouridine; modified nucleosides; selenium; transfer RNA; wobble nucleoside
    DOI:  https://doi.org/10.1002/chem.71130
  26. bioRxiv. 2026 May 08. pii: 2026.05.07.723538. [Epub ahead of print]
    A Phosphorylation Switch Modulates Configurational Codes in the Oncofetal IGF2BP RNA Binding Paralogs.
    Vikas Kaushik, Vaishnavi Sanjayan, Jenna Mattice, Monika Tokmina-Lukaszewska, Ricarda Törner, Rahul Chadda, Rajnandani Kashyap, Abhinav Vayyeti, Pralambika Roy, Ryan A Mehl, Richard B Cooley, Snorri Th Sigurdsson, Reza Dastvan, Haribabu Arthanari, Brian B Bothner, Sofia Origanti, Edwin Antony.
      The insulin-like growth factor 2 mRNA-binding proteins (IGF2BP1-3) are oncofetal RNA regulators that control translation, stability, and localization of several transcripts, yet display paralog-specific functions despite high structural similarity. Each paralog contains six RNA-binding domains (two RRMs and four KH domains) linked by intrinsically disordered segments. mTORC2 phosphorylates IGF2BP1 and IGF2BP3 at a single conserved serine within the disordered linker between the RRM2 and KH1 domains, a modification required for proper regulation of mRNA translational fate. Pairing site-specific phosphoserine incorporation with structural and biophysical interrogations, we show that this phosphorylation acts as a configurational switch that reorganizes long-range arrangements of RNA-binding domains and linkers without altering the secondary structure, and with only modest effects on RNA-binding affinity. Critically, pSer-driven rearrangements occur both in the RNA-free state and upon RNA engagement, and the resulting architectures differ markedly between IGF2BP1 and IGF2BP3 despite >70% sequence identity. These paralog-specific, phosphorylation-dependent configurational landscapes likely underlie differences in mRNA recognition modes and functional outcomes. Our work identifies a post-translational mechanism that tunes IGF2BP paralog dynamics across free and RNA-bound states to program target mRNA selection, processing, and translational fate.
    DOI:  https://doi.org/10.64898/2026.05.07.723538
  27. Cell Adh Migr. 2026 Dec;20(1): 2674357
    RBM15B-mediated m6A modification of FOXM1 activates the AURKA/TPX2 axis to promote epithelial-mesenchymal transition-driven endometrial cancer progression.
    Lijing Zhang, Ping Wu.
      Endometrial cancer(EC) is increasing worldwide, but its molecular mechanisms remain unclear. This study explored whether RBM15B-mediated m6A modification of FOXM1 promotes EC progression through the AURKA/TPX2 axis and epithelial-mesenchymal transition(EMT). Bioinformatics analyses assessed FOXM1 expression and prognosis in EC. RNA pull-down, MeRIP-PCR, dot blot, and RNA stability assays examined m6A regulation. Colony formation, Transwell, wound healing, and tumor sphere assays evaluated malignant behaviors. FOXM1 was significantly upregulated in EC and associated with unfavorable prognosis. Functional assays showed that FOXM1 enhanced proliferation, migration, invasion, and stemness of EC cells. Mechanistically, RBM15B increased m6A modification of FOXM1 mRNA and promoted expression. RBM15B knockdown inhibited malignant phenotypes and reduced activation of the downstream AURKA/TPX2 pathway. RBM15B-mediated m6A methylation stabilizes FOXM1 expression, activates the AURKA/TPX2 axis, and promotes EMT and EC progression. Targeting the RBM15B/FOXM1/AURKA/TPX2 pathway may offer therapeutic potential.
    Keywords:  Endometrial cancer; FOXM1; N6-methyladenosine; epithelial-mesenchymal transition
    DOI:  https://doi.org/10.1080/19336918.2026.2674357
  28. Curr Genomics. 2025 ;26(7): 802-818
    RNA Modifications as Drug Targets: Unlocking the Therapeutic Potential of the Epitranscriptome.
    Dhananjay Taumar, Atul Pratap Singh, Himanchal Sharma, Vatan Chaudhary.
       Introduction: The epitranscriptome covers reversible changes to RNA. These changes help control gene expression by making RNA more stable, easier to use, or more prone to degradation. They are increasingly implicated in disease development and offer a promising target for treatment. This review covers RNA alterations and their potential clinical applications.
    Methods: The systematic analysis of the peer-reviewed literature was performed, including experimental, clinical, and computational research. The biochemical properties and biological functions were used to classify RNA modifications. In addition, we evaluated current therapeutic options, including small molecules, CRISPR/Cas-based technologies, and RNA-targeted approaches.
    Results: RNA undergoes immense changes, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), and pseudouridine. By these modifications, the genes are regulated by coordinated writers, erasers, and readers. Targeted therapeutics aim to regulate changes in cancer, neurodegenerative disease, and viral diseases. Several limitations remain, including overly general framing, suboptimal clarity in conveying the message, and inadequate response mechanisms.
    Discussion: The epitranscriptome provides an additional regulatory layer with significant therapeutic applications. New techniques appear to be successful. Researchers, in turn, should be more specific. These therapies require improved delivery vehicles and reduced side effects not associated with the treatment to be safe and effective for the patient.
    Conclusion: Therapy targeting RNA-based modifications is a breakthrough in disease treatment. These chemical modifications affect gene function and expression patterns. The next step in the research requires overcoming current limitations to fully realize the therapeutic potential of epitranscriptomics-based interventions.
    Keywords:  CRISPR; Epitranscriptome; RNA modifications; disease therapies; gene expression; m6a; small molecules; therapeutic targets
    DOI:  https://doi.org/10.2174/0113892029406032260414100243
  29. Nat Rev Mol Cell Biol. 2026 May 19.
    Elucidating structure-function relationships in the mammalian nucleolus.
    Lin Shan, Yunsheng Sun, Sarah A Woodson, Ling-Ling Chen.
      The nucleolus is the site of ribosomal RNA synthesis and ribosome biogenesis. Advances in high-resolution imaging and next-generation sequencing have unveiled unprecedented details of its intricate architecture and dynamic organization. In this Review, we focus on the dynamic organization of mammalian nucleoli, while drawing selective comparisons with other organisms to highlight conserved and divergent principles of nucleolar organization. We discuss recent progress in deciphering the multilayered compartments of nucleoli, the physical principles driving their organization and dynamics, and their functional interplay during stepwise ribosomal RNA processing, ribosome assembly and maintenance of compartment integrity. We also discuss how disruptions of nucleolar structure-function relationships can drive cellular stresses and diseases, offering new opportunities for therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41580-026-00975-z
  30. mSphere. 2026 May 20. e0021226
    Interaction between Rsp5-dependent ubiquitination and trehalose production during Cryptococcus neoformans temperature stress adaptation.
    Alejandro L Antonia, Lukas M du Plooy, Siobhan R Duffy, Jeffrey Kuhn, Erik J Soderblom, J Andrew Alspaugh.
      Microorganisms, including fungi, adapt to profound changes in their local environment during human infections. After exposure to high temperature and other stress conditions, the opportunistic fungal pathogen Cryptococcus neoformans enacts changes in metabolism, cell wall structure, and transmembrane transport that allow it to survive and proliferate in a mammalian host. This stress response program is regulated by the HECT E3-ubiquitin ligase Rsp5, which is required for growth at high salinity, pH, and temperature. However, the complete set of Rsp5 substrates that direct these molecular changes remains incompletely understood. Here, we demonstrate that C. neoformans Rsp5 confers increased tolerance to temperature and salt stress in part through regulation of the trehalose biosynthesis pathway. Two enzymes in the trehalose biosynthesis pathway, Tps1 and Tps2, are differentially ubiquitinated by Rsp5 after exposure to stress conditions. We directly measured trehalose production after exposure to high temperature and found that a C. neoformans strain lacking Rsp5 is unable to induce trehalose production. Quantitative proteomic analysis of the C. neoformans response to high salinity identified Rsp5-dependent and independent adaptations to osmotic stress, and Rsp5-dependent ubiquitination does not alter the abundance of Tps1 or Tps2. These results suggest that regulation of trehalose biosynthesis is one of the cellular mechanisms by which Rsp5-dependent ubiquitination in C. neoformans facilitates survival in response to stressors encountered in the human infection environment.IMPORTANCECryptococcus neoformans is an opportunistic fungal pathogen that kills over 180,000 people every year, with few effective treatment options. As a yeast that normally lives in the environment, C. neoformans has to survive large changes in its physical environment, including elevated body temperature, which causes human infections. Here, we show how C. neoformans uses a protein modification to regulate production of a fungus-specific metabolic pathway important for survival at human body temperature. Unraveling how environmental fungi tolerate and survive temperature and other stressors will help us to understand how they cause disease and identify new and better ways to treat these deadly infections.
    Keywords:  Cryptococcus neoformans; fungal pathogenesis; osmotic stress; stress response; temperature stress; trehalose; ubiquitination
    DOI:  https://doi.org/10.1128/msphere.00212-26
  31. bioRxiv. 2026 May 04. pii: 2026.04.30.721999. [Epub ahead of print]
    Probing RNA-protein interactions in the early mouse embryo.
    Pablo Bora, Oliver J Rando.
      The union of two germ cells to form a zygote, and subsequent early embryo development, are marked by radical remodeling of virtually every major class of biomolecules as the specialized germline states give way to the rapid and active growth that marks early development. In recent years, advances in ultra-low input genome-wide methods have enabled systematic analyses of mRNA abundance, and of chromatin organization, throughout early development in a variety of model systems. Here, we extend these efforts to the study of RNA binding protein (RBP) function in early mouse embryos, adapting REMORA 1 - based on fusing an RNA-editing enzyme to an RBP of interest - for use in early embryos. We benchmark our approach for several well-studied RBPs, successfully recovering expected features of their RNA cargos, and assayed the RNA cargos for 17 RBPs of interest for early gene regulation. Analysis of changes in mRNA metabolism following knockdowns of the RBPs surveyed here allowed us to identify direct regulatory functions for a subset of RBPs in the early mammalian embryo, including an unanticipated role for the RNA export adaptor Alyref in control of 3' polyadenylation sites. Together, our data provide a proof of concept resource for systematically exploring RBP functions in mammalian embryogenesis.
    DOI:  https://doi.org/10.64898/2026.04.30.721999
  32. Biomed Pharmacother. 2026 May 20. pii: S0753-3322(26)00523-8. [Epub ahead of print]200 119487
    ER-phagy drives resistance to mitochondria-targeted therapy in breast cancer.
