bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–08–09
fifty-nine papers selected by
Cédric Chaveroux, CNRS
  1. Ribosomal protein bL27 protects translating ribosomes from tmRNA-SmpB.
  2. Effects of RNAi of Ribophorin 1, Eukaryotic translation initiation factor 2 beta and Peptidylprolyl isomerase A in Acyrthosiphon pisum.
  3. Heat stress promotes pre-tRNA capping to modulate cap-dependent translation in Saccharomyces cerevisiae.
  4. Metabolic control of RNA methylation in rheumatoid arthritis: from synovial stress to pathogenic cellular adaptation.
  5. Functional interplay between TTP/ZFP36 and HuR/ELAVL1 in cancer: a post-transcriptional regulatory network.
  6. The (European) protein homeostasis network.
  7. Bruno 1 remodels P-bodies to protect select mRNAs during the early ER stress response.
  8. Targeting Ubiquitinated Protein Aggregates in Neurodegenerative Diseases: current Status and Future Directions.
  9. Comprehensive post-transcriptional modification profiles in individual Staphylococcus aureus tRNA species.
  10. Targeting mitochondrial ribosomal proteins: a functional and translational framework for neurodegenerative disease research.
  11. Translational repression of 5' TOP mRNAs in chronically activated CD8+ T cells in vitro.
  12. Probing the complexity of cellular RNA folding: Ensembles, intermediates, and isoforms.
  13. Co-phase separation of KRI1 and NPM1 sustains nucleolar integrity and ribosome biogenesis to fuel liver cancer progression.
  14. The role, regulatory mechanisms, and therapeutic implications of FTO in gastrointestinal cancer.
  15. Yeast Gcn2 retains activity following humanization of its auto-phosphorylation region.
  16. Biomolecular condensates in fungi: mechanisms and regulatory roles.
  17. Multiple quality control checkpoints safeguard small nuclear RNA biogenesis and prevent assembly of aberrant spliceosomes.
  18. CNOT11 depletion is associated with autophagy-related responses and IL-6-JAK-STAT signaling in cancer cells.
  19. Targeting SARS-CoV-2 programmed -1 ribosomal frameshifting: structural dynamics and RNA-directed antiviral strategies.
  20. Adaptive response to long-term high temperatures during the reproductive development in Arabidopsis thaliana.
  21. Condensates on the Move: Midbody Remnants as Large, Translation-Competent Extracellular Vesicles.
  22. Spatial control of mRNA translation underlies MKRN3-mediated delay of puberty.
  23. Cytoplasmic RBM20 granules modulate non-RBM20 target splicing through interactions with other splicing factors.
  24. Blocked transcription-translation complexes are rescued by transcript release followed by trans-translation.
  25. Decoding the SUMO Proteome: A Mass Spectrometry Workflow for Site-Specific Identification.
  26. Multilevel genomic constraints shape nuclear tRNA gene organization in plants.
  27. Novel Insights into the Human Hsc70 Structure by Cross-Linking Mass Spectrometry and Molecular Modeling.
  28. Circular RNAs in cervical cancer: from ceRNA networks to epitranscriptomic regulation, immune modulation, and metastatic reprogramming.
  29. No Significant Secondary Structural Change of α-Synuclein Monomer by Site-Specific DOPA or Phosphorylation Introduction in Its C-Terminal Region.
  30. HSP70CA2 is associated with cytoskeletal, membrane repair, and chaperone responses during acute heat shock in Urechis unicinctus.
  31. MiaA-mediated tRNA modifications couple tryptophan attenuation and changes in tRNA abundance to complex phenotypes in Pseudomonas aeruginosa.
  32. The Evolutionarily-conserved C-terminal tail of the Dib1 Protein is Required for Spliceosome Efficacy and Dib1 Protein Stability.
  33. Local RNA Structure, not Primary Sequence, Governs the Binding Specificity of PCID2 in Drosophila melanogaster.
  34. Translation factors that keep the ribosome Pro-active.
  35. Potential structure induced effects of the hairpin motif in RNA to form the phase separated droplet like associate in different solution condition.
