bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–03–29
53 papers selected by
Cédric Chaveroux, CNRS
  1. Ribosome Biogenesis and Translational Control in Skeletal Muscle Atrophy and Hypertrophy: Mechanisms and Therapeutic Perspectives.
  2. RNA Tailing by Nucleotidyltransferases in Plants: Mechanisms, Functions, and Biological Significance.
  3. Viruses and RQC: a molecular arms race at the heart of translation.
  4. Ribosome Molecular Aging Shapes Translation Dynamics.
  5. Organelle-anchored translation factories: the roles of neuronal RBP condensates in organizing local protein synthesis in neurological diseases.
  6. Beyond the Sequence: Chemical and Topological Design and Innovations in mRNA Therapeutics.
  7. Mechanism of 30S subunit recognition and modification by the conserved bacterial ribosomal RNA methyltransferase RsmI.
  8. RNA G-quadruplexes mediate cooperativity in HNRNPH binding and splicing regulation.
  9. Optimized tRNA structure-seq reveals robust tRNA secondary structures in S. cerevisiae under mild stress conditions.
  10. Genes near tRNAs are enriched in translational machinery.
  11. Modern RNA Quantification Methods: From RT-qPCR to Advanced Microscopy.
  12. Direct RNA Sequencing Reveals Stress-Dependent and Pathway-Specific rRNA Modification Reprogramming during 50S Biogenesis.
  13. RNF25 confers mRNA damage tolerance by curbing activation of the integrated stress response.
  14. Sensing of double-stranded RNA in human cells: molecular mechanisms and cellular consequences.
  15. Molecular determinants and therapeutic targeting of stop codon readthrough in eukaryotic translation.
  16. Hidden Diversity in Yeast tRNAs: Comparative Genomics and Modification Mapping in a Eukaryotic Subphylum.
  17. eIF4G2-dependent translation restrains pancreatic cancer progression.
  18. Translational Fidelity Decline in the Aging Oocyte and Embryo Development.
  19. The METTL3 inhibitor STM2457 suppresses gastric cancer progression by modulating m6A RNA modification.
  20. m 6 A RNA methylation modulates Zika virus infection by regulating serine proteases in Aedes albopictus.
  21. A bifunctional H/ACA snoRNP mediates both pseudouridylation and rRNA scaffolding during ribosome assembly.
  22. N4-acetylcytidine in LncRNA Gm26917 Promotes Translation in Female Germline Stem Cells by Recruiting Ribosomal Protein mRNA via EEF1A1.
  23. METTL3-driven m6A modification of NLRC5 promotes renal fibrosis in chronic kidney disease through Keap1/Nrf2/ARE signaling pathway.
  24. The Art of Domesticating Proteins: How Cancer Cells Adapt to Therapeutic and Environmental Stressors.
  25. Sexually dimorphic ATF4 expression in the fat confers female stress tolerance in Drosophila melanogaster.
  26. NMR investigation of the sliding motion of RNA helicase DDX3X along single-stranded RNA.
  27. m5C RNA methylation is dysregulated by oncogenic herpesviruses via c-Myc signaling to counteract host antiviral factors.
  28. Cellular Repair and Removal of Protein-Damage Modifications.
  29. AI foundation models for RNA biology.
  30. Salmonella Typhi asparaginase-dependent activation of GCN2 promotes bacterial killing in murine macrophages.
  31. Alternative splicing in voltage-gated sodium channels: mechanisms, regulatory networks and therapeutic implications.
  32. Stress-Encoded Mitochondrial Plasticity: ATF4 Control of Mega-Mitochondria and Nanotunnel Communication.
  33. Reduced YTHDF2 inhibits PD-L1 expression by stabilizing m6A-containing SPOP mRNA in colorectal cancer.
  34. Regulation of oncogenic C-terminal truncated p53β protein isoform expression by SRSF3-UPF1 splicing and surveillance axis.
  35. The coordinated action of UFMylation and the RQC pathways clears arrested polypeptides at the ER.
  36. Protocol for quantifying silent ribosome induction in yeast and mammalian cells using polysome profiling.
  37. Stress Responses Tied to Metastasis and Immune Evasion.
  38. Regulation of Pre-rRNA Processing in Plant: Mechanisms, Plasticity, and Developmental Implications.
  39. Preparation of K-Ras4B containing synthetic modifications via expressed protein ligation.
  40. Phototriggered Morphological and Compositional Change of UGGAA Repeat RNA Foci by Photoswitchable RNA-Binding Ligand.
  41. Replating Induces mTOR-Dependent Rescue of Protein Synthesis in Charcot-Marie-Tooth Diseased Neurons.
  42. Protein Arginine Methyltransferases in γ-Globin Regulation and Sickle Cell Disease: Emerging Connections to Oxidative Stress.
  43. What does it take to learn the rules of RNA base pairing? A lot less than you may think.
  44. Epitranscriptomic modulations optimize crop traits via messenger RNA modifications.
  45. METTL3-mediated TIGAR m6A modification and its role in microglia activation related to Alzheimer's disease.
  46. An SLCO2B1 mRNA Isoform Acts as a Noncoding RNA to Drive Cancer Progression by Triggering Protein Biosynthesis.
  47. mRNA 3' UTRs direct microRNA degradation to participate in imprinted gene networks and regulate growth.
  48. ZXDB Drives Macrophage Inflammatory Programming in Sepsis-Induced Acute Kidney Injury by Recruiting EIF4A3 to Enhance ACACA Translation.
  49. Dynamic translocation of Inside-Out proteins to the cell surface underlies cellular adaptation to cancer-induced stress.
  50. Circadian Dysregulation in Aging Alters Senescence and Inflammatory Pathways in a Sex- and Time-of-Day-Dependent Manner.
  51. Poly(ADP-ribose) (PAR) exhibits ion-dependent structural properties distinct from RNA.
  52. SOCS3 suppresses glioblastoma growth via JAK-STAT inhibition and mitochondrial unfolded protein response activation.
  53. Unfolded proteins and aggregates: The role of proteostasis in pseudoexfoliation pathology.
  1. Biomolecules. 2026 Mar 10. pii: 406. [Epub ahead of print]16(3):
    Ribosome Biogenesis and Translational Control in Skeletal Muscle Atrophy and Hypertrophy: Mechanisms and Therapeutic Perspectives.
    Miaomiao Xu, Xiaoguang Liu.
      Maintenance of skeletal muscle mass is essential for mobility, metabolic homeostasis, and clinical outcomes across a wide spectrum of physiological and pathological conditions. While muscle atrophy and hypertrophy have traditionally been interpreted through upstream anabolic-catabolic signaling and proteolytic pathways, accumulating evidence indicates that ribosome biogenesis and translational control represent rate-limiting determinants of muscle plasticity. However, this regulatory layer remains insufficiently integrated into current models of muscle adaptation and disease. In this review, we synthesize recent advances in ribosomal RNA transcription, ribosomal protein dynamics, and translational regulation in skeletal muscle, with particular emphasis on signaling networks governed by mTORC1, c-Myc, AMPK, and FOXO. We highlight ribosome biogenesis as a central hub linking mechanical loading, nutrient availability, inflammatory stress, and metabolic status to protein synthesis capacity. Evidence from human and animal studies demonstrates that impaired ribosome production and translational efficiency precede and predict muscle atrophy in disuse, aging, cancer cachexia, and chronic disease, whereas ribosome expansion is a prerequisite for sustained hypertrophy. Beyond quantitative regulation, we discuss the emerging concept of ribosome heterogeneity as a qualitative layer of translational control that may enable selective mRNA translation during muscle growth, stress adaptation, and degeneration. We further examine ribosome-mitochondria crosstalk as a critical but underexplored mechanism coordinating anabolic capacity with cellular energetics. Finally, we outline therapeutic implications, highlighting exercise, nutritional strategies, and indirect pharmacological interventions that preserve ribosomal competence, and propose ribosome-based biomarkers as promising tools for precision management of muscle-wasting disorders. Collectively, this review positions ribosome biology as a translationally relevant framework bridging molecular mechanisms with therapeutic perspectives in skeletal muscle atrophy and hypertrophy.
    Keywords:  ribosome biogenesis; ribosome heterogeneity; skeletal muscle atrophy; therapeutic strategies; translational control
    DOI:  https://doi.org/10.3390/biom16030406
  2. Plants (Basel). 2026 Mar 17. pii: 925. [Epub ahead of print]15(6):
    RNA Tailing by Nucleotidyltransferases in Plants: Mechanisms, Functions, and Biological Significance.
    Xintong Xu, Xinwen Qing, Xiaoli Peng, Xiangze Chen, Tengbo Huang, Beixin Mo, Yongbing Ren.
      RNA tailing, the non-templated addition of nucleotides to RNA 3' ends, is a conserved post-transcriptional modification that plays a critical role in regulating RNA metabolism. In plants, this process is primarily mediated by nucleotidyltransferase proteins (NTPs). In this review, we analyze current knowledge of plant NTPs by integrating evidence from genetic, biochemical, and phylogenetic analyses of the gene-family across model plants and crops. We summarize the composition and evolutionary diversification of the plant NTP gene family, with emphasis on lineage-specific expansion and conservation patterns. Using Arabidopsis thaliana as a reference framework, we then describe the molecular roles of NTPs in the tailing of distinct RNA classes, emphasizing how tail type and length confer context-dependent regulatory outcomes including stabilization versus degradation and processing/maturation versus clearance. We further examine the determinants of substrate choice, focusing on RNA type, terminal structure, and subcellular localization. Finally, we discuss the biological functions of NTP-mediated RNA tailing in plants, linking RNA tailing to development, stress responses, antiviral immunity, and agronomic traits in crops. We conclude by outlining key mechanistic and physiological challenges that define future directions for understanding and harnessing NTP-mediated RNA regulation. Collectively, this review provides an integrated framework for understanding how RNA tailing by NTPs shapes plant RNA metabolism and biological fitness.
    Keywords:  RNA stability; RNA tailing; agronomic traits; gene expression; nucleotidyltransferase protein (NTP); plant antiviral immunity; plant development; stress response
    DOI:  https://doi.org/10.3390/plants15060925
  3. Trends Microbiol. 2026 Mar 25. pii: S0966-842X(26)00041-7. [Epub ahead of print]
    Viruses and RQC: a molecular arms race at the heart of translation.
    Maria G Masucci.
      Viruses rely exclusively on host ribosomes for protein synthesis, but the translation of viral mRNA depletes host resources and imposes structural constraints that trigger translational stress. Translational stress activates cellular surveillance responses, including the ribosome-associated quality control (RQC), which safeguards translation fidelity by degrading aberrant translation products and mRNAs, with potential antiviral effects. Here, I review emerging evidence detailing the complex interplay between viral infections and the RQC, highlight its antiviral properties, and discuss how viruses have evolved RQC-reprogramming strategies to optimize viral protein production and evade immune detection. The evidence points to the RQC as a critical regulatory hub in host-pathogen dynamics. This insight may inform novel antiviral strategies targeting translational control mechanisms, offering potential new avenues to combat viral diseases.
    Keywords:  innate immunity; integrated stress response; ribosome-associated quality control; ribotoxic stress response; translational stress response; viral mRNA translation
    DOI:  https://doi.org/10.1016/j.tim.2026.03.002
  4. bioRxiv. 2026 Mar 09. pii: 2026.03.08.710403. [Epub ahead of print]
    Ribosome Molecular Aging Shapes Translation Dynamics.
    Jordy F Botello, Lifei Jiang, Peter J Metzger, Troy J Comi, Aya A Abu-Alfa, Qiwei Yu, Margaret S Ebert, Minkyu Lee, Lennard W Wiesner, Maya Butani, Claire J Weaver, Andrej Košmrlj, Ileana M Cristea, Clifford P Brangwynne.
      Cellular homeostasis relies on continual renewal of cellular components, yet some complexes like ribosomes persist for long periods, raising the question of whether extended molecular age impacts functional fidelity. Here, we introduce a spatiotemporal mapping strategy to resolve biomolecular life stages, and show that intracellular ribosome aging alters translational dynamics at specific transcripts. Molecularly aged ribosomes exhibit impaired elongation at basic amino acid-rich sequences, leading to increased pausing, premature termination, and ribosome collisions. By profiling ribosomal RNA modifications, we find that molecular aging increases the collision propensity of specific ribosome subpopulations. Consistent with our findings, enrichment of aged ribosomes in cells amplifies molecular age-dependent translation defects. In vivo labeling of ribosomes in aged C. elegans demonstrates that molecularly aged ribosomes shape translational dynamics during organismal aging. These findings identify ribosome molecular age as a determinant of translational dynamics, and link molecular aging of a core gene-expression complex to organismal aging.