    Aleksandra Bogucka, Daria Korewo-Labelle, Mariola Gimła, Elwira Smolińska-Fijołek, Anna Herman-Antosiewicz, Natalia Sowa-Rogozińska, Krzysztof Urbanowicz, Agnieszka Pyrczak-Felczykowska.
      Endoplasmic reticulum stress and ER-phagy are emerging regulators of cancer cell adaptation to metabolic and oxidative stress, yet their integration with mitochondrial dysfunction remains poorly understood. Here, we identify ER-phagy as a previously unrecognized adaptive response to ISOXUS, an isoxazole derivative of usnic acid with selective anticancer activity. ISOXUS, a mitochondrial respiratory complex II inhibitor, induces bioenergetic collapse, reactive oxygen species accumulation, and extensive ER-derived vacuolization. Using integrated transcriptomic and metabolomic analyses, we demonstrate that ISOXUS selectively triggers ER-phagy in mitochondria-dependent MCF-7 breast cancer cells, but not in more glycolytic triple-negative MDA-MB-231 cells, revealing a cell-type-specific stress adaptation program. ER-phagy induction is associated with upregulation of the ER-phagy receptor FAM134B and depends on ER stress signalling, as pharmacological ER stress inhibition suppresses this process. Multi-omics profiling uncovers coordinated repression of mitochondrial gene expression together with activation of ER-centered metabolic pathways, including amino acid metabolism, the tricarboxylic acid cycle, and one-carbon folate metabolism. Notably, we also identify UFMylation-related genes (CDK5RAP3, DDRGK1) as novel candidates involved in ER-phagy induced by ISOXUS. Moreover, mitochondrial inhibitors, rotenone and oligomycin, unexpectedly promote, while antioxidant a-tocopherol blocks ISOXUS-induced ER-phagy, and all compounds partially improve cell viability under ISOXUS treatment, implicating ROS-driven ER-phagy as a cytoprotective mechanism. Integrated analyses further reveal activation of the integrated stress response (ISR), dominated by the PERK-ATF4 axis, driving glutamine-dependent metabolic reprogramming and suppression of apoptosis-related pathways. The late-stage autophagy inhibition lowered the glutathione synthesis after ISOXUS treatment. Collectively, our findings uncover a previously unappreciated mitochondria-ER-ISR axis that governs metabolic adaptation to ISOXUS and identifies ER-phagy as a potential therapeutic vulnerability in breast cancer.
    Keywords:  Breast cancer; Cancer resistance; ER stress; ER-phagy; ISOXUS; Integrated Stress Response; Metabolic adaptation; Mitochondrial complex II inhibition; Usnic acid derivative
    DOI:  https://doi.org/10.1016/j.biopha.2026.119487
  33. Front Med (Lausanne). 2026 ;13 1808254
    Oxidative stress and endoplasmic reticulum stress in acute kidney injury: mechanistic crosstalk and therapeutic modulation.
    Xiaoqi Xu, Qiongqiong Xing, Hanqing Li, Zichao Ding, Xianqing Ren.
      Acute kidney injury (AKI) is a complex syndrome with multiple causes, associated with high morbidity and mortality rates. Despite advances in intensive care, effective therapeutic strategies for AKI remain limited. In this review, we examine the roles of oxidative stress and endoplasmic reticulum stress (ERS) in the pathogenesis of AKI. Oxidative stress, marked by the excessive production of reactive oxygen species (ROS), can trigger ERS, leading to misfolded protein accumulation and activation of the unfolded protein response (UPR) in an attempt to restore cellular homeostasis. When ERS becomes prolonged or excessive, persistent activation of UPR pathways such as IRE1, PERK and ATF6 induces apoptosis and further worsens kidney injury. In addition to apoptosis, oxidative stress and ERS also regulate autophagy, a cellular stress response. Together, these pathways promote cellular dysfunction and advance AKI progression. We also discuss potential therapies that target oxidative stress and ERS, such as antioxidants and pharmacological agents targeting UPR pathways, which may offer promising approaches to mitigate AKI. A deeper understanding of the interplay between oxidative stress and ERS in AKI is essential for developing effective therapeutic interventions to improve patient outcomes.
    Keywords:  acute kidney injury; apoptosis; autophagy; endoplasmic reticulum stress; oxidative stress
    DOI:  https://doi.org/10.3389/fmed.2026.1808254
  34. Annu Rev Nutr. 2026 May 21.
    Impact of Prematurity on Nutrient Signaling and Protein Synthesis in Skeletal Muscle.
    Antonio C Ramos Dos Santos, Ki Beom Jang, Marta L Fiorotto, Teresa A Davis.
      Preterm birth disrupts nutrient-responsive signaling pathways critical for skeletal muscle growth and long-term metabolic health. Despite improvements in neonatal care, preterm infants often experience postnatal growth failure marked by impaired lean mass accretion. This review examines how prematurity intrinsically alters insulin and amino acid signaling to mechanistic target of rapamycin complex 1 (mTORC1), a central regulator of translation initiation and protein synthesis. Evidence from translational models reveals blunted activation of mTORC1 and its downstream effectors, independent of birth weight or comorbidities. Defects in insulin-PDK1/mTORC2-Akt signaling and amino acid sensing, particularly leucine sensing, contribute to impaired mTORC1-dependent translation initiation and reduced muscle protein synthesis. Feeding strategies that mimic physiological nutrient pulsatility, including intermittent bolus feeding and pulsatile leucine supplementation during continuous feeding, show promise in restoring anabolic signaling. Understanding these molecular impairments provides a foundation for targeted nutritional and therapeutic interventions to improve muscle growth and mitigate long-term health risks in individuals born preterm.
    DOI:  https://doi.org/10.1146/annurev-nutr-111225-024640
  35. Mol Med Rep. 2026 Jul;pii: 198. [Epub ahead of print]34(1):
    m6A modification in skeletal system diseases (Review).
    Xi Xie, Chen Li, Haotian Zheng, Guang Gan, Xi Gao.
      N6‑methyladenosine (m6A) modifications are key epigenetic regulatory mechanisms in mammals and serve key roles in both normal skeletal development and the pathogenesis of skeletal disorder. The dynamic and reversible regulation of m6A relies on three core factors: Methyltransferases (writers), demethylases (erasers) and m6A‑binding proteins (readers), which collectively ensure proper physiological functions. Despite this, the functions and regulatory mechanisms of numerous m6A‑associated factors in skeletal diseases remain insufficiently understood. m6A modification maintains bone homeostasis during skeletal development primarily by regulating the balance between osteoblasts and osteoclasts. Under pathological conditions, dysregulated m6A modification contributes to aberrant osteoclast proliferation and chondrocyte apoptosis, leading to bone loss and cartilage degeneration. These pathological changes are key contributors to common types of skeletal disorder, including osteoporosis, osteoarthritis, rheumatoid arthritis and intervertebral disc degeneration, imposing a burden on human health. Non‑coding RNAs are major targets of m6A modification and their interactions exert post‑transcriptional regulation in skeletal biology. The present review summarizes the roles and mechanisms of m6A modification in skeletal diseases and highlights its therapeutic potential, offering novel perspectives for disease prevention and treatment.
    Keywords:  N6‑methyladenosine methylation; epigenetics; m6A regulatory factor; skeletal system disease
    DOI:  https://doi.org/10.3892/mmr.2026.13908
  36. Mol Cell. 2026 May 21. pii: S1097-2765(26)00277-7. [Epub ahead of print]
    Ribo-Tweezer: Rapid removal of ribosomal proteins reveals additional layers of post-transcriptional gene regulation.
    Yuxiang Chen, Ching Pin Cheng, Kitra Cates, Georgi K Marinov, Travis C Lantz, Haojun Yang, Isabelle Liu, Naomi R Genuth, Christina Andronescu, Victoria Hung, Abel Bermudez, Daphna Rothschild, Joseph Georgeson, Sonia Bustos Barocio, Anshul Kundaje, Sharon Pitteri, Davide Ruggero, Maria Barna.
      The ribosome is a ribozyme, but it also acts as a dynamic regulator of gene expression. Although ribosomal protein (RP) composition varies, dissecting the functional contributions of individual RPs beyond their housekeeping roles is challenging because of the lack of tools for manipulation in situ. Here, we developed Ribo-Tweezer, a degron-based system directly tethered to mature ribosomes that enables rapid, reversible, and selective depletion of specific RPs. Using Ribo-Tweezer in mouse embryonic stem cells (mESC), we find a previously uncharacterized role for RACK1 in stem cell fate control via translational regulation of zinc-finger transcriptional networks and long interspersed nuclear element-1 (LINE1) expression. This translation-transcription coupling provides a mechanism by which translation control is further amplified in gene regulation. Distinct translational programs induced by RPLP0 and RPLP1 depletion further demonstrate RP-specific regulatory functions in translation. Together, these findings establish Ribo-Tweezer as a powerful platform that has illuminated selective functions for RPs in gene regulation, which gives biological meaning to ribosome heterogeneity.
    Keywords:  LINE-1; P-stalk; Poly(A/U) leader; RACK1; mESC differentiation; ribosome; ribosome heterogeneity; translation control
    DOI:  https://doi.org/10.1016/j.molcel.2026.04.023
  37. Mol Cancer. 2026 May 21.
    Increased mRNA translation delays tumour initiation and exposes a therapeutic vulnerability in lung cancer.
    Luis Pardo, Madeleine Moore, Ruhi Deshmukh, Ian Powley, Joseph A Waldron, Bjorn Kruspig, Lynn McGarry, Lobsang Dolma, America V Campos, Colin Wood, Holly Leslie, Mark Hughes, Emanuel Jeldes, June Munro, Louise Mitchell, Leah Officer-Jones, Rachel Baird, Hugo Coquelet, Nigel B Jamieson, David Sumpton, Douglas Strathdee, John le Quesne, Martin Bushell, Daniel J Murphy, Jim C Norman.
       BACKGROUND: Although inhibitors of mRNA translation are being evaluated as anti-cancer agents, the dynamics of protein synthesis throughout tumour progression are still poorly understood. Here we assess how alterations in mRNA translation during early tumorigenesis affect tumour development in KRAS-driven lung adenocarcinoma (LuAd).
    METHODS: We deployed autochthonous mouse models of LuAd driven by oncogenic KRASG12D combined with moderate overexpression of MYC and simultaneously manipulated mRNA translation by deleting the mRNA helicases eIF4A1 and eIF4A2 or by administering pharmacological inhibitors of protein synthesis, such as rapamycin. This permits synchronous assessment of LuAd initiation and progression in vivo and is amenable to parallel ex vivo culture of tumour-derived cells for detailed analysis of protein synthesis (using ribosome footprinting) and metabolic landscapes. These approaches also allowed us to perform multiplex imaging and spatial transcriptomics to characterise tumour formation in altered mRNA translation conditions and to compare results obtained in mice against the Lattice-A cohort of non-small cell lung cancer (NSCLC) patients.