  36. Profiling of Yeast Saccharomyces cerevisiae Mitochondrial AMPylome Reveals a Regulation of OXPHOS Coupling through ATP Synthase Subunit Delta.
  37. Vitamin B deficiency and sarcopenia: an integrated narrative review of metabolic, inflammatory, endoplasmic reticulum stress, and myokine signaling pathways.
  38. Dual regulatory mechanisms of YGP1 expression in response to glucose availability in Saccharomyces cerevisiae.
  39. ZFP36L2 orchestrates stress-adaptive plasticity in regeneration and cancer.
  40. The CRISPR/Cas-associated scaRNA modulates efeUOB expression and stress responses in Neisseria meningitidis.
  41. METTL3 promotes proliferation and invasion and inhibits ferroptosis in hepatocellular carcinoma by mediating m6A methylation modification of NUPR1.
  42. Centriolar satellites regulate CEP350 mRNA stability and centrosome amplification.
  43. CDK5RAP3-Mediated Mitochondrial RQC Alleviates Pathological Cardiac Hypertrophy.
  44. tRNA-Derived Small RNAs in Digestive Cancers: From Translational Regulation to Immune and Extracellular Communication.
  45. Promoter-Level Regulation of Melatonin Biosynthesis in Plant Stress Responses: A Framework for Climate-Resilient Crop Improvement.
  46. Generalizable Strategies for the Synthesis of Cereblon-Recruiting PROTAC Prodrugs.
  47. Exploring the role of CaMKII in exercise-induced cardioprotection.
  48. Reader-dependent functional duality of FTO: a context-switching node at the intersection of immune evasion and therapeutic resistance.
  49. An ER stress-responsive RNA rheostat for programmable gene and mRNA therapies.
  50. eIF6 affects the occurrence and development of esophageal cancer.
  51. A molecular switch for coordinating kinesin and dynein transport of mitochondrial cargo.
  52. Purification of Protein-Free and Protein-Linked Poly(ADP-Ribose) from Biochemical Reactions and from Human Cells.
  53. Meta-PseU: A meta-classifier for robust prediction of RNA pseudouridine modification sites from long sequences.
  54. IGF2BP3-mediated regulation of the RNA isoform and modification landscape in pancreatic cancer.
  55. METTL14-dependent N6-methyladenosine modification of FGF16 participates in IGFBP5 deficiency-enhanced angiogenesis.
  56. The Emerging Role of UCHL1 in Neurological and Musculoskeletal Diseases.
  57. Neddylation pathway promotes the ubiquitinated degradation of FBXO21 in lung cancer cells.
  58. Lactation-stage profiles of rRNA-derived small RNAs in human milk exosome-enriched fractions: Compositional features and relevance to infant nutrition.
  59. Vitamin B12 alleviates spliceosomopathy via phospholipid remodeling.
  1. Sci Adv. 2026 Aug 07. 12(32): eaef7696
    Ribosomal protein bL27 protects translating ribosomes from tmRNA-SmpB.
    Divyasorubini Seerpatham, George Wanes, Chathuri Pathirage, Mynthia Cabrera, Edu Usoro, Kristin S Koutmou, Christine M Dunham, Paul C Whitford, Kenneth C Keiler.
      Bacterial ribosomal protein bL27 is universally conserved, and its amino terminus is adjacent to the peptidyl transfer center, yet its roles in translation remain unclear. Combining genetics, biochemistry, and molecular dynamics, we show that bL27 has an unexpected role in preventing transfer-messenger RNA (tmRNA)-small protein B (SmpB), molecules involved in the trans-translation bacterial ribosome rescue mechanism, from interfering with protein synthesis. Deletion of the bL27 gene causes a 10,000-fold decrease in viability, and this defect is partially rescued by deletion of the gene encoding tmRNA. Addition of tmRNA-SmpB to in vitro translation reactions decreases the rate of protein synthesis by ribosomes lacking bL27 but has no effect on wild-type ribosomes. Molecular dynamics simulations also indicate that bL27 can slow the movement of tmRNA on the ribosome. These data link trans-translation and bL27 and support a model in which the amino terminus of bL27 acts as a gatekeeper to prevent tmRNA from sterically interfering with tRNA (transfer RNA) on the ribosome.