    HIGHLIGHTS: A pulse-chase labeling strategy enables mapping subcellular demographics of macromolecular complexes in space and time.Molecular aging of ribosomes drives differential mRNA translation and shapes elongation dynamics.The collision propensity of specific ribosome subpopulations increases with molecular age.Older ribosomes shape translation dynamics during organismal aging.
    DOI:  https://doi.org/10.64898/2026.03.08.710403
  5. Protein Cell. 2026 Mar 25. pii: pwag026. [Epub ahead of print]
    Organelle-anchored translation factories: the roles of neuronal RBP condensates in organizing local protein synthesis in neurological diseases.
    Semin Park, Hari Lim, Jin-A Lee.
      Neurons face a fundamental proteostasis challenge: synapses and axons located far from the soma must rapidly remodel their proteome during activity, stress, and development. While local protein synthesis has long been recognized as essential for meeting these demands, classical models largely focused on ribonucleoprotein (RNP) granules as autonomous carriers of translationally silent mRNAs, treating membranous organelles as parallel logistics or metabolic systems. Recent work overturns this view, revealing that endosomes, lysosomes, axonal endoplasmic reticulum, mitochondria, and their contact sites actively function as mobile translation platforms. In this review, we propose an RBP-centered framework in which phase-separated condensates physically tether specific mRNA cohorts to organelle surfaces, coupling mRNA transport, translational control, and organelle dynamics into a unified network. By organizing recent discoveries into functional modules-long-range transport, localized translation, and stress buffering-this neuron-focused framework identifies organelle-anchored translation factories as a unifying principle of synaptic proteostasis and a broadly applicable design paradigm for highly polarized cells.
    Keywords:  RNA-binding proteins; neuronal local translation; organelle-anchored translation; ribonucleoprotein granules
    DOI:  https://doi.org/10.1093/procel/pwag026
  6. Chem Rev. 2026 Mar 24.
    Beyond the Sequence: Chemical and Topological Design and Innovations in mRNA Therapeutics.
    Dangliang Liu, Hongyu Chen, Alisia Pan, Xiao Wang.
      Messenger RNA (mRNA) has rapidly emerged as a transformative therapeutic modality, exemplified by its growing applications in infectious diseases, oncology, and genetic disorders. The chemical programmability of mRNA allows researchers to modulate its function by introducing synthetic modifications across the molecule─from the cap structure, untranslated regions (UTRs), coding sequence (CDS) to poly(A) tail and from base, backbone to ribose sugars. Beyond sequence-level design, recent advances have introduced a new dimension of control: topological engineering. Circular RNAs, branched structures, and synthetic lariat architectures are reshaping how we approach RNA stability, immunogenicity, and translation. This review surveys recent advances in the chemical and topological engineering of mRNA, emphasizing four key areas: (1) enzymatic, chemical, and hybrid methodologies that expand the repertoire of accessible mRNA modifications; (2) synthesis strategies for linear, circular, and branched mRNA topologies; (3) structure-activity relationships governing translation efficiency, decay, and immune activation; and (4) implications for next-generation mRNA-based therapeutics. By integrating chemical synthesis, synthetic biology, and RNA structural design, researchers are beginning to unlock the full therapeutic potential of engineered mRNA molecules.
    DOI:  https://doi.org/10.1021/acs.chemrev.5c00347
  7. Proc Natl Acad Sci U S A. 2026 Mar 31. 123(13): e2523453123
    Mechanism of 30S subunit recognition and modification by the conserved bacterial ribosomal RNA methyltransferase RsmI.
    Mohamed I Barmada, Erin N McGinity, Suparno Nandi, Debayan Dey, Natalia Zelinskaya, George M Harris, Lindsay R Comstock, Christine M Dunham, Graeme L Conn.
      Ribosomal RNA (rRNA) modifications are important for ribosome function and can influence bacterial susceptibility to ribosome-targeting antibiotics. The universally conserved 16S rRNA nucleotide C1402, for example, is the only 2'-O-methylated nucleotide in the bacterial small (30S) ribosomal subunit and this modification fine-tunes the shape and structure of the peptidyl tRNA binding site. The Cm1402 modification is incorporated by the conserved bacterial 16S rRNA methyltransferase RsmI, but it is unclear how RsmI recognizes its 30S substrate and specifically modify its buried target nucleotide. We determined a 2.42 Å resolution cryo-EM structure of the RsmI-30S complex and, with accompanying functional analyses, show that RsmI anchors itself to the 30S subunit through multiple contacts with a conserved 16S rRNA surface previously only seen in the assembled subunit. This positions RsmI to bind a h44 conformation that is substantially reorganized compared to its structure in the mature 30S subunit allowing access to C1402. These analyses also reveal an essential contribution to 30S subunit interaction made by the previously structurally uncharacterized RsmI C-terminal domain, RsmI-induced RNA-RNA interactions with C1402, and an unappreciated dependence on a divalent metal ion for activity that suggests RsmI may be a member of a distinct class of metal- and SAM-dependent RNA O-methyltransferases. This study significantly expands our mechanistic understanding of how intrinsic bacterial methyltransferases like RsmI modify their rRNA targets. Further, recognition of distant ribosome features and reorganization of a critical rRNA functional center point to a potential role in accurate 30S subunit biogenesis.
    Keywords:  30S subunit; methylation; methyltransferase; ribosome; substrate recognition
    DOI:  https://doi.org/10.1073/pnas.2523453123
  8. bioRxiv. 2026 Mar 03. pii: 2026.03.03.709289. [Epub ahead of print]
    RNA G-quadruplexes mediate cooperativity in HNRNPH binding and splicing regulation.
    Kerstin Tretow, Mario Keller, Mikhail Mesitov, Miona Corovic, Mirko Brueggemann, Jonas Busam, Farica Zhuang, Nadine Koertel, Nicolas Melchior, Anke Busch, Simon Braun, Nadja Hellmann, Heike Haenel, Pol Basenius, Susanne Strand, Yoseph Barash, Stefan Legewie, Friederike Schmid, Julian Koenig, Kathi Zarnack.
      Alternative splicing, regulated by RNA-binding proteins (RBPs), enables the generation of diverse transcript isoforms critical for cellular function. However, how RNA secondary structure impacts RBP binding and function remains poorly understood. Here, we unravel how RNA G-quadruplexes (rG4s) facilitate cooperativity in splicing regulation by the RBP heterogeneous nuclear ribonucleoprotein H (HNRNPH). Through high-throughput in vivo and in vitro studies combined with theoretical modeling, we dissect how rG4s mediate cooperative HNRNPH binding to RNA, ultimately modulating the splicing of hundreds of exons. rG4 unfolding by HNRNPH exposes multiple G-rich binding sites, thereby establishing indirect cooperativity, which is further amplified to achieve switch-like splicing regulation. HNRNPH-mediated regulation is evident in breast cancer patients, with tumors showing rG4-disrupting variants and global HNRNPH alterations, driving distinct splicing patterns that distinguish tumor subtypes. Overall, our findings offer valuable insights into the mechanistic role of RNA secondary structures in cooperative RBP binding and splicing regulation and highlight the clinical relevance of HNRNPH-dependent splicing in cancer.
    DOI:  https://doi.org/10.64898/2026.03.03.709289
  9. bioRxiv. 2026 Mar 08. pii: 2026.02.24.707850. [Epub ahead of print]
    Optimized tRNA structure-seq reveals robust tRNA secondary structures in S. cerevisiae under mild stress conditions.
    Komei Yanagihara, Futa Konishi, Teppei Matsuda, Akira Hirata, Hiroyuki Hori, Philip C Bevilacqua, Ryota Yamagami.
      RNA structure plays a crucial role in diverse biological processes beyond the translation of genetic information. Therefore, the development of reliable methods for RNA structure prediction is essential for understanding RNA structure-related functions, however accurate and comprehensive RNA structure prediction remains challenging. Here, we focus on secondary structure prediction of transfer RNA (tRNA) using structure probing coupled with next-generation sequencing (tRNA Structure-seq). In silico prediction of Saccharomyces cerevisiae tRNA secondary structures achieves only 56.9% accuracy on average. Incorporation of dimethyl sulfate (DMS) probing data improve prediction accuracy to 87.4%, which is still not sufficient for practical tRNA structure prediction. To overcome this, we optimized the tRNA Structure-seq analysis pipeline by explicitly incorporating natural tRNA modifications detected in tRNA sequencing data and by refining pseudo-free energy parameters specifically optimized for tRNA structure prediction. Using this optimized pipeline, the average prediction accuracy is remarkably improved to 94%. Furthermore, analysis of multiple structural conformations predicted from DMS probing data indicates that S. cerevisiae tRNAs predominantly adopt the canonical cloverleaf secondary structure under in vivo conditions. Finally, we examined tRNA structures under mild stress conditions, including heat stress, osmotic stress, and antibiotic stress. These perturbations had minimal effects on in vivo tRNA secondary structure, demonstrating that S. cerevisiae tRNAs maintain structural stability under physiologically relevant stress conditions. In summary, our results establish an optimized tRNA Structure-seq analysis that enables highly accurate tRNA secondary structure prediction and reveals the intrinsic robustness of tRNA structures in living cells.
    Keywords:  mutation profiling; prediction of RNA structure; stress; tRNA; tRNA modification; tRNA structure
    DOI:  https://doi.org/10.64898/2026.02.24.707850
  10. bioRxiv. 2026 Mar 16. pii: 2026.03.12.711363. [Epub ahead of print]
    Genes near tRNAs are enriched in translational machinery.
    Caroline West, Lauren Dineen, Abigail Leavitt LaBella.
      Transfer RNAs (tRNAs) are known for delivering amino acids to the growing polypeptide chain during translation. They can also influence gene expression, especially in times of nutrient starvation, through differential tRNA expression and modification. tRNAs have a highly consistent cloverleaf structure, but relatively few known regulatory elements govern this conserved structure despite the 20 different standard isotypes. This study examines gene enrichment patterns near tRNA in 1154 fungal genomes. Genes enriched in proteasome regulation, ion transport, and rRNA were found to be significantly closer to tRNAs than other pathways. These results were consistent across KEGG over-representation analysis (ORA), KEGG Gene Set Enrichment Analysis (GSEA), and Gene Ontology (GO) analysis. Proteasome, ion transport, and RNA are all important aspects of protein production and regulation, suggesting that genes required for the synthesis and quality control of proteins, including tRNAs, are located near each other. Protein regulation is an energetically expensive process, and local co-regulation could increase efficiency and stress impacts on proteins.
    DOI:  https://doi.org/10.64898/2026.03.12.711363
  11. J Phys Chem B. 2026 Mar 26. 130(12): 3259-3281
    Modern RNA Quantification Methods: From RT-qPCR to Advanced Microscopy.
    Tyrese Boddie, Arianna Lacen, Hui-Ting Lee.
      RNA plays a crucial role in gene expression, regulation, protein synthesis, and other cellular functions. The diversity that exists between different RNAs makes information beyond their expression level necessary for understanding more about their complex functions in a cell. Conventional ensemble approaches to RNA quantification have been used extensively to measure the quantity of RNA but lack cellular-level spatial information. This review highlights important contributions that high resolution microscopy has made to RNA quantification and cellular biophysics. Using advanced microscopy for precise localization, real-time tracking, and quantitative measurements of RNA increases our understanding of different disease states, cell- and tissue-specific gene regulation, and cellular architecture.
    DOI:  https://doi.org/10.1021/acs.jpcb.5c07484
  12. Biochemistry. 2026 Mar 27.
    Direct RNA Sequencing Reveals Stress-Dependent and Pathway-Specific rRNA Modification Reprogramming during 50S Biogenesis.
    Luis A Gracia Mazuca, Salvador Rodarte, Isaac S Weislow, Jonathon E Mohl, Eda Koculi.
      Ribosomal RNA (rRNA) modification and processing are essential steps in the ribosome assembly. Using Oxford Nanopore direct RNA sequencing, we simultaneously detect and quantify N2-methyladenosine (m2A), pseudouridine (Ψ), 2'-O-methyluridine, 1-methylguanosine, 7-methylguanosine, dihydrouridine, 3-methylpseudouridine, and 5-methyluridine modification in 23S rRNA of the mature 50S large subunit (LSU) from Escherichia coli cells expressing either wild-type DbpA or the helicase-inactive R331A DbpA variant and in two LSU assembly intermediates, 35S and 45S, which accumulate along distinct maturation pathways in R331A DbpA-expressing cells. Furthermore, we analyze the 3'-end processing of 23S and 5S rRNAs across these particles. Many 23S rRNA modifications are incorporated at similar levels in LSU assembly intermediates and mature 50S subunits from both wild-type and R331A DbpA-expressing cells, indicating that these modifications are incorporated prior to intermediate accumulation and are not preferentially reprogrammed under R331A DbpA-induced assembly stress. A subset of three modifications exhibits altered incorporation patterns. m2A 2507 incorporation is reduced in the 50S LSU from R331A DbpA-expressing cells compared with the cells expressing wild-type DbpA, whereas Ψ 2508 is increased. In addition, Ψ 2608 is reduced in the 50S subunit from R331A DbpA-expressing cells compared with the 35S and 45S intermediates from the same cells and the 50S subunit from wild-type cells. Because the 35S and 45S pathways account for only ∼40% of ribosome assembly in R331A DbpA-expressing cells, these findings demonstrate that Ψ 2608 incorporation is selectively reprogrammed across alternative in vivo assembly routes, revealing an additional regulatory layer in ribosome biogenesis.