    RESULTS: Deletion of the mRNA-translation repressor, eIF4A2 in KRAS-driven LuAd leads to a dysregulated protein synthesis landscape characterised by a strongly upregulated secretome, enlarged secretory compartments, increased oxidative metabolism and acquisition of senescence-like characteristics. Paradoxically, this overdriven secretory protein synthesis landscape delays tumorigenesis and leads to the appearance of clusters of non-proliferative, p21-positive KRASG12D-expressing cells in the lung. Consistently, reduction of mRNA translation with rapamycin in Eif4a2-deleted tumours suppresses senescence and restores tumorigenesis. Importantly, some Eif4a2 knockout cells overcome senescence to form tumours that exhibit enhanced MAP-kinase signalling and, in contrast to eIF4A2+/+ lesions, these were eradicated by administration of a MEK inhibitor. Consistently, MAP-kinase signalling was significantly increased in human NSCLC expressing low levels of eIF4A2.
    CONCLUSIONS: Our study highlights that restraint of mRNA translation by eIF4A2 is critical in the early-stages of KRAS-driven LuAd to allow bypass of oncogene-induced senescence and tumour progression. Importantly, because tumours with dysregulated mRNA translation rely heavily on MAP-kinase signalling they are exquisitely sensitive to MEK inhibition, and this indicates the possibility that low expression of eIF4A2 could be used to identify potential responders to MEK inhibitors in clinical trials.
    Keywords:  KRAS; Lung adenocarcinoma; Metabolism; Oncogene-induced senescence; Rapamycin; Trametinib; eIF4A; mRNA translation
    DOI:  https://doi.org/10.1186/s12943-026-02680-z
  38. Elife. 2026 May 18. pii: RP106662. [Epub ahead of print]14
    Mapping of in vivo cleavage sites uncovers a major role for yeast RNase III in regulating protein-coding genes.
    Lee-Ann Notice-Sarpaning, Mathieu Catala, Catherine Stuart, Sherif Abou Elela, Ambro van Hoof.
      A large fraction of newly transcribed RNA is degraded in the nucleus, but nuclear mRNA degradation pathways remain largely understudied. The yeast nuclear endoribonuclease Rnt1 has a well-characterized role in the maturation of many ncRNA precursors. However, the scope and consequence of its function in mRNA degradation pathways are much less defined. Here, we take a whole-transcriptome approach to identify Rnt1 cleavage sites throughout the yeast transcriptome in vivo, at single-nucleotide resolution. We discover previously unknown Rnt1 cleavage sites in many protein-coding regions and find that the sequences and structures necessary for cleavage mirror those required for the cleavage of known targets. We show that the nuclear localization of Rnt1 functions as an additional layer of target selection control, and that cleaved mRNAs are likely exported to the cytoplasm to be degraded by Xrn1. Further, we find that several cleavage products are much more abundant in our degradome sequencing libraries than decapping products, and strikingly, mutations in one Rnt1 target, YDR514C, suppress the growth defect of an RNT1 deletion. Overexpression of YDR514C results in slow growth, further suggesting that Rnt1 may limit the expression of YDR514C to maintain proper cell growth. This study uncovers a broader target range and function for the well-known RNase III enzyme.
    Keywords:  Rnt1; S. cerevisiae; genetics; genomics; mRNA degradation; rnase III
    DOI:  https://doi.org/10.7554/eLife.106662
  39. Mol Diagn Ther. 2026 May 19.
    Heat Shock Proteins as Cancer Biomarkers: From Mechanism to Clinical Application.
    Prajjwal Kushwaha, Ipsita Roy.
      Molecular chaperones are an integral part of the proteostasis network of the cell that regulate client protein folding, substrate interactions, disaggregation, degradation, and intracellular trafficking, either independently or through coordinated action with co-chaperones. Among them, heat shock proteins have emerged as key players in cancer, largely owing to their ability to stabilize oncogenic proteins and support tumor initiation and malignant progression. Their expression is dysregulated in cancer cells and secreted into circulatory system as a consequence of oncogenic signaling pathways. Because of these properties, molecular chaperones, particularly heat shock proteins have gained traction as potential biomarkers for cancer detection, including in point-of-care diagnostic applications. However, as heat shock proteins are involved in basal cellular activities, their levels are perturbed in several other benign cellular conditions. This review highlights the multifaceted roles of molecular chaperones, with a focus on heat shock proteins, in cancer development and progression. It further discusses recent advances and perspectives on major heat shock proteins as biomarkers for cancer diagnosis, emphasizing their potential to improve diagnostic accuracy. Additionally, this review addresses current challenges and limitations associated with the diagnostic use of heat shock proteins, providing insights to guide future research and clinical translation.
    DOI:  https://doi.org/10.1007/s40291-026-00851-8
  40. Biochem Biophys Res Commun. 2026 May 16. pii: S0006-291X(26)00738-2. [Epub ahead of print]823 153974
    Heme oxygenase-1 does not affect formation of stress granules.
    Jan Paczesniak, Milena Cichon, Patryk Chudy, Wojciech Krzeptowski, Witold Nowak, Jakub Kochan, Lucie Muchova, Alicja Jozkowicz, Anna Grochot-Przeczek.
      Heme oxygenase-1 (HO-1) is a cytoprotective enzyme responsible for heme degradation and is commonly upregulated during cellular stress. Stress granules (SGs), membraneless assemblies formed from untranslated messenger ribonucleoproteins, constitute an important component of the adaptive stress response. In this study, we examined whether HO-1 expression levels or its intracellular localization influence SG formation in murine induced pluripotent stem cells (miPSCs). Using immunofluorescence-based visualization of the canonical SG marker G3BP1, we found that neither HO-1 abundance nor its partitioning between cytosolic and nuclear compartments influenced SG induction in response to arsenite. These observations indicate that HO-1, despite being a key stress-responsive enzyme, is not directly involved in modulating SG assembly in iPS cells during oxidative challenges. In contrast, we observed that protein overexpression, irrespective of the identity of the introduced transgene, facilitates SG formation in response to MG-132 treatment. These results show that SG induction under proteotoxic stress conditions is sensitive to increased protein burden. Importantly, without appropriate controls, such effects could be misinterpreted as protein-specific regulation of SG formation. Therefore, experimental overexpression of proteins may act as a confounding factor in studies of SG formation in response to proteasome inhibition.
    Keywords:  Heme oxygenase-1; Oxidative stress; Proteotoxic stress; Stress granules; iPSCs
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153974
  41. Proc Natl Acad Sci U S A. 2026 May 26. 123(21): e2536912123
    A mechanism for substrate quality control in outer membrane protein assembly.
    Ashton N Combs, Anna Konovalova, Thomas J Silhavy.
      The assembly of β-barrel proteins into the outer membrane (OM) of Gram-negative bacteria is catalyzed by the β-barrel assembly machine (Bam) complex, which consists of two essential proteins, the BamA β-barrel and the lipoprotein BamD, and three nonessential lipoproteins BamBCE. While it is well established that BamD serves an essential role in regulating the activity of BamA, the physiological reasons underpinning the need for BamD-mediated regulation of β-barrel assembly are unclear. Here, we demonstrate that BamD-mediated regulation of BamA functions as a mechanism of substrate quality control that ensures the efficient assembly of β-barrel proteins into the OM. Through the use of substrate C-terminal fragments and multiple alleles of bamA and bamD that prevent effective regulation of BamA by BamD, we show that BamD activity is necessary to prevent the accumulation of defective β-barrel substrates on BamA. Notably, these bamAD alleles all confer resistance to the Bam complex inhibitor MRL-494 in a manner that correlates with the degree to which BamD activity is bypassed, suggesting that MRL-494 inhibits β-barrel assembly by disrupting BamD-mediated conformational changes in BamA. We further show that BamD activity functions to prevent the uptake of toxic small molecules across the OM through a mechanism that functionally overlaps with that of the substrate quality control protein Skp. Collectively, these results not only establish that BamD, like Skp, functions to ensure proper quality control of β-barrel substrates but also demonstrate the importance of substrate quality control functions in maintaining the integrity of the OM permeability barrier.
    Keywords:  Bam complex; gram-negative bacteria; outer membrane proteins; protein folding; protein quality control
    DOI:  https://doi.org/10.1073/pnas.2536912123
  42. bioRxiv. 2026 May 04. pii: 2026.04.30.721893. [Epub ahead of print]
    Synergy of RNA Concentration, RNA Binding Proteins, and RNA Palindrome Drives clustering of oskar mRNA in vivo.
    Ziqing Ye, Siran Tian, Ayse Ecer, Tatjana Trcek.
      Organization of mRNAs into clusters has been 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 (Stau), and intermolecular base-pairing driven by an RNA palindrome influence clustering of oskar (osk) mRNA in Drosophila embryos. We find that these factors collectively optimize osk clustering by promoting its dimerization and subsequent oligomerization. Both processes depend on all three factors, although oligomerization is more sensitive to their perturbation, indicating that the driving force for osk oligomerization is partially distinct from that governing dimerization. Furthermore, expression of Stau nearly doubles the likelihood of osk dimerization whereas disruption of the palindrome reduces it fourfold indicating that the presence of Stau and the palindrome lowers the concentration threshold of osk mRNA required for dimerization. Notably, insertion of the osk palindrome into a reporter mRNA markedly increased its association with the endogenous osk, further supporting the conclusion that the palindrome potently drives intermolecular base pairing. Importantly, this experiment also identified the palindrome as the major contributor to heterotypic clustering between the endogenous osk and the reporter mRNA. Finally, computational analyses identified a subset of early embryonic mRNAs predicted to harbor palindromes similar to those found in osk. Among these, eIF3a mRNA emerged as a candidate whose clustering may likewise be driven by intermolecular base pairing. Together, our findings 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 early Drosophila development.
    DOI:  https://doi.org/10.64898/2026.04.30.721893
  43. Cell Mol Life Sci. 2026 May 22.
    eIF5A coordinates the transcription and translation of its target genes.
    Marina Barba-Aliaga, Lianqi Chi, Samoa Prieto-Díez, Jordi Planells, José García-Martínez, José E Pérez-Ortín, Paula Alepuz.