    DOI:  https://doi.org/10.1126/sciadv.aef7696
  2. Biochem Mol Biol J. 2026 ;pii: 2. [Epub ahead of print]12(3):
    Effects of RNAi of Ribophorin 1, Eukaryotic translation initiation factor 2 beta and Peptidylprolyl isomerase A in Acyrthosiphon pisum.
    Brandon Kennemer, James R Balthazor.
      Three genes found in the Unfolded protein response, Ribophorin 1, Eukaryotic translation initiation factor 2 beta and peptidylprolyl isomerase a are thought to be potential targets for RNA interference (RNAi) in Acyrthosiphon pisum. Ribophorin 1 (RPN1) is a transmembrane glycoprotein that assists in anchoring ribosomes to the rough endoplasmic reticulum membrane. It acts as a substrate specific chaperone. It facilitates N-glycosylation by delivering newly synthesized proteins to the Oligosaccharyl Transferase (OST) complex. Eukaryotic translation Initiation Factor 2 Beta (eIF2B) is a key component of the eIF2 heterotrimer that facilitates protein synthesis initiation by binding GTP and recruiting a specific transfer RNA to the 40S ribosome. The RNA it recruits is tRNAiMet, which delivers the first methionine to the ribosome to start protein synthesis. eIF2B is part of both the Unfolded Protein Response (UPR) and the Integrated Stress Response (ISR). Peptidylprolyl Isomerase A (PPIA) is also known as Cyclophilin A (CypA). CypA is a molecular chaperone that catalyzes the cis-trans isomerization of peptide bonds, which facilitates protein folding and maturation during stressful conditions. Previous studies confirm that RNAi can affect the lifespan and fecundity of pea aphids. The objective of this study was to determine whether the selected genes would also affect the lifespan of pea aphids. Decreasing concentrations of double-stranded Ribo Nucleic Acid (dsRNA) were fed to the aphids to test the effects of each chosen gene. The experiment's objective is to identify the effects of each dsRNA knockdown on the aphids. Higher concentrations had a greater effect on decreasing aphid survival. RPN1 and CypA reduced aphid survival only at the highest concentration tested. eIF2B showed a greater effect on aphid survival at lower concentrations than the other genes tested. It was effective at decreasing survival at a concentration of 100 ng/mL. The result of this study agrees with previous studies that aphid survival can be affected by the introduction of dsRNAs.
    Keywords:  Pest mitigation; RNAi; UPR; dsRNA
  3. Nat Commun. 2026 Aug 07. pii: 7853. [Epub ahead of print]17(1):
    Heat stress promotes pre-tRNA capping to modulate cap-dependent translation in Saccharomyces cerevisiae.
    Ittoku Kikuchi, Takayuki Ohira, Taichi Nakatsuka, Yuma Ishigami, Tsutomu Suzuki.
      Methylguanosine capping, a post-transcriptional modification of the 5' terminus of RNA polymerase II transcripts, influences RNA function, stability, and protein synthesis. Previously, we identified the cap modification in specific transfer RNA (tRNA) precursors (pre-tRNAs) transcribed by RNA polymerase III in Saccharomyces cerevisiae, and demonstrated that pre-tRNA capping prevents 5' exonucleolytic degradation of pre-tRNAs. Herein, we comprehensively mapped pre-tRNA capping and found that nearly all pre-tRNAs undergo cap modification. This analysis enabled precise determination of transcription start sites for all tRNA genes, and the capping efficiency was strongly influenced by the base-pairing probability between 5' leaders and 3' trailers of pre-tRNAs. Furthermore, pre-tRNA capping was significantly upregulated under heat stress, resulting in capped pre-tRNA-derived fragments. Capped pre-tRNAs modulated cap-dependent translation by sequestering eukaryotic initiation factor 4E (eIF4E). Overall, these findings suggest that pre-tRNA capping contributes to the regulation of cap-dependent translation under heat stress conditions in Saccharomyces cerevisiae.