    DOI:  https://doi.org/10.1021/acs.biochem.6c00004
  13. Mol Cell. 2026 Mar 23. pii: S1097-2765(26)00138-3. [Epub ahead of print]
    RNF25 confers mRNA damage tolerance by curbing activation of the integrated stress response.
    Shubo Zhao, Chloe S Palma-Chaundler, Carla M Engel, Jacqueline Cordes, Daniel Nixdorf, Michael Y Luo, Selay Kaya, Aldwin Suryo Rahmanto, Diana van den Heuvel, Timur Mackens-Kiani, Pedro Weickert, Simon Lam, Vipul Gupta, Julia Philippou-Massier, Ivan Bagarić, Jonathan Bohlen, Graeme Hewitt, Martijn S Luijsterburg, Roland Beckmann, Petra Beli, Danny D Nedialkova, Christopher J Carnie, Marion Subklewe, Stephen P Jackson, Julian Stingele.
      Excessive RNA damage activates cellular stress responses, triggering cell death. However, pathways that negatively regulate RNA damage responses are largely uncharacterized. Using genetic screens, we find that the ubiquitin ligase RNF25 provides tolerance to RNA damage caused by the nucleoside analogue azacytidine, a chemotherapeutic agent used to treat acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Mechanistically, we show that azacytidine is incorporated into mRNA, where it causes lesions that stall elongating ribosomes, leading to cytotoxic activation of the GCN2-dependent integrated stress response (ISR). Furthermore, we establish that RNF25 prevents ISR hyperactivation by ubiquitylation of ribosomal protein eS31, thereby suppressing cell death upon azacytidine treatment. Our study reveals an mRNA damage tolerance mechanism that determines cellular survival in response to azacytidine, highlighting RNA damage-induced stress response as a potentially critical component of chemosensitivity in AML and MDS.
    Keywords:  GCN1; GCN2; RNA damage; RNF25; acute myeloid leukemia; azacytidine; chemotherapy; integrated stress response; ribosome collisions; ubiquitylation
    DOI:  https://doi.org/10.1016/j.molcel.2026.02.024
  14. Biochem Soc Trans. 2026 Mar 25. pii: BST20250259. [Epub ahead of print]54(3):
    Sensing of double-stranded RNA in human cells: molecular mechanisms and cellular consequences.
    Julia Cieslicka, Karolina Pianka, Karolina Drazkowska, Pawel J Sikorski.
      Double-stranded RNA (dsRNA) is a universal indicator of viral replication and dysregulated RNA metabolism. Detection of dsRNA triggers some of the most powerful innate immune responses in human cells. Although these molecules differ in origin and structure, viral dsRNAs share the defining geometric and electrostatic features of the A-form helix, enabling their sequence-independent recognition by multiple sensor systems. Cytosolic receptors, like retinoic acid-inducible gene I (RIG-I), melanoma differentiation associated gene 5 (MDA5), and protein kinase R (PKR), as well as the oligoadenylate synthase (OAS)/RNase L pathway, convert dsRNA binding into interferon induction, translational arrest, and widespread RNA decay, while endosomal Toll-like receptor 3 (TLR3) and the inflammasome sensor NLR family pyrin domain containing 1 (NLRP1) expand surveillance to internalised or structurally disruptive RNAs. Counterbalancing these pathways, the RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) marks endogenous dsRNA through A-to-I conversion, preventing inadvertent activation of innate immune response and maintaining self versus non-self discrimination. Although all of these sensors recognise the A-form helix, each extracts distinct structural and chemical information from dsRNA and converts it into a specific response: RIG-I detects short duplexes with 5'-triphosphorylated ends; MDA5 assembles cooperatively along long uninterrupted helices; PKR integrates duplex length with translational control; OAS proteins act as strict reporters of helix regularity; and TLR3 as well as NLRP1 respond to dsRNA in compartment- and context-dependent ways. Epitranscriptomic marks and chemical modifications-including 2'-O-methylation, N6-methyladenosine, pseudouridine, and ADAR1-mediated inosine-further refine sensing by modulating helical stability and end structure, establishing a biochemical 'self-code' that shapes RNA immunogenicity. Together, these pathways form an integrated network that distinguishes between viral and endogenous dsRNA and coordinates antiviral defence with immune tolerance.
    Keywords:  RNA modifications; antiviral response; double-stranded RNA; innate immune sensing; self vs non-self discrimination
    DOI:  https://doi.org/10.1042/BST20250259
  15. J Mol Biol. 2026 Mar 24. pii: S0022-2836(26)00138-5. [Epub ahead of print] 169765
    Molecular determinants and therapeutic targeting of stop codon readthrough in eukaryotic translation.
    Wojciech Teodorowicz, Oliver Mühlemann.
      Accurate translation termination is essential for proteome integrity and is primarily governed by the release factors eRF1 and eRF3, which ensure precise recognition of stop codons and efficient release of nascent polypeptides. However, proteome integrity is challenged by mutations that generate premature termination codons (PTCs), leading to truncated, nonfunctional proteins and degradation of the aberrant transcript via nonsense-mediated mRNA decay (NMD). Collectively, these events account for ∼1800 human genetic diseases. Translational readthrough, the process by which near-cognate tRNAs decode stop codons and allow ribosomes to continue elongation beyond the stop codon, represents a possibility to suppress PTCs and restore full-length protein synthesis. Initially discovered in viruses as a mechanism to expand coding capacity, readthrough is now recognized as a regulated feature of eukaryotic gene expression influenced by both cis-acting sequence elements and trans-acting factors. Recent evidence highlights the remarkable context dependence of readthrough, revealing variation across transcripts, tissues, and developmental stages. In this review, we examine the molecular determinants that define stop codon recognition and readthrough efficiency, with particular emphasis on nucleotide context. We further discuss the mechanisms and binding sites of small molecules that promote PTC readthrough, and summarize the clinical development landscape of readthrough-inducing compounds for the treatment of diseases caused by nonsense mutations.
    Keywords:  Premature termination codon (PTC); nonsense-mediated mRNA decay (NMD); translation termination; translational readthrough (TR)
    DOI:  https://doi.org/10.1016/j.jmb.2026.169765
  16. bioRxiv. 2026 Mar 21. pii: 2026.03.20.712421. [Epub ahead of print]
    Hidden Diversity in Yeast tRNAs: Comparative Genomics and Modification Mapping in a Eukaryotic Subphylum.
    Lauren Dineen, David Wilson, Abigail Leavitt LaBella.
      tRNA are adapter molecules with an integral role in translation and further roles in stress adaptation. Processing of tRNA is tightly regulated and includes the enzymatic addition of several post-transcriptional modifications that are required for translation efficiency, recognition, selective translation, and structure. We currently lack a multi-species wide view of tRNA modifying enzymes across eukaryotes. Here, we performed a comparative analysis of tRNA gene sequence, modification enzymes, and modification profiles across the Saccharomycotina subphylum. We employed machine learning methods to explore tRNA sequence conservation and to annotate modifying enzymes known to exist in fungi, humans, and prokaryotes. We then applied Nano-tRNAseq to three species (Saccharomyces cerevisiae, Hanseniaspora uvarum, and Yarrowia lipolytica) to profile modification signatures and compare modification patterns. We identified substantial lineage-specific conservation of tRNA sequences despite the highly conserved tRNA structure. We found significant variation in tRNA modifying enzyme repertoires across Saccharomycotina, including lineage-specific losses, and annotated a prokaryotic-associated enzyme, tilS. Integrating genomic and sequencing data enabled us to link enzyme repertoires with tRNA gene sequences. tRNA sequencing revealed distinct modification signatures across the three focal species, and further analysis using General Linearized modelling suggested tRNA enzyme loss is associated with target tRNA nucleotide absence in gene sequences. This work provides the first integrated view of tRNA gene and modification diversity in eukaryotes and expands the field of tRNA diversity in fungi.
    DOI:  https://doi.org/10.64898/2026.03.20.712421
  17. bioRxiv. 2026 Mar 17. pii: 2026.03.14.711799. [Epub ahead of print]
    eIF4G2-dependent translation restrains pancreatic cancer progression.
    Justin Powers, Wei Lai, Hiroki Kobayashi, Alvaro Curiel-Garcia, Pardis Ahmadi, Elizabeth Valenzuela, Marko Jovanovic, Alejandro Chavez, Iok In Christine Chio.
      Pancreatic ductal adenocarcinoma (PDA) is among the most lethal cancers, driven by cellular plasticity that fuels therapeutic resistance and early dissemination. The contribution of translational control to this plasticity remains poorly understood. Through an in vivo CRISPR/Cas9 screen, we identify the non-canonical initiation factor eIF4G2 (DAP5/NAT1) as a translational checkpoint restraining PDA progression. Loss of eIF4G2 accelerated tumor growth, induced poorly differentiated, basal-like histology, and triggered widespread metastasis. Ribosome profiling revealed that eIF4G2 loss does not alter bulk protein synthesis but instead impairs translation of a selective regulon, including tumor suppressors such as PTEN and CREBBP. Functional studies confirmed that PTEN loss was sufficient to drive dedifferentiation but insufficient to promote metastasis, implicating the broader eIF4G2-dependent program, including translational control of transcriptional regulators like CREBBP, in limiting dissemination. Consistently, eIF4G2-deficient tumors exhibited transcriptomic enrichment of programs related to migration and wound healing. Computational inference from human PDA datasets revealed reduced eIF4G2 activity in metastases, aligning with basal-like features and predicting poorer survival. These results support a model in which eIF4G2 maintains epithelial identity and restrains metastatic potential, highlighting selective translation as a determinant of PDA subtype and clinical outcome.
    DOI:  https://doi.org/10.64898/2026.03.14.711799
  18. Int J Mol Sci. 2026 Mar 12. pii: 2614. [Epub ahead of print]27(6):
    Translational Fidelity Decline in the Aging Oocyte and Embryo Development.
    Charalampos Voros, Fotios Chatzinikolaou, Georgios Papadimas, Ioannis Papapanagiotou, Aristotelis-Marios Koulakmanidis, Diamantis Athanasiou, Kyriakos Bananis, Antonia Athanasiou, Aikaterini Athanasiou, Charalampos Tsimpoukelis, Athanasios Karpouzos, Maria Anastasia Daskalaki, Christina Trakateli, Nana Kojo Koranteng, Marianna Theodora, Nikolaos Thomakos, Panagiotis Antsaklis, Dimitrios Loutradis, Georgios Daskalakis.
      Female reproductive aging is associated with a progressive decline in oocyte competence and reduced success in assisted reproductive technologies. While chromosomal abnormalities, mitochondrial dysfunction, and DNA damage have been extensively studied, these mechanisms do not fully explain developmental arrest in chromosomally euploid embryos or the variability in embryo competence. Human oocytes enter a transcriptionally quiescent state during meiotic maturation and rely almost entirely on the regulated translation of stored maternal messenger RNAs to support fertilization and early embryonic development until zygotic genome activation. In this context, translational fidelity becomes a critical determinant of proteome integrity and cellular function. Age-related alterations affecting ribosomal RNA integrity, transfer RNA modification, aminoacylation accuracy, and translational regulatory networks may impair the precision, timing, and coordination of protein synthesis. These defects can disrupt essential processes such as spindle assembly, cytoskeletal organization, and early cleavage dynamics, ultimately compromising embryo viability despite chromosomal normality. In addition, the follicular microenvironment, including redox balance, metabolic support, and signaling pathways, plays a crucial upstream role in maintaining translational integrity. This review integrates mechanistic evidence from molecular, cellular, and developmental studies to propose that progressive decline in translational fidelity represents a fundamental and previously underrecognized driver of reproductive aging. Understanding translational control as a central regulator of oocyte competence may provide new insights into unexplained IVF failure and support the development of novel biomarkers and therapeutic strategies aimed at preserving reproductive potential.
    Keywords:  assisted reproduction; embryo development; maternal mRNA; oocyte aging; ribosome fidelity; translational control
    DOI:  https://doi.org/10.3390/ijms27062614
  19. PLoS One. 2026 ;21(3): e0345744
    The METTL3 inhibitor STM2457 suppresses gastric cancer progression by modulating m6A RNA modification.