      Maintaining balanced cellular protein levels requires precise control of gene expression and effective coordination between the various stages of the process, from transcription to translation. In recent years, several components of the translation apparatus have been found in the nuclei of various eukaryotes, where they regulate transcription, mRNA processing or export, thereby integrating different stages of gene expression. eIF5A is an essential and evolutionarily conserved translation elongation factor that is involved in viral infection and in the development of diseases such as cancer and neurodevelopmental disorders. eIF5A promotes translation elongation by binding to ribosomes that stall at codons encoding problematic amino acids for peptide bond formation, such as consecutive prolines, also known as polyproline motifs. Although eIF5A shuttles between the nucleus and cytoplasm, its specific nuclear roles remain poorly defined. Here, we demonstrate that nuclear yeast eIF5A binds to chromatin and represses gene transcription by preventing the binding of RNA polymerase II. Importantly, chromatin binding and transcriptional repression by eIF5A have a higher impact on genes encoding its own translational targets. The presence of polyproline motifs in genes imposes both translation and transcriptional control by eIF5A. Furthermore, eIF5A's active engagement in cytoplasmic translation is necessary for its role in repressing transcription. Our results suggest that eIF5A coordinates gene expression by promoting the cytoplasmic translation of specific genes while repressing their transcription in the nucleus, thus ensuring efficient final protein synthesis.
    Keywords:  Gene expression; Polyprolines; Transcription-translation crosstalk; Translation efficiency; Translation elongation factor; eIF5A
    DOI:  https://doi.org/10.1007/s00018-026-06252-8
  44. Curr Opin Chem Biol. 2026 May 16. pii: S1367-5931(26)00047-5. [Epub ahead of print]93 102698
    Proximity chemistries to study RNA biology at the subcellular scale.
    Rachel Shu Ting Chan, Kanokpol Aphicho, Bryan C Dickinson.
      RNAs preferentially localize across virtually every subcellular compartment, from membrane-bound organelles, membrane-less condensates and even the cell surface, where they perform locale-specific functions in close coordination with RNA-binding proteins (RBPs) and other RNAs. Within the cell, proximity labeling strategies enable selective chemical tagging and covalent encoding of spatial information, converting molecular proximity into chemically tractable readouts for downstream multi-omic analyses. A growing suite of proximity chemistries targeted at RNA have yielded tools to dissect the local organization and interactions of RNAs with high spatiotemporal resolution within the native cellular milieu. Here, we review the recent expansion and emerging themes in proximity chemistries that enable spatially-resolved interrogation of RNA biology at subcellular resolution across the transcriptome.
    DOI:  https://doi.org/10.1016/j.cbpa.2026.102698
  45. bioRxiv. 2026 May 07. pii: 2026.05.03.720925. [Epub ahead of print]
    Stress-Responsive Protein IFRD1 Protects Assembled Ribosomes via a Ribosome-Salvaging Mechanism.
    Charles J Cho, Molly K Crowder, Amala K Rougeau, Thanh Nguyen, Steven J Bark, Sammy Lee, Jeffrey W Brown, Jason C Mills.
      The ability of epithelial cells to cope with injury and undergo regeneration depends on tightly coordinated cellular responses. IFRD1 is a stress-responsive protein that is evolutionarily conserved and required for the cellular regeneration program paligenosis; however, how IFRD1 works in paligenosis is not known. Here we demonstrate that IFRD1 is primarily a cytosolic ribosome-binding protein, specifically binding 80S monosomes that are not actively engaged in translation. Using multiple in vivo and in vitro injury models, including cerulein-induced pancreatitis in mice and tunicamycin-induced ER stress in cell culture, we demonstrate that IFRD1 acts as a ribosome-salvaging factor, preventing ribosomes from degradation. In the absence of IFRD1 during ER stress, non-translating 80S ribosomes were unstable and prone to disassembly and selective degradation. The resulting accumulation of degraded ribosomal subunits overwhelmed cellular autophagic machinery, as evidenced by accumulation of the autophagy-tagging protein p62, even though overall autophagic flux remained unaffected. Ultimately, cells lacking IFRD1 showed reduced mTORC1 activity followed by increased cell death, consistent with patterns observed in cells lacking IFRD1 during paligenosis. Thus, we detail a previously unrecognized cellular function for IFRD1 in stabilizing and preserving the mature ribosome pool during metabolic and translational transitions such as paligenosis.
    DOI:  https://doi.org/10.64898/2026.05.03.720925
  46. Sci Adv. 2026 May 22. 12(21): eaeb6806
    Unlocking translational control of specialized metabolism in plants through 5'UTR structure.
    Makou Lin, Doosan Shin, Jie Hao, Masood Jan, Minkyu Park, Veronica Perez, Benjamin Breuer, Ying Wang, Jeongim Kim.
      Plant-specialized metabolites are essential for plant fitness and human health, with their biosynthesis pathways tightly regulated at multiple levels. However, the translational regulation of their biosynthesis remains poorly understood. Here, we reveal a 5' untranslated region (5'UTR)-mediated translational mechanism that controls glucosinolate production in Arabidopsis. A forward genetic screen exploring the metabolic interaction between auxin and glucosinolates identified two dominant Arabidopsis alleles, each carrying a single-nucleotide substitution located 13-base pair apart within the 5'UTR of MYB28, a master regulator of aliphatic glucosinolate biosynthesis. These mutations markedly increase MYB28 protein abundance without affecting transcript levels, leading to enhanced glucosinolate production. Mutational profiling of the 5'UTR revealed that alterations in RNA tertiary structure influence translation efficiency, establishing a link between RNA conformation and metabolic output. Our findings uncover a previously uncharacterized layer of posttranscriptional regulation in plant-specialized metabolism and highlight the 5'UTR as a potential target for precision breeding to enhance crop performance and nutritional quality.
    DOI:  https://doi.org/10.1126/sciadv.aeb6806
  47. Invest Ophthalmol Vis Sci. 2026 May 01. 67(5): 51
    YTHDF1-Mediated m6A Modification of NREP Promotes Corneal Fibrosis via TGF-β-Smad Signaling.
    Yi Guan, Yapeng Jing, Shumei Yang, Xinlin Yan, Xuan Li.
       Purpose: Corneal fibrosis ranks among the foremost drivers of global vision loss and blindness, yet therapeutic options remain scarce. This study investigated neuronal regeneration-related protein (NREP), which is recognized by the N6-methyladenosine (m6A) modification reader protein YTH domain family member 1 (YTHDF1), in promoting corneal fibrosis in keratocytes.
    Methods: In vivo, a standardized alkali burn model was created in C57BL/6 mice with corneas harvested on days 7, 14, and 21. Fibrosis, NREP, and m6A modifications were estimated using slit-lamp, real-time quantitative polymerase chain reaction (RT-qPCR), and western blotting. In vitro, isolated keratocytes were treated with TGF-β1. Small interfering RNA (si-RNA) was used to downregulate NREP and YTHDF1 expression in keratocytes. SKLB-Y13 was used to specifically inhibit YTHDF1. Cell proliferation, migration, and alpha-smooth muscle actin (α-SMA) expression were assessed using CCK-8 assays, scratch-wound assays, flow cytometry, immunofluorescence, and liquid chromatography-mass spectrometry. Following keratocyte fibrosis induction using 10% fetal bovine serum, the indicators were evaluated.
    Results: Corneal fibrosis peaked on day 14 post-injury, coinciding with increased NREP protein levels versus controls. NREP knockdown reduced keratocyte proliferation and migration and abolished TGF-β1-induced α-SMA expression. YTHDF1 depletion phenocopied these effects and lowered NREP protein levels, suggesting translational control. Sequence-based RNA adenosine methylation site predictor (SRAMP) revealed enriched m6A modifications in NREP mRNA. YTHDF1 deficiency reduced NREP translation and impaired TGF-β-Smad signaling, leading to decreased keratocyte proliferation and motility and impaired fibroblast-to-myofibroblast differentiation.
    Conclusions: YTHDF1 promotes corneal fibrosis through m6A-dependent enhancement of NREP translation, potentiating TGF-β-Smad and myofibroblast transdifferentiation, and thus may serve as a therapeutic target for fibrotic corneal disorders.
    DOI:  https://doi.org/10.1167/iovs.67.5.51
  48. Angew Chem Int Ed Engl. 2026 May 19. e1777033
    Reengineering Protease Inhibitors to Disrupt Hsp70 Chaperone Function.
    Aweon Richards, Ascensión Ariza-Mateos, Antara Ghosh, Max Kim, Sterling Sandler, Isabelle Yardumian, Gideon Yawson, Jeremy Baryza, Alexander Serganov, Tania J Lupoli.
      The heat shock protein 70 (Hsp70) family consists of ATP-driven molecular chaperones essential for maintaining protein homeostasis (proteostasis) across all cell types, however, modulation of chaperone activity by small molecules remains challenging. In bacteria, a major Hsp70 called DnaK represents a putative antibacterial target, as it plays essential roles in growth, antibiotic resistance, and stress response. While Hsp70 inhibitors are in development as potential cancer and neurodegenerative disease treatments in humans, we lack generalizable methods to target Hsp70s across species. Here, we address how peptidomimetic scaffolds designed to inhibit proteases, exemplified by the drug telaprevir, interact with two different bacterial DnaKs to disrupt chaperone function. We perform extensive structure-function studies of telaprevir analogs against DnaK to inform the design of synthetic unnatural peptide sequences with a range of inhibitory potencies. X-ray crystallography analysis of telaprevir and several synthetic peptidomimetics reveal interactions with DnaK's substrate binding domain via ligand side chain recognition reminiscent of that observed in protease active sites, but in two orientations. These co-complexes inspire the synthesis of shorter peptidomimetics capable of allosterically inhibiting DnaK's ATPase activity. Overall, this work demonstrates that chemical scaffolds devised for protease inhibition may be modified to disrupt Hsp70 chaperone activities.
    Keywords:  DnaK; allosteric inhibition; molecular chaperones; peptidomimetics; proteotoxic stress
    DOI:  https://doi.org/10.1002/anie.1777033
  49. Nucleic Acids Res. 2026 May 20. pii: gkag495. [Epub ahead of print]54(10):
    Dynamic sumoylation is essential in yeast for suppressing stress-induced gene expression in non-stress conditions.
    Marjan Moallem, J Bryan McNeil, Benjamin G Bergey, Emanuel Rosonina.