    DOI:  https://doi.org/10.1038/s41467-026-76325-6
  4. Front Immunol. 2026 ;17 1865927
    Metabolic control of RNA methylation in rheumatoid arthritis: from synovial stress to pathogenic cellular adaptation.
    Shu Li, Lei Wan, Jin Yang, Kun Wang, Xiaojun Zhang, Xiaochuang Liu.
      Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent synovitis, invasive pannus formation, cartilage degradation, and bone erosion. Although metabolic reprogramming and epigenetic dysregulation are increasingly recognized as central features of rheumatoid arthritis, the mechanisms by which local metabolic stress is converted into durable pathogenic cellular states remain incompletely understood. Recent advances in epitranscriptomics suggest that dynamic RNA modifications, particularly RNA methylation, act as critical post-transcriptional regulators of immune and stromal cell adaptation. Local hypoxia, enhanced glycolytic flux, lactate accumulation, mitochondrial dysfunction, oxidative stress, and lipid metabolic imbalance collectively influence the expression, activity, substrate availability, and transcript selectivity of RNA methylation regulators. These metabolically conditioned RNA modification programs, including canonical N6-methyladenosine (m6A) and emerging non-m6A marks such as internal N7-methylguanosine (m7G), may help stabilize pathogenic phenotypes across multiple cell types. In fibroblast-like synoviocytes (FLS), RNA methylation sustains glycolytic fitness, invasive behavior, and resistance to apoptosis and ferroptosis. In macrophages, it reinforces inflammatory polarization and extracellular vesicle-mediated communication. In T cells and neutrophils, it contributes to Th17 skewing, defective autophagy, oxidative stress responses, and excessive neutrophil extracellular trap (NET) formation. We further discuss how RNA methylation integrates non-coding RNA networks, extracellular vesicle signaling, and regulated cell death pathways to maintain chronic synovial inflammation and tissue destruction. Finally, we highlight the translational implications of this metabolic-epitranscriptomic interface, including biomarker discovery, patient stratification, and microenvironment-informed therapeutic strategies. Targeting both metabolic stress and RNA methylation-dependent adaptation may provide new opportunities for precision-oriented intervention in rheumatoid arthritis.
    Keywords:  RNA methylation; cellular adaptation; cellular metabolism; epitranscriptomics; rheumatoid arthritis; synovial microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1865927
  5. Front Oncol. 2026 ;16 1913053
    Functional interplay between TTP/ZFP36 and HuR/ELAVL1 in cancer: a post-transcriptional regulatory network.
    Roberta Lotti, Tommaso Selmi, Alexis Grande, Tommaso Zanocco-Marani.
      Post-transcriptional regulation of gene expression has emerged as a fundamental determinant of cancer initiation, progression, and therapeutic response. Among the RNA-binding proteins (RBPs) involved in mRNA turnover and translational regulation, tristetraprolin (TTP), encoded by the ZFP36 gene, and "Human antigen R" (HuR), encoded by ELAVL1, represent two functionally antagonistic regulators of AU-rich element (ARE)-containing transcripts. TTP promotes the degradation of target mRNAs through recruitment of deadenylation and decay complexes, whereas HuR generally stabilizes and enhances the translation of overlapping mRNA subsets. Because many oncogenic, inflammatory, angiogenic, and metastasis-associated transcripts contain AREs within their 3' untranslated regions, the balance between TTP-mediated decay and HuR-mediated stabilization critically influences tumor biology. Accumulating evidence demonstrates that loss of TTP expression or activity and cytoplasmic accumulation of HuR are recurrent features across multiple cancer types, including breast, colorectal, pancreatic, gastric, liver, ovarian, and lung cancers. Importantly, several studies indicate that the reciprocal interplay between these proteins establishes a post-transcriptional rheostat controlling cancer-associated RNA regulons. This review summarizes current knowledge regarding the molecular biology of TTP and HuR, emphasizing their opposing functions in mRNA metabolism and cancer progression. We discuss mechanisms regulating their expression, localization, phosphorylation, and RNA-binding activity; analyze cancer-specific evidence; and examine models in which both proteins are co-expressed or functionally interconnected. Finally, we evaluate therapeutic strategies aimed at restoring TTP function or inhibiting HuR activity and discuss future perspectives for targeting post-transcriptional regulatory networks in oncology.