    Hang Sun, Haozhi Xu, Junying Li, Xiaoman Xie, Junmei Zhang, Hongjie Dong, Huanhuan Xie, Qi Wang, Guihua Zhao, Kun Yin, Jingyu Yang, Jianwei Zhou, Ruili Wu, Chao Xu.
      Gastric cancer (GC) is one of the most common and lethal cancers globally. methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine (m6A) RNA methylation plays a crucial role in tumor initiation and progression by regulating RNA function. STM2457, a highly efficient METTL3 inhibitor, can inhibit METTL3 activity and may serve as a potential therapeutic strategy in cancers. However, the role of STM2457 for GC cells is still unknown. In this study, we analyzed the expression profile data of GC in TCGA and GEO databases, and further explored the expression involvement of METTL3 in GC cell line, investigated the therapeutic effect of STM2457 targeted inhibition of METTL3 in GC both in vitro and in vivo experiments. The results indicated that STM2457 could suppress GC cell proliferation and migration by inhibiting METTL3, and also promoted cell apoptosis and arrest the cell cycle in S phase. In addition, STM2457 could inhibit tumor growth in subcutaneous xenotransplantation mouse model. Our findings suggested that STM2457 had great potential for the treatment of GC and could serve as a foundation for future clinical applications.
    DOI:  https://doi.org/10.1371/journal.pone.0345744
  20. bioRxiv. 2026 Mar 18. pii: 2026.03.16.711780. [Epub ahead of print]
    m 6 A RNA methylation modulates Zika virus infection by regulating serine proteases in Aedes albopictus.
    Anderson de Mendonça Amarante, Lucas Tirloni, Jonas Koch, Felix Bormann, Serena Rosignoli, Alessandro Paiardini, Dante Rotili, Tarcisio Brito, Laura de Andrade Tavares, Juan Diego de Paula Li Yasumura, Vitor Coutinho Carneiro, Laura Menendez Kury, Attilio Pane, Frank Lyko, Marcelo Rosado Fantappié.
      Epitranscriptomic RNA modifications, particularly N 6 -methyladenosine (m⁶A), have emerged as important regulators of host-virus interctions. However, the role of m⁶A in arbovirus infection within mosquito vectors remains poorly defined. Here, we characterized the m⁶A RNA methylation machinery in Aedes albopictus C6/36 cells and examined its contribution to Zika virus (ZIKV) replication. Arbovirus infection did not significantly alter the transcriptional levels or enzymatic activity of the core m⁶A methyltransferase components METTL3 and METTL14. In contrast, pharmacological inhibition of METTL3 markedly enhanced ZIKV replication, indicating an antiviral role for m⁶A in mosquito cells. Transcriptome-wide analysis of C6/36 cells treated with the METTL3 inhibitor STM2457 revealed extensive changes in gene expression, including the pronounced upregulation of multiple serine proteases, particularly members of the CLIP family. Single-nucleotide-resolution mapping of m⁶A using GLORI-sequencing showed that m 6 A is absent from Zika virus RNA, but readily detectable in the A. albopictus transcriptome. Data analysis defined key features of the mosquito epitranscriptome and demonstrated that m⁶A modifications are enriched within the coding regions of serine protease transcripts, supporting their direct regulation by m⁶A. Functionally, inhibition of serine protease activity using AEBSF resulted in a significant reduction of ZIKV replication. Together, these findings identify m⁶A RNA methylation as a critical regulator of ZIKV infection in mosquito cells and uncover an epitranscriptomic pathway linking m⁶A-dependent control of serine proteases to vector-virus interactions.
    Author Summary: Mosquito-borne viruses such as Zika virus pose a major threat to global public health. Successful transmission of these viruses depends not only on infection in humans, but also on their ability to replicate efficiently inside mosquito vectors. Chemical modifications of RNA, collectively known as epitranscriptomic marks, have recently emerged as important regulators of gene expression and virus-host interactions. Among these, N 6 -methyladenosine (m 6 A) is the most abundant internal RNA modification in eukaryotic cells. While m 6 A has been extensively studied in mammalian systems, its role in mosquito antiviral responses remains poorly understood. In this study, we investigated how m 6 A RNA methylation influences Zika virus infection in mosquito cells derived from Aedes albopictus . We found that reducing m 6 A levels enhances viral replication, indicating that this RNA modification restricts infection in mosquito cells. Notably, Zika virus RNA itself does not contain detectable m 6 A modifications. Instead, m 6 A regulates the expression of specific mosquito genes, including a group of serine proteases that influence viral replication. Pharmacological inhibition of these proteases significantly impaired virus growth, identifying them as key downstream effectors. Our findings reveal an antiviral role for m 6 A in mosquito cells and uncover a previously unrecognized epitranscriptomic pathway that shapes mosquito-virus interactions. Understanding how RNA modifications regulate arbovirus infection in vectors may open new avenues for strategies aimed at limiting virus transmission.
    DOI:  https://doi.org/10.64898/2026.03.16.711780
  21. bioRxiv. 2026 Mar 21. pii: 2026.03.20.713187. [Epub ahead of print]
    A bifunctional H/ACA snoRNP mediates both pseudouridylation and rRNA scaffolding during ribosome assembly.
    Jutta Hafner, Matthias Thoms, Hussein Hamze, Anna Forstner, Ismaël Alidou-D'Anjou, Hafiza Hebbachi, Marina Kalinina, Annika Hausharter, Sébastien Favre, Simon Lebaron, Sherif Ismail, Timo Denk, Katharina Schlick, Thomas Fröhlich, Priya Bhutada, Erik Farquar, Katharina Schindlmaier, Sara Sormaz, Ed Hurt, Dieter Kressler, Yves Henry, Sarah A Woodson, François Dragon, Roland Beckmann, Anthony K Henras, Brigitte Pertschy.
      The early steps of eukaryotic large ribosomal subunit assembly remain poorly understood due to the structural flexibility of pre-60S intermediates, whose rRNA is extensively modified by small nucleolar RNPs (snoRNPs). Some snoRNPs, however, lack any modification function and instead scaffold ribosome assembly through largely unknown mechanisms. Here, we show that the H/ACA snoRNP snR37 integrates both modifying and scaffolding roles. Biochemical and structural analyses reveal a canonical H/ACA core that pseudouridylates a conserved uridine in the A site of the peptidyl transferase center, the catalytic heart of the 60S subunit. Additional RNA helices recruit non-core proteins, the Upa1-Upa2 heterodimer and Rbp95, which mediate stable snR37 association with pre-60S complexes. These proteins cooperate with the Npa1 rRNA chaperone complex to link four rRNA domains, thereby structurally organizing early pre-60S intermediates and promoting proper formation of the PTC. This dual organization establishes a paradigm for snoRNPs combining rRNA modification and scaffolding functions.
    DOI:  https://doi.org/10.64898/2026.03.20.713187
  22. Adv Sci (Weinh). 2026 Mar 17. e20059
    N4-acetylcytidine in LncRNA Gm26917 Promotes Translation in Female Germline Stem Cells by Recruiting Ribosomal Protein mRNA via EEF1A1.
    Xinyue Li, Xiaopeng Hu, Ji Wu.
      N4-acetylcytidine (ac4C) modification, present in both long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs), regulates cell fate decisions, yet its role in female germline stem cell (FGSC) development remains poorly understood. Here, we demonstrate that ac4C modification depletion (in vitro or in vivo) impairs FGSC maintenance by disrupting the EEF1A1-mediated Gm26917-Rpl10 interaction, leading to attenuated protein synthesis. Reduced ac4C levels suppress FGSC viability and proliferation, dysregulate cell cycle progression, and promote differentiation and apoptosis. Integrated acRIP-seq and RNA in situ conformation sequencing (RIC-seq) analyses demonstrate that diminished ac4C modification in lncRNA Gm26917 compromises its stability and weakens its interaction with Rpl10. Strikingly, the reduction of RPL10 is primarily caused by impaired Gm26917-Rpl10 interaction rather than direct ac4C modification. Gm26917 or Rpl10 knockdown disrupts FGSC fate, while ribosome profiling sequencing (Ribo-seq) reveals that Gm26917 depletion significantly reduces mRNA translation efficiency (TE), a defect rescued by Rpl10 overexpression. Furthermore, EEF1A1 disruption diminishes the Gm26917-Rpl10 interaction and decreases mRNA TE. This work establishes that ac4C modification on lncRNAs governs their spatial interactions with mRNAs, elucidates a novel ac4C-Gm26917-EEF1A1-Rpl10 axis in FGSC maintenance, and provides a potential molecular target for modulating germ cell development and fertility.
    Keywords:  N4‐acetylcytidine; RNA in situ conformation; long noncoding RNAs; sequencing; translation efficiency
    DOI:  https://doi.org/10.1002/advs.202520059
  23. Front Immunol. 2026 ;17 1739011
    METTL3-driven m6A modification of NLRC5 promotes renal fibrosis in chronic kidney disease through Keap1/Nrf2/ARE signaling pathway.
    Mingzhi Xu, Ruman Chen, Xin Zeng, Mingjiao Pan, Chunli Wang, Yonghui Qi, Na An, Yafei Bai.
       Background: METTL3-mediated m6A RNA methylation has been implicated in renal fibrosis, a central pathological feature of chronic kidney disease (CKD). NLRC5, the largest NLR family member, is a direct m6A target of METTL3, but its role in METTL3-driven renal fibrosis remains unclear.
    Methods: An in vitro renal fibrosis model was established using TGF-β1-stimulated human proximal tubular (HK-2) cells. METTL3-mediated m6A modification and stabilization of NLRC5 mRNA were assessed by m6A quantification, RNA stability, MeRIP, and RIP assays. Functional impacts on the Keap1/Nrf2/ARE pathway and fibrotic responses were examined using METTL3 inhibition (STM2457, 10 μM), NLRC5 knockdown or overexpression, Keap1 overexpression, and Nrf2 inhibition (ML385, 5 μM). Fibrotic markers, inflammatory cytokines (IL-1β, TNF-α; ELISA), and oxidative stress (ROS/DCF-DA, SOD, MDA) were measured. NLRC5-overexpression effects on the Keap1/Nrf2/ARE pathway were additionally evaluated. In vivo validation employed a unilateral ureteral obstruction (UUO) mouse model, with kidney injury and fibrosis assessed via H&E, Masson's staining, IHC, ELISA, Western blot, and qRT-PCR.
    Results: TGF-β1 upregulated METTL3, NLRC5, and global m6A levels in HK-2 cells. METTL3 directly bound and stabilized NLRC5 mRNA via m6A modification. METTL3 overexpression exacerbated TGF-β1-induced inflammation, oxidative stress, and fibrosis, which were reversed by STM2457. Conversely, METTL3 or NLRC5 inhibition suppressed fibrosis, coinciding with Keap1 downregulation and Nrf2/HO-1/NQO1 upregulation. Keap1 overexpression negated the anti-fibrotic effects of NLRC5 knockdown, while NLRC5 overexpression decreased nuclear Nrf2 and downstream antioxidant targets, confirming NLRC5's inhibitory role on Keap1/Nrf2 signaling. Nrf2 inhibition (ML385) or NLRC5 overexpression rescued METTL3 knockdown phenotypes. In vivo, METTL3 knockdown attenuated UUO-induced renal injury and fibrosis, activating the Keap1/Nrf2/ARE pathway.
    Conclusions: METTL3 promotes renal fibrosis by stabilizing NLRC5 mRNA via m6A modification, leading to suppression of the protective Keap1/Nrf2/ARE pathway. Targeting the METTL3/NLRC5/Keap1/Nrf2/ARE axis may represent a promising therapeutic strategy for CKD-associated fibrosis.
    Keywords:  Keap1/Nrf2/ARE pathway; M6A RNA methylation; METTL3; NLRC5; renal fibrosis
    DOI:  https://doi.org/10.3389/fimmu.2026.1739011
  24. Int J Mol Sci. 2026 Mar 14. pii: 2662. [Epub ahead of print]27(6):
    The Art of Domesticating Proteins: How Cancer Cells Adapt to Therapeutic and Environmental Stressors.
    Slovénie Pyndiah.
      Cellular survival and adaptability depend on the dynamic regulation of proteins-the central actors of biological systems. Through mechanisms such as post-translational modifications, protein turnover, and the formation of membraneless organelles, cells can sense and respond to a variety of stressors. Recent advances in artificial intelligence and chemical biology have provided powerful tools to study and manipulate these processes, paving the way for novel therapeutic strategies in cancer. This review explores how cells "tame" their proteome in response to stress by coordinating protein synthesis, modification, degradation, and structural organization to maintain functional resilience.