      Environmental stresses such as heat shock trigger widespread changes in gene expression, collectively known as the environmental stress response (ESR), along with a global increase in SUMO conjugation. However, whether elevated sumoylation contributes to establishing the ESR gene expression program remains unclear. Here, we show that mutant yeast with constitutively high sumoylation levels due to a defect in the SUMO protease Ulp1, ulp1-mt, displays stress-like gene expression changes, including upregulation of heat shock-induced genes, in the absence of external stress. The ESR regulators Hog1 and Msn2 are constitutively active in this mutant and drive the observed transcriptional changes. Surprisingly, both heat shock and Ulp1 impairment lead to a reduction in levels of SUMO that are stably associated with gene loci, suggesting that increased sumoylation of tightly-bound chromatin factors does not underlie stress-like transcriptional changes. Intriguingly, mutant yeast with reduced sumoylation due to impairment of sumoylation enzymes also show ESR-like transcription effects, including expression of heat shock genes. These findings indicate that disruption of normal sumoylation/desumoylation cycling, rather than absolute SUMO conjugation levels, triggers an ESR-like transcriptional program. This work reveals a new layer of regulation in stress-responsive gene expression and implicates SUMO homeostasis as key in modulating transcriptional stress signaling.
    DOI:  https://doi.org/10.1093/nar/gkag495
  50. Front Mol Biosci. 2026 ;13 1800738
    RNA duplex formation and competing endogenous RNA, proposed as mechanisms in regulating expression of natural antisense transcripts- from hypotheses to potential therapeutic applications.
    Richi Nakatake, Tetsuya Okuyama, Tominori Kimura, Mikio Nishizawa.
      Natural antisense transcripts (NATs) from eukaryotic genes, known as long non-coding RNAs (lncRNAs), are long transcripts that do not encode proteins. NATs play diverse functional roles in regulating the transcription, stability, and translation of protein-coding genes at the epigenetic and post-transcriptional levels. Here, we outline recent studies on NAT-mediated RNA networks and discuss their potential as therapeutic targets across diseases. Interferon-α1 (IFNA1) mRNA expression is regulated by its overlapping antisense transcript IFNA1-AS through IFNA1 mRNA-AS duplex formation, and microRNA-sponging through common microRNA response elements (MREs) as competing endogenous RNAs. The competitive interactions between NATs and mRNA MRE(s) fine-tune mRNA and protein levels. The receptor tyrosine kinase, ephrin type-A receptor 2 (EPHA2) mRNA and its antisense partner (EPHA2-AS) are transcribed from the EPHA2 gene and are overexpressed in breast cancer. EPHA2-AS interacts with EPHA2 mRNA, forming an mRNA-AS duplex that modulates both EPHA2 mRNA and protein levels, potentially contributing to tumorigenesis; hence, it is a potential target for breast cancer treatment. RNA methylation, such as N 6-methyladenosine, may also play a role in regulating gene expression in various diseases. NAT-targeted therapeutics, such as synthetic oligonucleotides, mRNA, and drugs, can be introduced into cells either directly or via extracellular vesicles and lipid nanoparticles. The administration of NAT-targeted therapeutics in animal disease models is useful for evaluating their efficacy. The mechanisms of NAT-mediated gene regulation should be further investigated to develop NAT-targeted therapeutics for the treatment of various diseases.
    Keywords:  circular RNA; competing endogenous RNA; extracellular vesicle; methyladenosine; miRNA; natural antisense transcript; non-coding RNA; oligonucleotide
    DOI:  https://doi.org/10.3389/fmolb.2026.1800738
  51. Front Genet. 2026 ;17 1790963
    Identification and exploration of potential N6-methylation related mRNAs in endometriosis.
    Yanan He, Chengcheng Ren, Liang Lei, Jixin Li, Guangmei Zhang.
       Background: N6-methyladenosine (m6A) modification regulates the processes of RNA splicing, subcellular localization, translation and stability by changing the RNA structure and the interaction between RNA and RNA-binding proteins to ensure the timely and accurate expression of genes. In this study, we investigated m6A-related mRNAs and for the first time explored effective prevention and treatment targets in endometriosis (EM).
    Methods: By arraystar m6A-mRNA epitranscriptomic microarray, biological information analysis technologies, and validation of other databases, aberrant m6A-related mRNAs were uncovered, as well as efficient therapeutic drugs.
    Results: FN1, VCAM1, RAP1A, BRCA1, CCNA2 and CDK1 might be vital m6A-related mRNAs, and VCAM1 and RAP1A may be the most important two. A few crucial small-molecule agents supply new views for the treatment of EM.
    Conclusion: These results demonstrated novel insights into m6A modification of EM and revealed potential biomarkers and precision medicine strategies for EM.
    Keywords:  RAP1A; VCAM1; endometriosis; m6A-related mRNAs; therapeutic drugs
    DOI:  https://doi.org/10.3389/fgene.2026.1790963
  52. Mol Genet Genomics. 2026 May 20. pii: 119. [Epub ahead of print]301(1):
    Genome comparison of the bacteria in Mycobacterium avium complex (MAC) reveals the role of translational selection in shaping codon usage patterns.
    Anindita Banerjee, Saubashya Sur.
      The Mycobacterium avium complex (MAC) houses several pathogens that cause diseases in humans, ruminants, and birds. They are widely distributed in soils and water worldwide. In immunocompromised humans, MAC is responsible for nodular bronchiectasis and fibrocavitary lung diseases. The treatment of lung diseases induced by MAC remains difficult owing to antibiotic intolerance and disease recurrence. In this study, we compared the genome sequences of 90 complete MAC genomes and explored the factors shaping codon usage bias in the bacteria within MAC. Additionally, we studied the relationship between codon bias and pathogenic adaptation. The genome sizes ranged from 4.7 to 6.5 Mb. Variation in the mobile genetic elements and the number of CRISPR candidates was observed amongst the bacteria within MAC. Synonymous codon usage analysis divulged variations among subspecies, high codon usage bias, substantial heterogeneity in codon usage patterns, and moderate use of optimal codons. High GC3 content and elevated levels of CAI (a metric for gene expression levels) in all probability assisted the bacteria within MAC in adjusting to different host environments. Translational selection pressure prevailed over compositional bias and mutational selection in these organisms. Our analysis revealed differences in the tRNA content amongst the bacteria in MAC. The translational selective pressure enabled the adaptation of these pathogenic bacteria to competitive pressure in diverse environments and niches by maintaining a lesser number of tRNAs and lower tAI values.
    Keywords:   Mycobacterium avium complex; Codon usage bias; Infectious diseases; Pathogenic bacteria; Translational selection; tRNA adaptation index
    DOI:  https://doi.org/10.1007/s00438-026-02447-7
  53. Biochem Biophys Rep. 2026 Jun;46 102614
    Long-read transcriptomic profiling of a glioma cell line following m6A regulator perturbations.
    Hanna Lee, Syeda Maheen Batool, Ana K Escobedo, Denalda Gashi, Kesli Faber, Pavithra Ponnolu, Nina R Barretts, Prerna Khanna, Kase D Haas, Tiffaney Hsia, Bob S Carter, Leonora Balaj.
      N6-methyladenosine (m6A) is the most prevalent internal mRNA modification and is enriched in the central nervous system (CNS), yet its role in glioma remains incompletely defined. Using long-read direct RNA sequencing, we mapped transcriptome-wide m6A modifications in a single glioma cell line following targeted knockdown of the m6A reader IGF2BP2, writer METTL3, and eraser ALKBH5. Across perturbations, the global architecture of m6A, including transcript class, positional enrichment, and site multiplicity, was largely preserved, while differential methylation was weakly coupled to gene expression. In contrast, m6A regulator perturbation coincided with widespread isoform switching and with changes in untranslated regions, coding potential, and predicted transcript fate, largely independent of bulk gene expression changes. Public glioma datasets further supported the relevance of isoform-specific changes in glioma. Together, these findings highlight isoform-level transcript variation associated with m6A regulator perturbation and support the use of long-read, isoform-resolved approaches to study RNA regulatory states in glioma.
    Keywords:  Alternative splicing; Epitranscriptomics; Glioma; Isoform; N6-methyladenosine (m6A); RNA; Signaling
    DOI:  https://doi.org/10.1016/j.bbrep.2026.102614
  54. Aging Dis. 2026 May 12.
    circHIPK3 Sustains Ribosome Biogenesis and Protects Against Cardiac Aging by Stabilizing Ncl mRNA and Supporting its LLPS.
    Huiling Zhang, Tonggan Lu, Xinlan Lv, Yu Zhang, Ao Li, Zirui Zhao, Han Zhou, Bin Liu, Yan Xu, Yangxin Li.
      To investigate the molecular mechanism of cardiac aging and identify novel regulatory targets, we focused on circular RNA HIPK3 (circHIPK3) and its role in regulating Nucleolin (Ncl)-mediated biological processes. circHIPK3 expression was progressively downregulated with age in mouse hearts. We generated cardiomyocyte-specific circHIPK3 knockout (CKO) mice, and found that these mice exhibited cardiac aging phenotypes, cardiac dysfunction, hypertrophy, and fibrosis. Mechanistically, circHIPK3 is directly bound to the 5' UTR of Ncl mRNA to enhance its stability, thereby preserving Ncl protein levels and supporting Ncl-mediated liquid-liquid phase separation (LLPS), a critical process for efficient ribosome biogenesis. circHIPK3 deficiency is accompanied by altered Ncl LLPS dynamics, reduced ribosomal RNA synthesis and ribosomal protein expression, and impaired de novo ribosome production. Conversely, circHIPK3 overexpression restored Ncl expression, rescued LLPS and ribosome biogenesis defects, and alleviated aging-related cardiac phenotypes in vitro and in vivo. In conclusion, we identify a novel "circHIPK3-Ncl-ribosome biogenesis" axis that protects against cardiac aging through post-transcriptional and biophysical regulation. circHIPK3 represents a potential biomarker and warrants further investigation as a therapeutic candidate for age-related cardiovascular dysfunction, providing new insights into the intersection of non-coding RNA function, ribosome biogenesis and organ aging.
    DOI:  https://doi.org/10.14336/AD.2026.0142
  55. NAR Genom Bioinform. 2026 Jun;8(2): lqag049
    The use of Benzonase to produce ribosome footprints simplifies translational levels quantification by Ribo-seq.
    Guillermo Eastman, George S Bloom, José R Sotelo-Silveira.
      Gene expression quantification through genomics methods is crucial for understanding diverse biological contexts. Among these methods, ribosome profiling (Ribo-seq) stands out as a valuable tool for uncovering post-transcriptional gene expression regulation by providing a comprehensive view of the translatome. While current protocols are time-intensive with limited variations, we introduced the use of the Benzonase enzyme to generate ribosome footprints from a polysome-enriched fraction, streamlining the workflow and reducing time, cost and potential sources of bias. Comparing translatome from Benzonase- and RNAse I-derived footprints reveals minimal differences, with both separating from RNA-seq-based transcriptome quantification. Benzonase acts more gently on ribosomes, yielding larger footprints and a weaker triplet periodicity compared to RNAse I, while enabling its application to low-input samples. We further demonstrate Ribo-seq application in primary neuronal cultures, using Benzonase to digest the post-mitochondrial supernatant, thereby bypassing the labor-intensive ribosome/polysome purification step. The introduction of such protocol variations for Ribo-seq, especially for challenging low-input samples, offers a significant advancement of this resource for the community.
    DOI:  https://doi.org/10.1093/nargab/lqag049
  56. bioRxiv. 2026 May 05. pii: 2026.05.03.722550. [Epub ahead of print]
    Dynamics of synthetic transcriptional condensates emerge from RNA synthesis and degradation.
    Jane Liao, So Yeon Ahn, Allie C Obermeyer.
      At sites of active gene expression, dynamic compartments known as transcriptional condensates assemble and dissolve on timescales relevant to RNA synthesis and degradation. Yet how the non-equilibrium dynamics of these condensates emerge from the coupling of RNA concentration and phase separation remains poorly understood. Here we engineer synthetic active condensates in which T7 RNA polymerase transcribes RNA in situ, triggering phase separation with a cationic scaffold protein. By using RNA concentration as a tunable parameter, we drive condensates along defined paths through a characterized phase diagram. This reaction-phase separation coupling gives rise to three emergent dynamic phenomena not accessible in passive systems: a rapid switch-like nucleation burst, RNA-mediated positive and negative feedback regulation of transcription, and oscillatory condensate formation in which RNA degradation spontaneously renucleates condensates. Together, these results show that the dynamic functions of transcriptional condensates emerge from their reaction-driven paths through phase space, providing a quantitative framework for understanding how RNA flux governs condensate dynamics in living cells.
    DOI:  https://doi.org/10.64898/2026.05.03.722550
  57. Front Physiol. 2026 ;17 1787963
    Epigenetic signatures and cellular stress response pathways in metabolic dysfunction-associated steatotic liver disease: a personalized medicine perspective.
    Fabian M Cortés-Mancera, Marianne G Rots, Han Moshage, Johanna C Arroyave-Ospina.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease around the world, with at least 40% global prevalence. Although genetic susceptibility contributes to disease risk, it does not fully explain the marked interindividual variability in disease onset, severity, and progression. Increasing evidence indicates that epigenetic mechanisms act as critical mediators between genetic predisposition and environmental exposures, shaping hepatic stress responses and metabolic dysfunction in MASLD. Epigenetic regulation, including DNA methylation and histone modifications, plays a fundamental role in maintaining metabolic homeostasis and coordinating cellular responses to metabolic, oxidative, and organellar stress, e.g., endoplasmic reticulum stress. Dysregulation of these processes has been consistently associated with hepatic steatosis, inflammation, fibrosis, and disease progression. Moreover, epigenetic control of circadian rhythms and molecular clock pathways further link metabolic imbalance to liver dysfunction and biological aging. Importantly, epigenetic signatures are stable, positioning them as attractive biomarkers for disease diagnosis, prognosis, and patient stratification, but also potentially reversible, making them promising targets for therapeutic intervention. Advances in epigenomic profiling and translational research are increasingly supporting the integration of epigenetic information into personalized medicine approaches for MASLD. In this review, we synthesize current experimental and translational evidence on epigenetic alterations involved in MASLD pathophysiology, with a particular focus on their role in cellular stress response pathways. We discuss the potential of epigenetic signatures as biomarkers and therapeutic targets, highlighting their relevance for the development of precision-based strategies in the management of MASLD.
    Keywords:  DNA methylation; cellular stress response pathways; epidrugs; epigenetic editing; histone post-translational modifications; metabolic dysfunction-associated steatotic liver disease (MASLD); metabolic stress; mitochondrial dysfunction
    DOI:  https://doi.org/10.3389/fphys.2026.1787963
  58. Toxicol Sci. 2026 May 22. pii: kfag060. [Epub ahead of print]
    Stress-Activated Pathways Mediate PFAS Effects on Human Placental Syncytiotrophoblast Cells.
    Keisuke Kozai, Kaela M Varberg.
      Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants associated with placenta-mediated pregnancy complications, including preeclampsia, fetal growth restriction, and preterm birth. The syncytiotrophoblast (STB), which forms the placental barrier at the maternal-fetal interface and is directly exposed to maternal blood, is a primary site of PFAS exposure. Although PFAS induce STB apoptosis, the upstream stress-signaling pathways involved remain poorly defined. Here, we investigated stress-responsive signaling mechanisms mediating PFAS-induced STB cell death. STB differentiated from human trophoblast stem cells were exposed to vehicle or an environmentally relevant mixture of five PFAS (PFOA, PFOS, PFHxS, PFNA, and PFDA; 0.0138-34.5 µM) for 3 or 6 hours. Cytotoxicity, apoptosis, mitochondrial membrane potential, and stress-signaling pathway activation were assessed by lactate dehydrogenase release, immunoblotting, JC-10 assay, and RT-qPCR. PFAS mixtures did not induce cytotoxicity at 3 hours but significantly increased cytotoxicity at 6 hours at 34.5 µM, coinciding with induction of cleaved caspase-3, cleaved PARP, and NOXA. The pan-caspase inhibitor z-VAD-FMK prevented cytotoxicity, indicating caspase-dependent apoptosis. PFAS exposure reduced mitochondrial membrane potential and activated the integrated stress response (ISR), as evidenced by eIF2α phosphorylation, ATF4 induction, and increased ATF4 target gene expression. In parallel, c-Jun N-terminal kinase (JNK) signaling was activated, as evidenced by JNK phosphorylation and induction of immediate-early genes (JUN, FOS, EGR1). Pharmacologic inhibition of the ISR modestly attenuated PFAS-induced cytotoxicity, whereas pharmacologic inhibition of JNK rescued cytotoxicity and apoptotic signaling. Together, these findings identify JNK-driven stress signaling as the dominant mediator of PFAS-induced STB apoptosis, with a secondary contribution from the ISR.
    Keywords:  JNK signaling; PFAS mixtures; apoptosis; placenta; syncytiotrophoblast
    DOI:  https://doi.org/10.1093/toxsci/kfag060
  59. Front Immunol. 2026 ;17 1779307
    RNA methylation in autoimmune rheumatic diseases: mechanisms and therapeutic potential.
    Yuyao Wang, Guanhui Song, Yujin Xue, Xiaoya Li, Shiping Cheng, Meijie Liu, Hong Liu, Jinghua Pan, Hongyan Zhao, Bin Liu, Danping Fan.
      Autoimmune rheumatic diseases (ARDs), often characterized by pain, constitute a diverse group of autoimmune conditions involving inflammation-mediated injuries to bones, joints, surrounding connective tissues, and occasionally other organs. RNA methylation is a key epitranscriptomic modification that regulates gene expression by influencing stability, splicing, nuclear translocation and degradation. Recent studies have highlighted the crucial role of RNA modification in the pathogenesis and progression of various ARDs. RNA modification affects critical biologic processes of ARDs, such as inflammation, immune response. This review systematically explores the landscape of RNA modification in ARDs, elucidating its regulatory roles and therapeutic implications, including rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, primary Sjögren's syndrome, systemic sclerosis. The intricate mechanisms of RNA modification can lead to the development of novel diagnostic biomarkers and therapeutic strategies, ultimately improving patient outcomes.
    Keywords:  RNA methylation; ankylosing spondylitis; autoimmune rheumatic diseases; primary Sjögren’s syndrome; rheumatoid arthritis; systemic lupus erythematosus
    DOI:  https://doi.org/10.3389/fimmu.2026.1779307
  60. Annu Rev Plant Biol. 2026 May;77(1): 197-223
    A Multidimensional View of Biomolecular Condensates in Plant Biology.
    Yansong Miao, Yanning Wang, Eden Vina Lamoste Grate, Xiaofeng Fang.
      Biomolecular condensates have emerged as versatile regulators of plant cellular processes, offering a dynamic and reversible mechanism to coordinate development, stress response, and spatial organization. Through phase separation, these condensates spatially and temporally modulate biochemical reactions, sequester or activate specific proteins and RNAs, and reshape cellular architecture. This review presents a comprehensive and multidimensional framework for understanding biomolecular condensates in plant biology, from their biophysical properties and ensemble dynamics to their roles across diverse cellular compartments, including plasma membranes, cytoskeleton, intracellular compartments, and chromatin. We highlight their functions in growth, environmental sensing, and defense and discuss current challenges in studying their composition, material properties, and context-dependent behaviors. Understanding plant condensates not only deepens our knowledge of plant cell organization and adaptability but also opens new avenues for biotechnological innovation in agriculture.
    Keywords:  biomolecular condensates; development; function; phase separation; stress
    DOI:  https://doi.org/10.1146/annurev-arplant-070725-083459
  61. bioRxiv. 2026 May 07. pii: 2026.05.04.722644. [Epub ahead of print]
    Nuclear Speckles Regulate Splicing During Muscle Stem Cell Activation and Aging.
    Steve D Guzman, Pamela Duran, Yu Xiao, Yuxuan Song, Joshua D Welch, Chuan He, Carlos A Aguilar.
      Skeletal muscle contains a population of adult stem cells called satellite cells or muscle stem cells (MuSCs) that are responsible for regeneration after injury. MuSCs utilize gene expression programs to maintain quiescence and differentiate after injury and a key regulator of gene expression is splicing, which uniquely changes when transcripts interact with nuclear speckles (NS). NS are membrane-less biomolecular condensates that phase separate proteins, RNAs and chromatin, but how these organelles regulate molecular processes in MuSCs remains unknown. Herein, we build a comprehensive and systems-level understanding of NS influence on alternative splicing, transcriptional regulation and stem cell function before and after injury and in aging. We establish that NS increased in size and number in MuSCs following injury and influence MuSC activation dynamics. We generated a catalog of isoform-resolved splicing events and linked how RNA interactions with NS amplify splicing completion during the injury response. In old age, MuSCs lose NS, yet shifted towards longer, more completely spliced isoforms enriched for RNA binding protein motifs and multivalency. Our studies unveil evidence that RNA interactions with NS shape stem cell state and regenerative responses but are attenuated in old age.