    Keywords:  drug resistance; healthcare; protein turnover; stress adaptation; targeted therapy
    DOI:  https://doi.org/10.3390/ijms27062662
  25. Genetics. 2026 Mar 25. pii: iyag083. [Epub ahead of print]
    Sexually dimorphic ATF4 expression in the fat confers female stress tolerance in Drosophila melanogaster.
    Lydia Grmai, Melissa Mychalczuk, Aditya Arkalgud, Deepika Vasudevan.
      Metabolic differences between males and females have been well documented across many species. However, the molecular basis of these differences and how they impact tolerance to nutrient deprivation is still under investigation. In this work, we use Drosophila melanogaster to demonstrate that sex-specific differences in fat tissue metabolism are driven, in part, by dimorphic expression of the Integrated Stress Response (ISR) transcription factor, ATF4. We found that female fat tissues have higher ATF4 activity than their male counterparts under homeostatic conditions. This dimorphism was partly due to a female bias in transcript abundance of specific ATF4 splice isoforms. We found that the canonical sex determinants transformer (tra) and doublesex (dsx) drive such dimorphic ATF4 transcript abundance. These differences persist in a genetic model of methionine deprivation stress, where female animals showed greater resistance to lethality than males in an ATF4-dependent manner. These results suggest that higher ATF4 activity confers higher tolerance to stress in females. Together, our data describe a previously unknown facet of ISR signaling wherein sexual identity of adipose tissue confers differential stress tolerance in males and females. Since energy storage mechanisms are known to be dimorphic and have been linked to ATF4 regulation, our studies provide a mechanistic starting point for understanding how sexual identity influences metabolic disease outcomes.
    Keywords:  ATF4; adipose; dimorphism; doublesex; methioninase; splicing; stress; transformer
    DOI:  https://doi.org/10.1093/genetics/iyag083
  26. Biophys Chem. 2026 Mar 14. pii: S0301-4622(26)00048-7. [Epub ahead of print]334 107615
    NMR investigation of the sliding motion of RNA helicase DDX3X along single-stranded RNA.
    Yuki Toyama, Masanori Kumihara, Koh Takeuchi, Ichio Shimada.
      The complex interplay between the structural formation of nucleic acids and the helicase proteins that unwind them underlies a variety of essential biological processes. Among these helicases, DDX3X is one of the most well-recognized RNA helicases, involved in diverse physiological functions such as translational regulation of gene expression. Although many structural and biochemical studies have investigated how DDX3X unwinds stable double-stranded RNA (dsRNA) into single-stranded RNA (ssRNA), the exact mechanism remains under debate. A key question is whether DDX3X processively unwinds dsRNA by translocating or sliding along ssRNA, or instead locally destabilizes dsRNA by directly binding to exposed ssRNA stretches. To gain deeper insight into the molecular mechanism of DDX3X, we used solution NMR to monitor its sliding motion on ssRNA composed of poly-C and poly-A segments. We then examined how rapidly DDX3X slides along ssRNA, a prerequisite for the processive unwinding mechanism. Our two-dimensional line-shape analyses and ZZ-exchange experiments demonstrate that DDX3X does not slide rapidly along ssRNA, with a maximum sliding rate estimated to be 10 s-1 or slower. These findings support a model in which DDX3X unwinds dsRNA via local strand separation driven by preferential binding to ssRNA stretches, thereby providing molecular insight into its function as a non-processive helicase.
    Keywords:  DDX3X; NMR line-shape analysis; RNA helicase; Sliding motion; Solution NMR; ZZ-exchange experiment
    DOI:  https://doi.org/10.1016/j.bpc.2026.107615
  27. Nucleic Acids Res. 2026 Mar 19. pii: gkag251. [Epub ahead of print]54(6):
    m5C RNA methylation is dysregulated by oncogenic herpesviruses via c-Myc signaling to counteract host antiviral factors.
    Zhenyu Wu, Yan Liu, Dawei Zhou, Zhixian He, Guillaume N Fiches, Youngmin Park, Alan Zhu, Jinshan He, Jianwen Chen, Kateepe A S N Shanaka, Thurbu T Lepcha, Prashant Desai, Jian Zhu, Netty G Santoso.
      Herpesviruses are a group of double-stranded DNA viruses known to develop versatile viral strategies to escape host immune surveillance for promoting their replication and propagation. This is illustrated by Kaposi's sarcoma-associated herpesvirus (KSHV), an oncogenic gamma-herpesvirus that overcomes host immune suppression by multiple mechanisms. In this study, we reported that KSHV dysregulates 5-methylcytosine (m5C) modification and messenger RNA (mRNA) stability of host antiviral factors to benefit its lytic replication. KSHV lytic reactivation or de novo challenge led to downregulation of m5C RNA methyltransferases, NSUN2 and NSUN1 (NSUN2/1), while NSUN2/1 depletion promoted KSHV lytic replication. Such KSHV-mediated downregulation of NSUN2/1 is via suppression of the transcriptional factor c-Myc. We further performed the RNA bisulfite sequencing (RNA-BS-seq) to identify KSHV-dependent m5C modification of host mRNAs. KSHV lytic reactivation led to the significant reduction of m5C methylation and mRNA stability of TRIM25, a key activator of the RIG-I pathway, while TRIM25 depletion indeed promoted KSHV lytic replication. These host-virus interaction events were also observed in the infection of another oncogenic gamma-herpesvirus Epstein-Barr virus (EBV). Overall, our results highlighted a new strategy for human gamma-herpesviruses to counteract host antiviral factors and promote their lytic replication by manipulating host m5C RNA methylation.
    DOI:  https://doi.org/10.1093/nar/gkag251
  28. Annu Rev Biochem. 2026 Mar 24.
    Cellular Repair and Removal of Protein-Damage Modifications.
    Abigail K D Porter, Christina M Woo.
      Protein aging, stress, or metabolism can lead to the accumulation of numerous nonenzymatic chemical alterations that can threaten protein stability and function, particularly in long-lived proteins. Eukaryotic cells recognize these protein-damage events through repair and removal pathways, whose loss can lead to adverse effects and contribute to age-related disease pathogenesis. Here, we review recent advances in understanding the formation, repair, and removal mechanisms of posttranslational modifications arising from protein damage, including dehydroamino acids, early-stage glycation, isoaspartate, C-terminal cyclic imides, and C-terminal amides. We emphasize the emerging role of E3 ubiquitin ligases in facilitating the degradation of proteins bearing these modifications, highlight the approaches used to make these discoveries, and discuss the potential functions of these modifications beyond protein damage. Mounting evidence that protein-damage events influence cellular signaling and metabolism suggests the existence of vast undiscovered regulatory networks, creating opportunities to uncover tissue-specific repair mechanisms and their roles in development, aging, and stress responses across diverse biological contexts.
    DOI:  https://doi.org/10.1146/annurev-biochem-051024-045733
  29. RNA Biol. 2026 Mar 24.
    AI foundation models for RNA biology.
    Haopeng Yu, Yiliang Ding.
      RNA biology is undergoing a transformative revolution driven by AI foundation models. These models learn the intricate relationships between RNA sequence, structure, and function by training on vast, diverse datasets spanning millions of RNA molecules across various species. Through self-supervised learning on these sequences, these models acquire a generalizable understanding of RNA, which can then be fine-tuned for various downstream tasks, thereby enabling the decoding of functional rules embedded in RNA sequences. In this review, we provide a comprehensive guide to RNA foundation models. Using concrete examples of RNA biology, we begin with the concept of foundation models and review the importance of pre-training datasets, architectural innovations, self-supervised strategies, and fine-tuning approaches that allow general RNA representations to be translated into task-specific models. Crucially, we highlight how explainable AI (XAI) methods transform these models from black-box predictors into valuable discovery tools that reveal candidate cis-regulatory elements and structural motifs. As RNA foundation models keep advancing and integrating more multimodal biological data, they aim to uncover additional regulatory rules and functions encoded in RNA.
    Keywords:  Fine-tuning; Foundation model; Pre-training; RNA biology; RNA sequence-structure-function; explainable AI (XAI)
    DOI:  https://doi.org/10.1080/15476286.2026.2650517
  30. bioRxiv. 2026 Mar 17. pii: 2026.03.16.712107. [Epub ahead of print]
    Salmonella Typhi asparaginase-dependent activation of GCN2 promotes bacterial killing in murine macrophages.
    Zachary Powers, Michael McFadden, Gi Young Lee, Tracey L Schultz, Luiza Castro Jorge, Daniel Edwards, Simon Sanchez-Paiva, Jonathan Sexton, Katherine R Spindler, Jeongmin Song, Mary X O'Riordan.
      Many intracellular pathogens stimulate host cell stress by directly or indirectly causing an imbalance in host nutrients; depletion of amino acid pools in particular can act as a danger signal to infected cells. Using a restrictive host model of Salmonella enterica serovar Typhi (S. Typhi) infection, we identify early induction the integrated stress response (ISR) by viable bacteria, but not heat-killed bacteria. Genetic deletion of the amino acid sensing ISR kinase GCN2 (also known as EIF2AK4) prevented early ISR activation during S. Typhi infection, and murine macrophages lacking GCN2 show impaired bacterial clearance and decreased cytokine output. Supplementation of wildtype C57BL/6 murine macrophages with only the non-essential amino acid asparagine was sufficient to suppress S. Typhi-induced ISR activation and deletion of S. Typhi ansB, encoding an asparaginase, prevented ISR activation during infection. Pharmacological inhibition of mammalian target of rapamycin (mTOR), the other major amino acid sensing pathway in eukaryotic cells, prevented GCN2 activation and ISR induction in murine macrophages, indicating an upstream role for mTOR in signaling to GCN2. These findings suggest a role for the ISR in macrophage innate immune responses to S. Typhi infection and highlight a potential difference in nutrient-dependent signaling between the S. Typhi-susceptible human host and the restrictive murine host centered around asparagine, mTOR, and GCN2.
    DOI:  https://doi.org/10.64898/2026.03.16.712107
  31. Ann Med. 2026 Dec;58(1): 2645735
    Alternative splicing in voltage-gated sodium channels: mechanisms, regulatory networks and therapeutic implications.
    Jiaying Qiu, Pei Wu, Yalin Zhang, Yiqing Li, Chunli Xia, Siwan Peng, Junjie Sun.
       BACKGROUND: Voltage-gated sodium channels (VGSCs) are fundamental to electrical signalling in excitable cells, and their dysfunction underlies a wide range of channelopathies. While the existence of nine distinct α-subunit genes contributes to VGSC diversity, alternative splicing serves as a significant post-transcriptional mechanism that profoundly expands their proteomic and functional repertoire. Dysregulation of this splicing process is increasingly linked to disease pathogenesis.
    INTRODUCTION: This review aims to provide a comprehensive synthesis of the alternative splicing landscape across all nine VGSC α-subunits. It systematically catalogs known splicing variants, details their roles in developmental regulation, tissue-specific expression and fine-tuning of channel biophysics, and examines the regulatory networks controlling these events.
    DISCUSSION: We detail conserved splicing switches (e.g. the 5N/5A exon in neuronal channels) and isoform-specific events across the VGSC family (Nav1.1 to Nav1.9), evaluating their functional and clinical impacts. The regulation of these events by key RNA-binding proteins (RBPs), such as Rbfox and Nova2, within cell-type-specific networks is emphasized. Furthermore, we discuss how splicing dysregulation contributes to channelopathies and evaluate the promising potential of novel therapeutic strategies, particularly antisense oligonucleotides (ASOs), to correct pathogenic splicing defects.
    CONCLUSIONS: By integrating mechanistic insights with clinical implications, this review establishes alternative splicing as a central theme in VGSC biology and pathophysiology. It highlights the critical need for, and the emerging path towards, precision medicine approaches that target splicing defects for the treatment of VGSC-associated disorders, providing a foundational resource to guide future research and therapeutic development.
    Keywords:  RNA-binding proteins; VGSCs; alternative splicing; precision medicine; spliceopathy
    DOI:  https://doi.org/10.1080/07853890.2026.2645735
  32. bioRxiv. 2026 Mar 04. pii: 2026.03.04.709625. [Epub ahead of print]
    Stress-Encoded Mitochondrial Plasticity: ATF4 Control of Mega-Mitochondria and Nanotunnel Communication.
    Amber Crabtree, Suraj Thapliyal, Mohd Mabood Khan, Edgar Garza Lopez, Andrea Marshall, Calixto Pablo Hernandez Perez, Oleg Kovtun, Jenny C Schafer, Dea Pulatani, Yuho Kim, Sepiso K Masenga, Annet Kirabo, Jeremiah Afolabi, Melanie McReynolds, Renata O Pereira, Prasanna Venkhatesh, Prasanna Katti, Brian Glancy, Antentor Hinton.