    HIGHLIGHTS: 3D super-resolution imaging of nuclear speckles in muscle stem cells before and after muscle injury shows intricate relationship with activationIsoform-resolved profiling of muscle stem cells shows increases in gene expression and splicing during injury responseMapping RNA interactions with nuclear speckles shows RNAs undergo strongest splicing when proximal to nuclear specklesOld aged muscle stem cells lose nuclear speckles and display aberrant splicing, with longer transcripts, more exons, and increased RNA binding protein motifs.
    DOI:  https://doi.org/10.64898/2026.05.04.722644
  62. Oncogenesis. 2026 May 16.
    Multi-omics analysis reveals LARP1 as a key integrator of translation and metabolism in AML.
    Dominik A Nahotko, Brian Lee, Emely Lopez Fajardo, Aneta H Baran, Szymon K Filip, Peter A Faull, Elizabeth T Bartom, Masha Kocherginsky, Peng Gao, Jason Miska, Diana Saleiro, Elspeth M Beauchamp, Leonidas C Platanias.
      La-related protein 1 (LARP1) is an RNA-binding protein and downstream effector of mTOR and CDK9 signaling that regulates translation of mRNAs containing a 5'-terminal oligopyrimidine motif. While elevated LARP1 expression has been linked to poor prognosis in acute myeloid leukemia (AML), its mechanistic role remains unclear. Using CRISPR/Cas9-mediated LARP1 knockout and multi-omics analyses, we investigated LARP1's role in AML. LARP1 loss impaired proliferation, clonogenicity, and tumor growth in xenografts, and enhanced sensitivity of AML cells to 5-azacytidine and cytarabine. Polysome profiling and RNA sequencing revealed that LARP1 modulates a distinct set of transcripts involved in mitochondrial function, amino acid metabolism, and cell cycle regulation, independently of mTOR and CDK9. Proteomics analysis uncovered additional effects of LARP1 loss on immune signaling, lysosomal pathways, and protein stability, including changes not evident at the RNA level. Metabolomic profiling showed reprogramming of arginine/creatine metabolism and depletion of pyrimidine biosynthesis intermediates. Cytidine deaminase, a known resistance factor, was downregulated across omics layers upon LARP1 loss. These findings define LARP1 as a key integrator of translational regulation and metabolic control in AML, supporting leukemic cell survival and promoting drug resistance. Targeting LARP1 may uncover vulnerabilities in leukemia cells, not addressed by current therapies.
    DOI:  https://doi.org/10.1038/s41389-026-00623-3
  63. Cancer Med. 2026 May;15(5): e71917
    METTL16 Promotes Head and Neck Squamous Cell Carcinoma Progression via m6A-Mediated Stabilization of SREBP2 mRNA and Enhanced Cholesterol Biosynthesis.
    Xinrui Ma, Xiaojun Ding, Jianhua Deng, Qian Gao, Huiting Liu, Shuo Yuan, Zhi Xiao, Rui Jiang.
      N6-methyladenosine (m6A) modification is a crucial epigenetic event in the development of head and neck squamous cell carcinoma (HNSCC). Here, we show that methyltransferase-like 16 (METTL16) expression is elevated in the tumor tissues of patients with HNSCC and is associated with poor prognosis. In addition, our data show that METTL16 promotes the proliferation of HNSCC cells in vitro and in vivo by enhancing cholesterol biosynthesis. Mechanistically, METTL16 catalyzes a key transcription factor in cholesterol biosynthesis-sterol regulatory element-binding transcription factor 2 (SREBP2) m6A modification and then stabilizes SREBP2 mRNA and ultimately elevates SREBP2 mRNA expression in HNSCC cells. Moreover, we validate that METTL16 promotes HNSCC progression dependent on SREBP2 mRNA expression. Overall, our results reveal a novel function of METTL16 in regulating SREBP2 expression, revealing a previously unrecognized METTL16/SREBP2 pathway in HNSCC cells.
    DOI:  https://doi.org/10.1002/cam4.71917
  64. Nat Commun. 2026 05 18. pii: 4202. [Epub ahead of print]17(1):
    Diverse mechanisms of translation arrest by a Clostridia ribosome stalling peptide CliM.
    Mayu Yoshida, Felix Gersteuer, Ole Berendes, Keigo Fujiwara, Haaris A Safdari, Helge Paternoga, Hiraku Takada, Nozomu Obana, Helmut Grubmüller, Lars V Bock, Daniel N Wilson, Shinobu Chiba.
      Ribosome arrest peptides undergo programmed translational stalling in response to changes in the cellular environment to feedback-regulate gene expression. CliM, an arrest peptide in Clostridia, is encoded upstream of the YidC membrane protein insertase gene, but its function and mechanism remain unclear. Here we show that CliM monitors YidC activity to maintain adequate cellular YidC capacity. Interestingly, Clostridium kluyveri CliM induces elongation arrest at multiple sense codons, whereas Clostridioides difficile CliM causes termination arrest. Cryo-EM-based structural and mutational analyses demonstrate that C. difficile CliM adopts multiple α-helices within the nascent polypeptide exit tunnel, where it forms extensive arrest-essential interactions with the ribosome. The residue immediately N-terminal to the stalling site contributes to arrest by sterically interfering with full accommodation of the release factor or aminoacyl-tRNA in the A-site. Molecular dynamics simulations suggest that membrane insertion of CliM induces sequential unwinding of these α-helical structures and relocation of the penultimate residue, thereby triggering arrest release. These findings provide a unified mechanistic framework that explains the distinct arrest behaviors of CliM homologs.
    DOI:  https://doi.org/10.1038/s41467-026-72673-5
  65. bioRxiv. 2026 May 09. pii: 2026.05.06.723280. [Epub ahead of print]
    IRES-TrAPPr reveals novel insights into viral and cellular mRNA translation.
    Gemma E May, C Joel McManus.
      Ribosome recruitment to human mRNAs is thought to occur primarily via cap-dependent initiation (CDI). This process is suppressed during a variety of cellular stresses, including viral infection, suggesting stress-response genes and viral mRNAs use alternative mechanisms to initiate translation. Indeed, many viruses recruit ribosomes directly via Internal Ribosome Entry Sites (IRESes). Hundreds of human mRNAs have been reported to also contain IRESes due to their ability to enhance expression in bicistronic and backspliced circRNA plasmid reporters. These DNA-based screens also reported hundreds of novel IRESes from more than fifty human viruses. However, such assays are prone to false-positives due to promoter and splicing activity, do not compare CDI and IRES translation, and lack the temporal resolution necessary for stress-response studies. To address these issues, we developed IRES- Tr anslating A ffinity P rotein Pr ofiling (IRES-TrAPPr), a massively parallel reporter assay that simultaneously quantifies CDI and IRES activity from thousands of co-transfected mRNAs. We validated this new method using luciferase assays and structure-function analyses of established viral IRESes, demonstrating exquisite sensitivity and specificity. Using IRES-TrAPPr, we quantified the activities of IRES elements from hundreds of viruses from a diversity of hosts. Our results provide evidence that viral IRESes from warm-blooded hosts have adapted higher structural stability to maintain folding at higher temperatures. Finally, we find hundreds of candidate human and viral IRESes from DNA-based screens have negligible IRES activity. Altogether, our results show that IRES-TrAPPr provides a novel, accurate platform for IRES research.
    DOI:  https://doi.org/10.64898/2026.05.06.723280
  66. Nucleic Acids Res. 2026 May 20. pii: gkag502. [Epub ahead of print]54(10):
    A universal Fab targeting a conserved U1A-RNA epitope for RNA structure determination by cryo-EM.
    Ekaterina V Filippova, Daniel Krochmal, Somnath Mukherjee, Joseph A Piccirilli, Anthony A Kossiakoff.
      Recent advances in cryo-electron microscopy (cryo-EM) have made antigen-binding fragments (Fabs) essential tools in the field of structural biology. Fabs facilitate image alignment, thereby enhancing three-dimensional (3D) reconstruction, and increase the effective size of proteins, aiding in their structural elucidation. In this study, we sought to broaden the use of Fabs as fiducial markers to elucidate the structures of RNA molecules. Identifying an appropriate Fab for a specific RNA target can be particularly challenging due to RNA's inherent flexibility and tendency to assume multiple conformations, which complicate the process and prolong the structure determination timeline. To address this challenge, we designed a universal Fab that specifically recognizes a U1A-RNA epitope, thereby reducing the need for Fab selection tailored to each individual RNA target. We determined the cryo-EM structure of the class I ligase ribozyme complexed with a portable U1hpII loop bound to the U1A protein and the Fab. The resulting structure revealed that the Fab interacts with a conserved U1A-RNA binding region, which can be engineered into other RNA molecules. This strategy presents significant potential for streamlining the structural determination of various RNAs, which are essential for biological and biomedical research.
    DOI:  https://doi.org/10.1093/nar/gkag502
  67. Proc Natl Acad Sci U S A. 2026 May 26. 123(21): e2519235123
    OptoRibo-seq for spatiotemporally resolved mapping of the local protein translatome.
    Ruixuan Wang, Ruixiang Wang, Wentao Wang, Yanjun Liu, Fu Zheng, Huixin Luo, Peng R Chen, Peng Zou.
      Localized protein translation occurs in numerous subcellular compartments and regulates diverse biological processes by rapidly changing protein compositions in response to subcellular needs. Existing assays for subcellular local translation either require physical isolation, which is prone to contamination and loss of material, or imaging-based readout, which is often hampered with low throughput. In this study, we report the development of the optoRibo-seq method that features photoactivatable enzyme-mediated proximity labeling of ribosomes in genetically specified subcellular locations. We demonstrate the spatial specificity of optoRibo-seq at the endoplasmic reticulum (ER) membrane, with a temporal resolution of 1 min. In cells undergoing chemically induced ER stress, optoRibo-seq allowed mapping of the dynamic changes in the ER-proximal translatome, identifying transcripts involved in protein folding and targeting. Our strategy provides a general platform for spatiotemporally resolved profiling of subcellular protein translation.
    Keywords:  ER stress; biotin ligase; genetic codon expansion; proximity labeling; ribosome profiling
    DOI:  https://doi.org/10.1073/pnas.2519235123
  68. PLoS One. 2026 ;21(5): e0347598
    Decoding the genetic basis of demyelination: Prediction of potential pathogenic coding and regulatory noncoding MBP SNPs in multiple sclerosis.
    Arwa Ibrahim Alwabran, Ghalia Mahfod Aldoseri, Ghanem Mahfod Aldoseri, Samah O Mohager, Mobarak Mahfod Aldoseri, Ebtihal Kamal.