      Mitochondrial structural plasticity is a critical adaptive response to cellular stress, yet the transcriptional networks governing the formation of specialized mitochondrial architectures remain poorly defined. Here, we identified and demonstrated that activating transcription factor 4 (ATF4), the master regulator of the integrated stress response, directly regulates mitochondrial morphological remodeling through a novel ATF4-NRF1/Nrf2-MFN2 signaling axis. Using serial block-face scanning electron microscopy and three-dimensional reconstruction in Drosophila flight muscle, primary myotubes, and human skeletal muscle, we show that overexpression of ATF4 promotes significant mitochondrial elongation, increased cristae concentration, enhanced mitochondrial-endoplasmic reticulum contact site (MERC) formation, and the initiation of Mitochondrial Nanotunnels. In contrast, loss of ATF4 results in mitochondrial fragmentation and impaired aerobic capacity. Chromatin immunoprecipitation sequencing reveals direct ATF4 binding at the promoters of the genes encoding NRF1 and Nrf2, which in turn regulate MFN2 expression. Small-molecule inhibition studies further establish that activation of this hierarchical pathway is both necessary and sufficient for stress-induced mitochondrial structural adaptation. Together, these findings position ATF4 as a master regulator of mitochondrial architectural plasticity, providing a direct mechanistic link between cellular stress signaling and organelle remodeling.
    DOI:  https://doi.org/10.64898/2026.03.04.709625
  33. Cell Death Dis. 2026 Mar 24.
    Reduced YTHDF2 inhibits PD-L1 expression by stabilizing m6A-containing SPOP mRNA in colorectal cancer.
    Xian Xu, Hao Chen, Rongjie Zhao, Jiansheng Xie, Hao Liu, Binbin Xie, Jun Lou, Haidong Wang, Xinkai Wu, Weidong Han, Hongming Pan, Jiaying Shen.
      Colorectal cancer (CRC) is one of the most frequently diagnosed malignant tumors. However, clear evidence explaining the regulatory mechanisms of programmed death ligand 1 (PD-L1) in CRC has been limited. To illustrate the function of YTH N6-methyladenosine (m6A) RNA binding protein F2 (YTHDF2), we conducted a comprehensive evaluation of expression profiling datasets from online databases and clinical samples. We used a subcutaneous immunodeficient mouse model to investigate the impact of YTHDF2 on CRC. Western blots, flow cytometry, PD-1/PD-L1 binding assay, and cell killing assay were used to assess the relationship between YTHDF2 and PD-L1. We used RNA sequencing, along with methylated RNA immunoprecipitation (MeRIP) and RNA binding protein immunoprecipitation (RIP) sequencing to analyze mRNA expression, m6A methylation levels, and YTHDF2 target transcripts. The m6A methylation locations of mRNAs were verified using sequence-based RNA adenosine methylation site predictor (SRAMP), MeRIP-qRT-PCR, RIP-qRT-PCR, and a dual-luciferase reporter system. YTHDF2 was upregulated in CRC tissues, and patients with higher YTHDF2 expression had a worse prognosis. The in vivo model showed that YTHDF2 promoted CRC growth, whereas in vitro experiments showed that inhibiting YTHDF2 expression did not affect cell proliferation, migration, or invasion. Mechanistically, interference with YTHDF2 reduced PD-L1 expression and the binding ability between PD-1 and PD-L1. The use of RNA-seq, MeRIP-seq, RIP-seq, and bioinformatics tools confirmed that the speckle type BTB/POZ protein (SPOP) mRNA was a YTHDF2 target and validated its m6A methylation sites. After YTHDF2 knockdown, SPOP mRNA stability increased, causing an increase in SPOP expression and a decrease in PD-L1 expression. This study demonstrated that YTHDF2 might upregulate PD-L1 expression by destabilizing m6A-containing SPOP mRNA and promote CRC development. The biological effect of the YTHDF2-SPOP-PD-L1 axis presented a promising target for CRC treatment and provided an approach to enhance the efficacy of anti-PD-1/PD-L1 therapy.
    DOI:  https://doi.org/10.1038/s41419-026-08615-2
  34. Cell Biosci. 2026 Mar 23.
    Regulation of oncogenic C-terminal truncated p53β protein isoform expression by SRSF3-UPF1 splicing and surveillance axis.
    Jiwon Jeong, Dawon Hong, Tae Young Park, Jung Hur, Taeyoung Koo, Sunjoo Jeong.
      Dysregulated expression of tumor suppressor genes can impair their functions, even promoting oncogenesis. Expression of p53β mRNA can be regulated by alternative splicing and RNA surveillance, otherwise translated to a C-terminal truncated p53 protein with a unique neoepitope. Here, we identified that p53 introns bear the binding sites for serine and arginine-rich splicing factor 3 (SRSF3). SRSF3 binding to p53 intron 9 facilitates upstream frameshift 1 (UPF1) recruitment and regulates production of p53β mRNA. We also demonstrated that this ternary ribonucleoprotein complex forms cotranscriptionally in chromatin. SRSF3 depletion disrupts SRSF3-UPF1 axis, elevating the levels of p53β mRNA encoding a C-terminal-truncated isoform. Intriguitly, p53β protein isoform lacks tumor-suppressive activity and promotes oncogenic epithelial-mesenchymal transition through enhanced cell migration and invasion. We define the coordinated roles of the splicing factor SRSF3 and the RNA surveillance factor UPF1 in regulating p53 mRNA isoform expression, thereby linking splicing fidelity with RNA surveillance during transcription. Our findings highlight the SRSF3-UPF1 axis for preventing oncogenic p53β protein isoform accumulation, offering a potential therapeutic target to restore p53 function and impede cancer progression.
    Keywords:  Alternative splicing; Cancer; Intron retention; SRSF3; p53 mRNA isoforms
    DOI:  https://doi.org/10.1186/s13578-026-01556-5
  35. EMBO J. 2026 Mar 25.
    The coordinated action of UFMylation and the RQC pathways clears arrested polypeptides at the ER.
    Milica Mihailovic, Aleksandra S Anisimova, Bu Erte, Ni Zhan, Ioanna Styliara, Yasin Dagdas, Gülsün Elif Karagöz.
      Clearance of arrested nascent polypeptides resulting from ribosomal stalling is essential for proteostasis. Stalled endoplasmic reticulum (ER)-bound ribosomes are marked by ubiquitin-fold modifier 1 (UFM1) on the large ribosomal subunit protein RPL26, but the precise role of this modification in ribosome-associated quality control (RQC) remains poorly understood. Here, we define the interplay between the UFMylation machinery and the RQC in clearing arrested polypeptides upon ribosome stalling at the ER. Proteomic analysis shows that RQC factors associate with UFMylated ribosomes. Functional assays demonstrate that ribosome rescue factors ZNF598 and ASC-1 recognize and split stalled ribosomes at the ER, a prerequisite for RPL26 UFMylation. The UFM1 E3 ligase complex then binds and UFMylates the post-split 60S-peptidyl-tRNA complex, facilitating access of RQC factors. Depletion of the NEMF/LTN1 complex leads to accumulation of UFMylated ribosomes, whereas impaired UFMylation weakens NEMF/LTN1 binding to ER-stalled ribosomes, supporting a physical link between these pathways. These findings demonstrate that RQC cooperates with the UFMylation machinery to overcome the topological constraints of clearing the arrested polypeptides at the ER.
    Keywords:  Endoplasmic Reticulum; Ribosome Stalling; Ribosome-associated Quality Control; Translation; UFMylation
    DOI:  https://doi.org/10.1038/s44318-026-00753-9
  36. STAR Protoc. 2026 Mar 20. pii: S2666-1667(26)00100-0. [Epub ahead of print]7(2): 104447
    Protocol for quantifying silent ribosome induction in yeast and mammalian cells using polysome profiling.
    Sayanur Rahaman, Samuel Mondal, Nicole Schiffelholz, Attila Becskei.
      Translationally silent ribosomes lack bound mRNA and are difficult to quantify. Here, we present a protocol to measure silent ribosome induction under diverse conditions in yeast and mammalian cells. We describe steps to isolate polysome-profiling fractions, analyze ribosome-associated RNA by RNA sequencing with identification and removal of anomalously amplified rRNAs, and validate measurements by qPCR. For complete details on the use and execution of this protocol, please refer to Rahaman et al.1.
    Keywords:  Genomics; Molecular Biology; RNA-seq
    DOI:  https://doi.org/10.1016/j.xpro.2026.104447
  37. Cancer Discov. 2026 Mar 27. OF1
    Stress Responses Tied to Metastasis and Immune Evasion.
      Two studies show that cancer cells co-opt the integrated stress response, via the transcription factor ATF4, to drive both metastasis and immune evasion. Targeting this pathway or its downstream effectors, such as glutamine metabolism and the secreted protein LCN2, may offer a way to limit tumor spread and restore antitumor immunity.
    DOI:  https://doi.org/10.1158/2159-8290.CD-NW2026-0029
  38. Plants (Basel). 2026 Mar 19. pii: 940. [Epub ahead of print]15(6):
    Regulation of Pre-rRNA Processing in Plant: Mechanisms, Plasticity, and Developmental Implications.
    Nier Chen, Shiyi Huang, Beixin Mo, Wei Xiong.
      Ribosome biogenesis is a fundamental process underlying plant growth, development, and environmental adaptation, and processing of precursor rRNA (pre-rRNA) represents one of its most critical regulatory steps. This review provides a systematic overview of the multi-layered regulatory mechanisms controlling pre-rRNA processing in plants, with Arabidopsis thaliana as the primary model system. We focus on the genomic organization of ribosomal DNA (rDNA) and its epigenetic regulation, illustrating how highly repetitive and sequence-diverse rDNA arrays maintain genomic stability while enabling tissue-specific expression of distinct rDNA variants. We further summarize the dynamic pathways of pre-rRNA processing and their plastic regulation under environmental conditions such as elevated temperature. In addition, we review the quality control systems that monitor pre-rRNA maturation, including non-templated tailing and exonuclease-dependent degradation pathways, which play essential roles in removing aberrant processing intermediates. We further examine how perturbations in pre-rRNA processing give rise to plant ribosomopathies and discuss complementary models of ribosome homeostasis and ribosome heterogeneity as frameworks for interpreting shared developmental phenotypes. Finally, by synthesizing genetic and molecular evidence, we highlight the pivotal role of pre-rRNA processing in orchestrating plant development and propose directions for future research.
    Keywords:  plant development; pre-rRNA processing; quality control; ribosomal DNA
    DOI:  https://doi.org/10.3390/plants15060940
  39. Methods Enzymol. 2026 ;pii: S0076-6879(26)00007-8. [Epub ahead of print]728 211-234
    Preparation of K-Ras4B containing synthetic modifications via expressed protein ligation.
    Jiayue Hu, Yong-Xiang Chen, Mark D Distefano.
      Prenylation is a lipid post-translational modification (PTM) on proteins that plays a critical role in regulating the interaction of proteins with the membrane. Approximately 2 % of proteins in cells are prenylated. Dysregulation of prenylation has been implicated in several diseases where it affects protein localization and function of these proteins in the cell. Ras proteins are members of a broad family of small GTPases that are prenylated and therefore able to localize to the cell membrane and turn on downstream signaling. Because of these roles, inhibiting the prenylation of oncogenic Ras proteins may serve as a method to control Ras mutation-related cancers. To understand the mechanism of Ras protein prenylation and subsequent interactions, chemically modified forms of Ras can be particularly useful. In this chapter, a platform to prepare modified Ras proteins using expressed protein ligation is described. The workflow involves the expression and purification of a truncated Ras thioester protein, the synthesis of a hypervariable region peptide, and the subsequent ligation of these two fragments to obtain the full-length protein.
    Keywords:  Expressed Protein Ligation; Farnesylation; K-Ras4B protein Post-translation modification; Prenylation
    DOI:  https://doi.org/10.1016/bs.mie.2026.01.007
  40. Angew Chem Int Ed Engl. 2026 Mar 17. e22077
    Phototriggered Morphological and Compositional Change of UGGAA Repeat RNA Foci by Photoswitchable RNA-Binding Ligand.
    Yusuke Fujiwara, Tomonori Shibata, Chikara Dohno.
      The expansion of specific repeat sequences causes dozens of heritable neuromuscular diseases, where expanded repeat RNAs play key roles in the pathogenic mechanism. Although the formation of RNA foci has been identified as a common hallmark of repeat diseases, their properties, dynamics, and mechanisms underlying toxicity remain elusive. Here, we demonstrate a novel strategy for the optical control of UGGAA repeat RNA foci, a pathological hallmark of spinocerebellar ataxia type 31 (SCA31), based on the modulation of RNA-RNA interactions by a photoswitchable RNA-binding ligand, NCTA. In the presence of NCTA, UV irradiation induced the growth of UGGAA repeat RNA foci in cells. Subsequent visible light irradiation dissolved the structure into the original smaller RNA foci. Reversible photoisomerization between E- and Z-NCTA is responsible for the photocontrol of RNA foci, where Z-NCTA stabilizes the association between UGGAAs. These changes were accompanied by alterations in the composition of RNA-binding proteins within the RNA foci, suggesting that NCTA modulates their properties and functions by remodeling RNA foci. Our photocontrol system will be useful for investigating, manipulating and regulating dynamic structures containing RNA scaffolds, including disease-related repeat RNA foci and membraneless ribonucleoprotein organelles.
    Keywords:  LLPS; RNA foci; RNA‐binding ligand; photoswitch; repeat
    DOI:  https://doi.org/10.1002/anie.202522077
  41. eNeuro. 2026 Mar;pii: ENEURO.0337-25.2026. [Epub ahead of print]13(3):
    Replating Induces mTOR-Dependent Rescue of Protein Synthesis in Charcot-Marie-Tooth Diseased Neurons.
    Julianna Koenig, Alexys McGuire, Yara Homedan, Jessica Alberhasky, Daniel W Summers.
      Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy characterized by sensory dysfunction and muscle weakness, manifesting in the most distal limbs first and progressing more proximal. Over a hundred genes are currently linked to CMT with enrichment for activities in myelination, axon transport, and protein synthesis. Mutations in tRNA synthetases cause dominantly inherited forms of CMT, and animal models with CMT-linked mutations in these enzymes display defects in neuronal protein synthesis. Rescuing protein synthesis in CMT-mutant neurons could offer exciting therapeutic options beyond symptom management. To address this need, we expressed CMT-linked variants of tyrosyl-tRNA synthetase (YARS-CMT) in primary mouse sensory neurons derived from both male and female embryos and evaluated impacts on protein synthesis and cell viability. YARS-CMT expression reduced protein synthesis in these neurons prior to the onset of caspase-dependent axon degeneration and cell death. To determine how YARS-CMT expression affects axon outgrowth, we dissociated and replated these neurons to stimulate axon regeneration. To our surprise, axonal regrowth occurred normally in replated YARS-CMT neurons. Moreover, replating YARS-CMT neurons rescued protein synthesis. Inhibiting mammalian target of rapamycin suppressed rescue of protein synthesis after replating, consistent with its significant role in protein synthesis during axon regeneration. These discoveries identify new avenues for augmenting protein synthesis in diseased neurons and restoring protein synthesis in CMT or other neurological disorders.
    Keywords:  Charcot–Marie–Tooth disease; axon degeneration; axon regeneration; neurodegeneration; protein synthesis; tRNA synthetase
    DOI:  https://doi.org/10.1523/ENEURO.0337-25.2026
  42. Antioxidants (Basel). 2026 Mar 05. pii: 324. [Epub ahead of print]15(3):
    Protein Arginine Methyltransferases in γ-Globin Regulation and Sickle Cell Disease: Emerging Connections to Oxidative Stress.
    Waseem Chauhan, Rahima Zennadi.
      Reactive oxygen species (ROS) are unavoidable byproducts of cellular metabolism and are normally controlled by tightly regulated antioxidant systems. Red blood cells (RBCs) are particularly susceptible to oxidative stress due to their high oxygen exposure and iron content. In sickle cell disease (SCD), this vulnerability is exacerbated, as sickled RBCs generate chronically elevated ROS that contribute directly to disease pathophysiology. This review examines emerging evidence linking oxidative stress responses to regulation of fetal hemoglobin (HbF) expression through protein arginine methyltransferases (PRMTs). PRMTs catalyze arginine methylation of histone and non-histone substrates, thereby shaping chromatin structure, transcriptional programs, and translational control. We highlight recent findings demonstrating that specific PRMTs regulate γ-globin expression through distinct mechanisms, including transcriptional repression at the β-globin locus and post-transcriptional control of γ-globin mRNA translation. We propose that oxidative stress signaling may modulate PRMT activity, creating a mechanistic link between cellular stress responses and HbF induction. Because HbF inhibits pathological hemoglobin S polymerization, PRMT-dependent pathways represent an attractive therapeutic axis for SCD and related β-hemoglobinopathies. By integrating oxidative stress biology with PRMT-mediated epigenetic and translational regulation, this review outlines a unifying framework for HbF control, identifies critical knowledge gaps, and highlights future directions for the development of targeted epigenetic therapies.
    Keywords:  gamma-globin; oxidative stress; protein arginine methyltransferases; reactive oxygen species; red blood cell; sickle cell disease
    DOI:  https://doi.org/10.3390/antiox15030324
  43. Commun Biol. 2026 Mar 26.
    What does it take to learn the rules of RNA base pairing? A lot less than you may think.
    Jayanth S Pratap, Ryan K Krueger, Elena Rivas.
      Amidst the fast-developing trend of RNA large language models with millions of parameters, we asked what would be minimally required to rediscover the rules of RNA canonical base pairing that define secondary structure, namely the Watson-Crick-Franklin A:U, G:C and the wobble G:U base pairs. Here, we conclude that it does not require much at all. It does not require knowing secondary structures, it does not require aligning the sequences, and it does not require many parameters. We selected a probabilistic model (a stochastic context-free grammar or SCFG) with a total of just 21 parameters, that can describe arbitrary pairwise interactions including but not restricted to those of RNA base pairing. Using standard deep learning techniques, we estimate its parameters by implementing the generative process in an automatic differentiation (autodiff) framework and applying stochastic gradient descent (SGD). We define and minimize a loss function that does not use any structural or alignment information. Trained on as few as fifty RNA sequences, the specific rules of RNA base pairing emerge after only a few iterations of SGD. Crucially, the sole inputs are RNA sequences. When optimizing for sequences corresponding to structured RNAs, SGD also yields the rules of RNA base-pair aggregation into helices. In sharp contrast, when trained on shuffled sequences, the system optimizes by avoiding base pairing altogether. Trained on messenger RNAs, it reveals interactions that are different from those of structural RNAs, and specific to each mRNA. We demonstrate that our approach generalizes across diverse RNA families by testing on 1094 sequences from 22 structurally distinct RNA families. Our results show that the emergence of canonical RNA base-pairing can be attributed to sequence-level signals that are robust and detectable even without labeled structures or alignments, and with very few parameters. Autodiff algorithms for probabilistic models, such as, but not restricted to SCFGs, have significant potential as they allow these models to be incorporated into end-to-end RNA deep learning methods for discerning transcripts of different functionalities.
    DOI:  https://doi.org/10.1038/s42003-026-09921-3
  44. New Phytol. 2026 Mar 23.
    Epitranscriptomic modulations optimize crop traits via messenger RNA modifications.
    Yicheng Ren, Dong Li, Brian D Gregory, Fei Li, Fredy Agil Raynaldo, Quan Ma, Zisheng Luo.
      Rising global demand for food quantity and quality requires precision strategies on fine-tuning trait-related gene expression targeting crop improvement. Dynamic covalent modifications on mRNA add a reversible layer of post-transcriptional regulation on gene expression, yet their trait-level logic in crops remains fragmented. Recent studies connect epitranscriptomic enzymes and readers to yield components, quality traits and stress resilience. Here, we summarize regulatory mechanisms of covalent modifications emerging from 13 functionally validated crop cases across cereals, fiber and horticultural species, focusing on how m6A, m5C, m1A, ac4C, and Ψ reprogramme mRNA molecular functions, such as stability, translation, and RNA compartmentalization. We further discuss the sufficiency and insufficiency of applying current Arabidopsis-based mechanisms to crop improvements, where whole-genome duplication and paralog specialization diversify writer-eraser-reader repertoires and enable species-specific control circuits. Finally, we highlight future directions to transform descriptive maps into predictive breeding tools, emphasizing the need for quantitative, base-resolution profiling with stoichiometric accuracy and the development of programmable, site-specific perturbation systems that can test causal relationships in defined tissues and developmental stages. These advances position epitranscriptomic reprogramming as a complementary route to precision engineering of crop yield and quality.
    Keywords:  crop breeding; epitranscriptomic regulation; epitranscriptomic reprogramming; mRNA modification; molecular traits; stress responses
    DOI:  https://doi.org/10.1111/nph.71117
  45. Neuroreport. 2026 Mar 18. 37(5): 195-203
    METTL3-mediated TIGAR m6A modification and its role in microglia activation related to Alzheimer's disease.
    Jing Kang, Xin Du, Xiaoting Zhang, Yadong Li, Chunying Wang, Shiming Sun.
       OBJECTIVE: This study focused on clarifying whether methyltransferase3 (METTL3) participates in the polarization and activation of microglia in Alzheimer's disease (AD) by mediating the N6-methyladenosine (m6A) modification level of TP53-induced glycolysis and apoptosis regulator (TIGAR).
    METHODS: Human microglia HMC3 cells were transfected with overexpression or knockdown lentivirus of METTL3, TIGAR, or TIGAR before being induced by Aβ treatment to establish an in-vitro AD cell model. The expression of TIGAR and METTL3 was measured by real-time quantitative PCR and western blot. Microglial polarization was assessed by detecting the expression of M1 microglia marker CD86 and M2 marker CD206 using immunofluorescence and measuring the protein expression of M1-associated iNOS and IL-1β, and M2-associated Arg-1 and IL-10 using western blot. PAR-CLIP was employed to examine the binding of METTL3 to TIGAR mRNA, and MeRIP was used to measure the m6A level of TIGAR mRNA. The stability of TIGAR mRNA was evaluated by an actinomycin D assay.
    RESULTS: In Aβ-induced HMC3 cells, both METTL3 and TIGAR expressions were reduced. Aβ treatment in HMC3 cells increased M1 polarization and decreased M2 polarization. But this effect was partially reversed by overexpression of either METTL3 or TIGAR. METTL3 binds to TIGAR mRNA and increases its m6A level, thereby promoting TIGAR mRNA stability.
    CONCLUSION: METTL3 modulates the balance of Aβ-induced polarization and microglia activation in HMC3 cells by upregulating TIGAR, promoting polarization toward an anti-inflammatory profile.
    Keywords:  Alzheimer’s disease; METTL3; TIGAR; m6A; microglia polarization
    DOI:  https://doi.org/10.1097/WNR.0000000000002253
  46. Cancer Res. 2026 Mar 26.
    An SLCO2B1 mRNA Isoform Acts as a Noncoding RNA to Drive Cancer Progression by Triggering Protein Biosynthesis.
    Wenying Qiu, Yu Zeng, Zhichao Fan, Yue Su, Jiawen Jiang, Qili Shi, Xinrong Li, Shengli Li, Junjiao Song, Xianghuo He.
      The eukaryotic 5' untranslated region (5' UTR) canonically influences mRNA translation efficiency. Accumulating evidence has demonstrated that alternative promoters generate distinct transcription start sites (TSSs), producing many mRNA isoforms with divergent 5' UTR sequences. Herein, we comprehensively analyzed the 5' UTR sequence structure and protein abundance of RNA transcripts with altered TSSs in hepatocellular carcinoma (HCC). The analysis uncovered an mRNA isoform of solute carrier organic anion transporter family member 2B1 (SLCO2B1), named SLCO2B1-isoformNovel (SLCO2B1-isoN), that was highly expressed in HCC and correlated with poor patient prognosis but did not encode a detectable protein product. The 5' end stem‒loop of SLCO2B1-isoN abrogated its translational capacity and turned it into a noncoding RNA. The SLCO2B1-isoN noncoding isoform stabilized fragile X messenger ribonucleoprotein 1 (FMR1) to trigger HCC progression by facilitating de novo protein biosynthesis. Targeting SLCO2B1-isoN effectively inhibited orthotopic tumor xenograft growth and metastasis in vivo. In conclusion, this study revealed a noncoding isoform of SLCO2B1 mRNA and highlighted the dual characteristics of mRNAs harboring protein-coding and noncoding isoforms.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-4524
  47. Genes Dev. 2026 Mar 23.
    mRNA 3' UTRs direct microRNA degradation to participate in imprinted gene networks and regulate growth.
    Daniel H Lin, Lara E Elcavage, Ekaterina Khalizeva, David P Bartel.