       BACKGROUND: The Myelin Basic Protein (MBP) gene is essential for myelin sheath formation in the central nervous system. Coding and noncoding single-nucleotide polymorphisms (SNPs) can impair the protein structure and function, contributing to demyelinating diseases exemplified by multiple sclerosis. This study aimed to assess the impact of SNPs in the MBP gene on protein structure and function.
    METHODS: We employed a comprehensive approach to investigate the impact of both noncoding and coding SNPs of the MBP gene. Initially, we utilized RegulomeDB to assess the regulatory roles of SNPs located in the 3' untranslated regions (3' UTRs). Subsequently, we examined the influence of the 3' UTR SNPs on microRNA (miRNA) binding sites using PolymiRTS. Furthermore, we analyzed the functional 3' UTR SNPs using RNAfold to evaluate their impact on RNA structure. To predict deleterious nonsynonymous SNPs (nsSNPs), various bioinformatics tools, including SIFT, PolyPhen-2, PROVEAN, META-SNP, ESNPs&GO, PANTHER, and AlphaMissense, were employed. Protein stability was assessed using I-Mutant2.0, MUpro, and DDMut. Structural modeling was performed with AlphaFold, and both wild-type and mutant proteins were visualized in UCSF ChimeraX. Conservation analysis was conducted using the ConSurf tool, and protein interaction networks were explored using the STRING database.
    RESULTS: Eight noncoding SNPs were identified as potential regulatory SNPs, affecting the miRNA binding sites. Moreover, three nsSNPs, rs1971676214 (D173E), rs1242552448 (D173H), and rs772570115 (G176W), were consistently predicted to be pathogenic and to destabilize the protein structure. These variants were located in highly conserved sites and disrupted hydrogen bonds. STRING analysis revealed interactions between MBP and other myelin-related, immune, and signaling proteins, linking it to CNS and autoimmune pathways.
    CONCLUSIONS: This study identified eight noncoding 3' UTR SNPs and three potentially pathogenic nsSNPs that may compromise gene expression and protein structure and function, respectively, offering insight into genetic mechanisms of demyelination.
    DOI:  https://doi.org/10.1371/journal.pone.0347598
  69. Cell Rep. 2026 May 18. pii: S2211-1247(26)00426-2. [Epub ahead of print]45(5): 117348
    High-resolution mapping of CCR4-NOT recruitment elements reveals transcriptome-wide drivers of mRNA decay.
    Zijun Luo, Aldo Hernandez-Corchado, William R Brothers, Zahra Aryanpour, Zia Z Zhao, Justin Zhao, Lindsay Clarke, Connor CampbellSmith, Gene W Yeo, Hamed S Najafabadi, Marc R Fabian.
      The CCR4-NOT complex is a central regulator of gene expression, orchestrating mRNA turnover through interactions with RNA-binding proteins (RBPs) and the microRNA (miRNA)-induced silencing complex. However, identifying which RBP- and miRNA-associated RNA elements recruit CCR4-NOT remains challenging, due in part to the multiple modes by which the complex can be recruited. To address this, we developed TRACER (targeted RNA association with CCR4-NOT and element recovery), a high-throughput method for transcriptome-wide identification of RNA elements that recruit the CCR4-NOT to target RNAs. TRACER analysis in human epithelial cells uncovers thousands of CCR4-NOT-associated elements, including many that map to known and/or predicted RBP and miRNA target sites. We show that TRACER-identified elements drive mRNA repression and decay, and disrupting elements via gene editing or antisense oligonucleotides can relieve repression, boosting target gene expression. This positions TRACER as a powerful discovery platform for identifying regulatory RNA elements that can be targeted to control gene expression.
    Keywords:  CCR4-NOT complex; CP: molecular biology; RNA regulatory elements; RNA-binding proteins; RNA-protein interactions; mRNA decay; microRNA-mediated repression
    DOI:  https://doi.org/10.1016/j.celrep.2026.117348
  70. Int J Med Sci. 2026 ;23(6): 2088-2095
    Impact of IGF2BP2 genetic variants and expression levels with the progression of endometrial cancer.
    Chieh-Yi Kan, Yi-Hung Sun, Chung-Yuan Lee, Shih-Chi Su, Cheng-Chang Chang, Chih-Hsin Tang, Hsiao-Ju Chu, Po-Hui Wang, Shun-Fa Yang.
      Endometrial cancer (EC) is the most common gynecological cancer among women in high-income countries, and its intricate etiology involves a composite of genetic factors. Insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) targets distinct types of RNA species to orchestrate tumor cell metabolism, invasion, and metastasis. Nevertheless, the impact of IGF2BP2 gene polymorphisms on the development of EC remains poorly understood. Here, to clarify the genetic association between IGF2BP2 and EC development, genotyping of three single-nucleotide polymorphisms (SNPs) of IGF2BP2 gene, including rs11705701, rs4402960, and rs1470579, were conducted in 190 patients and 295 cancer-free women. We found that none of these three loci was in association with the risk of developing EC. Further evaluation on their correlation with key clinicopathological features revealed that EC patients carrying at least one minor allele of rs1470579 (C) or rs4402960 (T) tend to develop cervical invasion more frequently than do those homozygous for the major allele. Analysis of omics data available in the Genotype-Tissue Expression (GTEx) Portal and The Cancer Genome Atlas (TCGA) indicated that genotypes of rs1470579 and rs4402960 are associated with elevated IGF2BP2 expression, and IGF2BP2 induction in tumors was linked to progression to advanced disease and poor survival in patients with uterine corpus endometrial carcinoma. These results suggest that alterations in IGF2BP2 levels attributed by genetic variants may influence EC aggressiveness.
    Keywords:  endometrial cancer; insulin-like growth factor 2 mRNA binding protein 2; single-nucleotide polymorphisms
    DOI:  https://doi.org/10.7150/ijms.132120
  71. J Med Chem. 2026 May 19.
    Discovery of Fosigotifator, a Potent eIF2B Activator with Desired Properties for Human Studies.
    Jennifer M Frost, Yunsong Tong, Xiangdong Xu, Lei Shi, Marina Pliushchev, Kathleen J Murauski, Kathy Kohlhaas, Diana L Donnelly-Roberts, Michael M Sheehan, Stephan Riedmaier, Hardeep S Oberoi, Jun Chen, Janani Prakash, Charles W Hutchins, Clarissa G Jakob, Rinku Jain, Wei Qiu, Rodger F Henry, Rohinton Edalji, Chaohong Sun, Tracy Carr, Ana M Basso, Brian S Brown, Eric A Voight, Carmela Sidrauski, Michael J Dart.
      The integrated stress response (ISR) is a highly conserved cellular pathway triggered by a variety of insults, reducing protein synthesis and inducing ATF4, leading to broadly remodeling the cellular transcriptome and metabolome. ISRIB, 1, the first identified eIF2B activator, attenuates the ISR restoring protein synthesis, but its poor solubility limits absorption and advancement. To improve drug-like properties, we explored replacements for both the cyclohexyl core and side chains of ISRIB. This effort initially led to truncated analogue, 2BAct, 13, which demonstrated improved solubility relative to 1; however, cardiovascular effects in higher species limited its progression into the clinic. Potent analogue 9 was identified with significantly improved solubility vs 1 but was still projected to have solubility-limited absorption. A prodrug campaign resulted in the identification of compound 26 (fosigotifator), which exhibited significantly improved solubility and is currently being investigated in the clinic.
    DOI:  https://doi.org/10.1021/acs.jmedchem.6c00716
  72. Front Immunol. 2026 ;17 1828765
    PRMT3 in cancer: arginine methylation as a driver of tumor metabolism, immune evasion, and therapeutic resistance.
    Hui Jin, Hua Huang, Xin Pan.
      Protein arginine methyltransferase 3 (PRMT3) is a type I arginine methyltransferase that catalyzes asymmetric dimethylation of arginine residues on diverse substrate proteins. Initially characterized as a regulator of ribosomal protein methylation, PRMT3 has more recently been implicated in several cancer-related processes. Accumulating evidence suggests that PRMT3 is dysregulated in a variety of malignancies, including hepatocellular carcinoma, colorectal cancer, glioblastoma, breast cancer, pancreatic cancer, and non-small cell lung cancer. Through arginine methylation of selected regulatory proteins, PRMT3 has been linked to signaling pathways associated with tumor progression, metabolic adaptation, immune modulation, and therapeutic resistance. Mechanistically, available studies indicate that PRMT3 can regulate RNA-associated networks by methylating RNA-binding proteins and epitranscriptomic regulators such as IGF2BP1 and METTL14, thereby influencing mRNA stability and gene expression programs. In addition, PRMT3 has been reported to contribute to tumor metabolic reprogramming by promoting glycolytic activity and modulating amino acid metabolism through factors including HIF1A, PDHK1, and IDO1. These alterations may support tumor growth and, in some contexts, influence the tumor immune microenvironment. PRMT3 has also been associated with immune evasion, for example through effects on PD-L1 expression and innate immune signaling pathways such as cGAS-STING. Moreover, emerging evidence links PRMT3 to therapeutic resistance through mechanisms involving oncogenic transcript stabilization, immunometabolic remodeling, and drug efflux regulation. In this review, we summarize the current understanding of PRMT3 structure, catalytic mechanisms, and biological functions in cancer. We further discuss its emerging roles in metabolic regulation, immune suppression, and therapy resistance, while distinguishing mechanisms directly supported within specific cancer contexts from broader conceptual models inferred across studies. Overall, current evidence supports PRMT3 as an emerging and context-dependent regulator of tumor biology and a potential target for anticancer therapy.
    Keywords:  PRMT3; arginine methylation; immune evasion; therapeutic resistance; tumor metabolism
    DOI:  https://doi.org/10.3389/fimmu.2026.1828765
  73. Yeast. 2026 May 21.
    Twenty-Five Years of the Environmental Stress Response and the Enduring Power of Yeast in Stress Biology.
    Audrey P Gasch.
      All organisms must be able to sense and respond to adverse environments, especially those that threaten cellular integrity. The age of genomics clarified the breadth and specificity of cellular stress responses, including in free-living microbes directly exposed to a changing environment. The environmental stress response (ESR) in Saccharomyces cerevisiae was among the first responses defined at the transcriptome-wide level as a common program triggered by diverse types of stress. Since its original publication over 25 years ago, many studies have explored the role, regulation, and evolution of the ESR and underlying principles of stress defense. This perspective reviews the history of the ESR, recent insights and perspectives into its purpose and regulation, and remaining questions in stress biology primed for the power of yeast experimentation.
    Keywords:  Msn2/Msn4; environmental stress response; stress; transcriptome
    DOI:  https://doi.org/10.1002/yea.70028
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