      MicroRNAs direct downregulation of target mRNAs. Sometimes, however, this regulatory paradigm inverts, and a target RNA triggers degradation of a microRNA. This target-directed microRNA degradation (TDMD) requires ZSWIM8. Zswim8 -/- mice exhibit reduced growth and perinatal lethality, accompanied by stabilization of >40 microRNAs. Nonetheless, studies of TDMD function in mammals have been limited because only two TDMD-triggering RNAs have been identified in mice. Here, we computationally identify and validate five new TDMD-triggering sites in mouse models. One site in Atp6v1g1 and two sites in Lpar4 direct degradation of miR-335-3p, showing that in mammals, two sites in the same transcript and multiple sites in different transcripts can collaborate to destabilize a microRNA. Moreover, sites in Plagl1 and Lrrc58 direct degradation of miR-322 and miR-503, respectively. Mice lacking the Plagl1 and Lrrc58 sites were smaller, demonstrating that target-directed degradation of miR-322 and miR-503 promotes growth. Both miR-335-3p and Plagl1 are maternally imprinted, implying their participation in parental conflict, but their corresponding triggers or target microRNA partners are not imprinted. Thus, 3' UTRs can participate in parental conflict not only by regulating protein production but also by engaging TDMD to access an additional layer of regulation within a network of imprinted and biallelic genes.
    Keywords:  Zswim8; gene regulation; imprinting; miRNA; target-directed miRNA degradation
    DOI:  https://doi.org/10.1101/gad.353479.125
  48. FASEB J. 2026 Mar 31. 40(6): e71657
    ZXDB Drives Macrophage Inflammatory Programming in Sepsis-Induced Acute Kidney Injury by Recruiting EIF4A3 to Enhance ACACA Translation.
    Haiyang Wu, Wei Gang, Li Wang, Jing Sun, Shuangxi Li, Zhiyong Guo.
      Macrophage-driven inflammation is central to the pathogenesis of sepsis-induced acute kidney injury (SI-AKI), yet the role of RNA-binding proteins (RBPs) in post-transcriptionally regulating this process remains elusive. Here, we identify the RBP zinc finger X-linked duplicated B (ZXDB) as an upstream contributor to SI-AKI by promoting a pathogenic, pro-inflammatory macrophage activation state. We found that ZXDB expression is consistently elevated in M1-like macrophages within the kidney during SI-AKI, where it stimulates pro-inflammatory cytokine secretion and glycolytic reprogramming. Mechanistically, we discovered that ZXDB directly interacts with EIF4A3, a core exon junction complex (EJC) DEAD-box RNA helicase, via its aa151-300 region, thereby enhancing ACACA 5'UTR-dependent translation of ACACA, a metabolic enzyme that mediates downstream pathogenic effects associated with ZXDB activation. Critically, macrophage-specific deletion of Zxdb attenuated disease severity in a mouse model of SI-AKI, preserving renal function and attenuating inflammation. Taken together, our study uncovers a novel ZXDB-EIF4A3-ACACA axis that orchestrates macrophage-mediated kidney injury through translational control of metabolism, thereby suggesting ZXDB as a potential therapeutic candidate for SI-AKI.
    DOI:  https://doi.org/10.1096/fj.202502962RR
  49. Proc Natl Acad Sci U S A. 2026 Mar 31. 123(13): e2529493123
    Dynamic translocation of Inside-Out proteins to the cell surface underlies cellular adaptation to cancer-induced stress.
    Tomasz Slezak, Kelly M O'Leary, Tanya Guevara Avella, Natalia Musial, Jinyang Li, Anna Andrzejczak, Elizabeth F Scott, Duc Anh Le, Anthony A Kossiakoff.
      Inside-Out (I-O) protein display, the noncanonical surface localization of intracellular proteins, represents an underexplored feature of tumor cell biology. Here, we map the molecular landscape and trafficking mechanisms that control the presentation of I-O proteins on cancer cell membranes. Employing APEX2-mediated proximity biotinylation and a custom antibody generation and validation platform, we identified approximately 140 high-confidence I-O proteins, primarily ribosomal, proteasomal, chaperone, and translation factors, notably enriched in protein families associated with stress-response pathways. Validation of 500 antibodies encompassing 40 I-O targets across seven tumor cell lines confirmed selective and robust surface localization, while in vivo imaging in mouse xenografts demonstrated pronounced and tumor-specific antibody accumulation. I-O proteins were absent on peripheral blood mononuclear cells (PBMCs) and in normal tissues, indicating cancer cell selectivity. Functional analyses revealed that I-O protein tethering to the membrane is dependent on heparan sulfate interactions; enzymatic removal of these glycans led to the clearance of I-O proteins from the cell surface. Notably, the removed proteins returned to baseline levels within 6 h, indicating a dynamic balance related to Endoplasmic Reticulum (ER)-Golgi trafficking and cellular stress. Nearly half of these I-O proteins overlapped with known stress granule (SG) components; however, stress elements that promote SG formation do not similarly affect surface display of I-O proteins. Furthermore, I-O proteins are present on standard cancer cell lines under lower stress levels needed to induce SG formation, suggesting parallel yet mechanistically distinct aspects of the stress response. These findings position I-O display as a paradigm in protein trafficking, different from traditional secretion pathways and closely linked to stress response.
    Keywords:  Inside-Out proteins; cancer immunotherapy; cell surface proteome; tumor-specific biomarkers
    DOI:  https://doi.org/10.1073/pnas.2529493123
  50. bioRxiv. 2026 Mar 08. pii: 2026.03.05.709919. [Epub ahead of print]
    Circadian Dysregulation in Aging Alters Senescence and Inflammatory Pathways in a Sex- and Time-of-Day-Dependent Manner.
    Gretchen T Clark, Yue Zhao, Robyn E Reeve, Colleen M Farley, Courtney Willey, Susan Sheehan, Samantha Spellacy, Alicia Warren, Abigail Brackett, Nadia A Rosenthal, Ron Korstanje.
      The circadian rhythm orchestrates gene expression and critical physiological processes but becomes disrupted with aging, contributing to disease. How this disruption interacts with cellular senescence-a key driver of aging pathology-remains poorly defined. We studied renal gene expression at four timepoints over 24hrs in 6- and 24-month-old genetically diverse UM-HET3 mice of both sexes and performed complementary analyses in synchronized fibroblasts sampled at seven timepoints. Aging dysregulated core clock relationships, including loss of the canonical anti-phase expression between Bmal1 and Per2 . Senescence-associated genes were not static but exhibited pronounced oscillations, with senescence phenotypes varying by sex and time of day. Differential expression analysis revealed immune activation, metabolic rewiring, and epigenetic changes that were sex- and time-dependent. Variance analysis uncovered increased transcriptional noise in aging, particularly in circadian-regulated pathways such as RNA splicing, ribosome biogenesis, and TOR signaling. Single-nucleus RNA-Seq identified two cell populations lacking the normal Bmal1 - Cdkn1a expression relationship: one senescent-like and another profibrotic, revealing distinct cell states linked to circadian dysregulation. Fibroblasts recapitulated key age-related circadian changes seen in the kidneys, including phase shifts in mTOR and oxidative phosphorylation. Together, this work demonstrates that senescence phenotypes are dynamic, sex-specific, and time-of-day dependent, and introduces a new framework for detecting senescent cells based on circadian gene relationships. These findings underscore the need to integrate temporal context into aging research and therapeutic strategies.
    DOI:  https://doi.org/10.64898/2026.03.05.709919
  51. Nucleic Acids Res. 2026 Mar 19. pii: gkag265. [Epub ahead of print]54(6):
    Poly(ADP-ribose) (PAR) exhibits ion-dependent structural properties distinct from RNA.
    Lipika Baidya, Heyang Zhang, Hung T Nguyen.
      Poly(ADP-ribose) (PAR) is a highly charged, intrinsically flexible nucleic-acid-like homopolymer composed of ADP-ribose units. It serves as a critical post-translational modification that is rapidly synthesized in response to DNA damage and participates in diverse important cellular processes, including DNA repair, chromatin remodeling, and RNA biogenesis, often by promoting biomolecular phase separation. However, PAR's conformational heterogeneity coupled with limited experimental characterization has hindered a mechanistic understanding of these processes. To address this challenge, we develop a five-bead coarse-grained model of PAR and perform molecular dynamics simulations to compare its conformational ensemble and ion atmosphere with those of RNA across diverse ion environments. Our simulations reveal that PAR undergoes a markedly stronger structural transition than RNA in response to divalent ions, driven by its preferential ion binding and effective ion-mediated bridging between phosphate groups. These interactions facilitate cooperative conformational changes and produce a compact, ion-rich atmosphere that is fundamentally distinct from RNA. Together, our work provides a physically grounded model for PAR, uncovers molecular features that differentiate PAR from RNA, and offers mechanistic insight into how PAR nucleates phase separation and organizes protein interactions at sites of DNA damage.
    DOI:  https://doi.org/10.1093/nar/gkag265
  52. Cell Div. 2026 Mar 25.
    SOCS3 suppresses glioblastoma growth via JAK-STAT inhibition and mitochondrial unfolded protein response activation.
    Gaolei Hou, Zhaofei Song, Jingtao Wang, Junmei Wang, Hongbin Wang, Tao Li.
       INTRODUCTION: Glioblastoma (GBM) represents one of the most aggressive brain malignancies, characterized by rapid proliferation and pronounced resistance to apoptosis, resulting in poor therapeutic outcomes. Suppressor of cytokine signaling 3 (SOCS3), a crucial negative regulator of the JAK-STAT pathway, frequently undergoes epigenetic silencing in GBM. However, the tumor-suppressive functions of SOCS3 remain inadequately defined. The present study explores the role of SOCS3 in regulating mitochondrial stress responses and evaluates its therapeutic potential in GBM.
    METHODS: SOCS3 was overexpressed in GBM cell lines, and its effects on cell viability and apoptosis were assessed using MTT assays, TUNEL staining, and Western blotting. Proteomic profiling was performed to identify SOCS3-regulated pathways. A xenograft mouse model was used to validate tumor-suppressive effects in vivo. The impact of IL-6 (JAK-STAT activator) and Nicotinamide Riboside (NR, a mitochondrial stress inducer) was also examined.
    RESULTS: SOCS3 overexpression significantly suppressed GBM cell proliferation and induced apoptosis. Proteomic analysis revealed upregulation of mitochondrial unfolded protein response (UPRmt) and mitophagy-related proteins. In vivo, SOCS3 reduced tumor growth and enhanced apoptotic signaling. IL-6 treatment restored JAK-STAT activity and reversed SOCS3-mediated tumor suppression. In contrast, NR treatment synergistically augmented SOCS3-induced mitochondrial stress and apoptosis, suggesting that mitochondrial dysfunction contributes to enhanced cell death.
    CONCLUSION: SOCS3 exerts dual tumor-suppressive effects in GBM by inhibiting JAK-STAT signaling and activating mitochondrial stress pathways. These findings provide mechanistic insights into the function of SOCS3 and support its potential as a therapeutic target in GBM by promoting UPRmt-driven apoptosis.
    Keywords:  Apoptosis; Glioblastoma; JAK-STAT signaling; Mitochondrial unfolded protein response (UPRmt); Nicotinamide riboside (NR); SOCS3
    DOI:  https://doi.org/10.1186/s13008-026-00178-0
  53. Mol Vis. 2025 ;31 463-484
    Unfolded proteins and aggregates: The role of proteostasis in pseudoexfoliation pathology.
    Bushra Hayat, Debasmita Pankaj Alone.
       BACKGROUND: Proteostasis impairment is central to cellular dysfunction in protein aggregation disorders such as Alzheimer disease, Parkinson disease, and age-related macular degeneration. Pseudoexfoliation (PEX), a systemic age-related disorder and a leading cause of secondary glaucoma, is increasingly recognized as a protein aggregation disease. It is characterized by the deposition of pseudoexfoliative material (PEXM) in ocular tissues, leading to elevated intraocular pressure and optic neuropathy.
    OBJECTIVE: This review synthesizes current evidence on the role of proteostasis failure in PEX pathogenesis, with a focus on molecular mechanisms, stress response pathways, and potential therapeutic interventions.
    METHODS: We conducted a comprehensive literature review of studies examining proteostasis mechanisms in PEX. Emphasis was placed on cellular pathways regulating protein synthesis, folding, and degradation, including the unfolded protein response (UPR), ubiquitin-proteasome system (UPS), and autophagy, as well as environmental and aging-related triggers of proteotoxic stress.
    RESULTS: Evidence indicates that chronic proteotoxic stress, arising from aging, oxidative damage, and environmental influences, disrupts the proteostasis network (PN). Dysregulation of ER stress signaling, cytosolic stress responses, and protein degradation pathways contributes to the accumulation of misfolded proteins and extracellular matrix deposits in ocular tissues. These molecular alterations underlie disease onset and progression in PEX syndrome (PEXS) and PEX glaucoma (PEXG).
    CONCLUSIONS: Proteostasis dysfunction plays a pivotal role in PEX pathogenesis by promoting protein misfolding, aggregation, and extracellular deposition. Targeting the proteostasis network, through modulation of stress responses and enhancement of degradation pathways, represents a promising therapeutic strategy for PEXS and PEXG.
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