    Keywords:  AU-rich elements; ELAVL1; HuR; N6-methyladenosine; RNA-binding proteins; cancer; mRNA stability; tristetraprolin
    DOI:  https://doi.org/10.3389/fonc.2026.1913053
  6. FEBS J. 2026 Aug 05.
    The (European) protein homeostasis network.
    Eric Chevet.
      Proteostasis, the cellular network that governs protein synthesis, folding, trafficking, and degradation, is essential for maintaining cellular and organismal homeostasis. This review series highlights the breadth and impact of European research in the field of proteostasis, spanning fundamental mechanisms, organelle-specific quality control pathways, and emerging therapeutic opportunities. Contributions from leading laboratories across Europe examine key components of the proteostasis network, including translational regulation, molecular chaperones, ubiquitin-dependent protein degradation, organelle communication, and adaptive stress responses. Particular emphasis is placed on proteostasis mechanisms operating within the endoplasmic reticulum and mitochondria as well as on their roles in aging, inflammation, neurodegeneration, and other human diseases. The series also showcases the collaborative efforts that have strengthened the European proteostasis community through major networking initiatives and training programs. Together, these articles provide a comprehensive overview of current advances in proteostasis research and underscore its growing importance as a framework for understanding cellular adaptation and developing innovative therapeutic strategies.
    Keywords:  cellular signaling network; protein degradation; protein folding; protein quality control; protein synthesis; proteostasis; stress response; ubiquitin
    DOI:  https://doi.org/10.1111/febs.70663
  7. Life Sci Alliance. 2026 Oct;pii: e202603806. [Epub ahead of print]9(10):
    Bruno 1 remodels P-bodies to protect select mRNAs during the early ER stress response.
    Samantha N Milano, Livia V Bayer, Julie J Ko, Gwendolyn S Posner, Albina H Granovsky, Diana P Bratu.
      P-bodies are cytoplasmic membraneless organelles involved in mRNA storage, yet their role in cellular stress responses remains unresolved. Here, we demonstrate that P-bodies are remodeled during the early response to ER stress throughout Drosophila melanogaster oogenesis. Notably, this remodeling occurs within minutes of stress induction and precedes stress granule formation. This early remodeling is characterized by changes in P-body morphology and internal organization and promotes selective mRNA storage. Mechanistically, we find that this process is driven by transcriptional up-regulation of the RNA-binding protein, Bruno 1, downstream of ATF4-dependent stress signaling, thereby establishing a connection between the unfolded protein response and condensate regulation. Consistent with this model, loss of Bruno 1 abolishes, whereas its overexpression enhances, P-body remodeling, demonstrating that stress-induced changes in RNA-binding protein levels can reprogram condensate properties. Together, our findings reveal that P-bodies function as stress-responsive hubs enabling selective preservation of essential mRNAs during ER stress. More broadly, this work uncovers a previously unrecognized mechanism by which stress signaling pathways reorganize cytoplasmic architecture to shape mRNA fate.
    DOI:  https://doi.org/10.26508/lsa.202603806
  8. Mol Cell Biol. 2026 Aug 04. 1-19
    Targeting Ubiquitinated Protein Aggregates in Neurodegenerative Diseases: current Status and Future Directions.
    Masahiko Takahashi, Takayuki Abe, Masahiro Fujii.
      Various cellular stressors inhibit translation initiation and promote ribosome disassembly, thereby transiently inducing stress granules (SGs), dynamic ribonucleoprotein condensates that contain mRNAs and RNA-binding proteins. Although SG assembly is usually reversible, dysregulated SG dynamics can trigger the formation of persistent ubiquitin-positive protein inclusions. There is increasing evidence that this conversion of SGs into insoluble aggregates represents a central pathogenic mechanism in neurodegenerative proteinopathies, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). TAR DNA-binding protein 43 (TDP-43) and Tau are causative factors in ALS and AD, respectively, and both localize to SGs under stress conditions. During disease progression, TDP-43 or Tau within SGs undergoes pathological changes that promote the formation of neurotoxic inclusions, which propagate neuronal dysfunction and death. This review summarizes recent advances in understanding the molecular factors that regulate SG assembly and disassembly, as well as the pathological processes that drive the conversion of SGs into aggregates associated with neurodegenerative diseases. Particular emphasis is placed on the role of the ubiquitin-specific protease 10 (USP10), which modulates SG dynamics and has been mechanistically implicated in both ALS and AD. Finally, we discuss the therapeutic potential of targeting these pathways to mitigate neurodegenerative disease progression.
    Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; stress granule; ubiquitin-specific protease 10
    DOI:  https://doi.org/10.1080/10985549.2026.2705871
  9. Nucleic Acids Res. 2026 Jul 17. pii: gkag757. [Epub ahead of print]54(14):
    Comprehensive post-transcriptional modification profiles in individual Staphylococcus aureus tRNA species.
    Jose R Jaramillo-Ponce, Philippe Wolff, Virginie Marchand, Yuri Motorin, Maximilian Kohl, Béatrice Chane-Woon-Ming, Hiroki Kanazawa, Aila Ruiz-Paterson, Caroline Paulus, Johana Chicher, Marine Lenon, Martina Krämer, Anne-Sophie Gribling-Burrer, Constantinos Stathopoulos, Redmond Smyth, Mark Helm, Pascale Romby, Stefano Marzi.
      Post-transcriptional modifications modulate transfer RNA (tRNA) structure, stability, and codon decoding properties, contributing to translation regulation and adaptation across diverse organisms, including bacterial pathogens. We provide a comprehensive analysis of tRNA modifications in Staphylococcus aureus using extensive oligonucleotide mass spectrometry and deep-sequencing methods, generating a high-confidence modification map for each individual tRNA species, including non-proteogenic tRNAGly. While the overall tRNA modification landscape is conserved among Gram-positive bacteria, our data uncovered unexpected S. aureus-specific features. These include the absence of m2A37 in tRNAs despite the presence of the methyltransferase RlmN, a single multi-site DusB2 enzyme catalyzing all tRNA dihydrouridylation, and evidence suggesting a dedicated pseudouridine synthase responsible for Ψ32. Besides, heterogeneous modification patterns were observed in tRNALeu(UAA) and tRNALys(UUU), highlighting a complex interplay in anticodon hypermodification. Time-course proteomics revealed dynamic expression of tRNA modifying enzymes during growth. Integration of ribosome profiling and Nanopore tRNA sequencing offered a global view of S. aureus decoding properties, revealing efficient four-way wobble recognition, slower translation of rare codons by low abundant tRNAs, and distinctive decoding dynamics of Gly codons potentially influenced by the unusual modification status of tRNAGly(UCC). This work establishes a framework to dissect the role of tRNA modifications in S. aureus physiology and pathogenesis.
    DOI:  https://doi.org/10.1093/nar/gkag757
  10. Front Neurol. 2026 ;17 1882474
    Targeting mitochondrial ribosomal proteins: a functional and translational framework for neurodegenerative disease research.
    Luigi Del Giudice, Marco Guida, Maria Rosaria Aletta, Paola Pontieri.
      Mitochondrial dysfunction is a central feature of neurodegenerative diseases, yet the molecular mechanisms governing mitochondrial protein synthesis remain insufficiently understood. Mitochondrial ribosomal proteins (MRPs), essential for the translation of mitochondrial-encoded components of the oxidative phosphorylation system, are emerging as critical regulators of neuronal homeostasis and survival. In this mini-review, we examine current knowledge on mitochondrial ribosomes with a focused analysis of three mitochondrial ribosomal proteins-MRPL44, NAM9, and GEP3-highlighting their structural and functional roles in maintaining mitochondrial integrity. We discuss evidence linking alterations in these proteins to key pathogenic processes relevant to neurodegeneration, including impaired oxidative phosphorylation, increased oxidative stress, and defective mitochondrial quality control. Importantly, we propose an integrative research perspective that positions these MRPs as potential modulators of tissue-specific vulnerability in neurodegenerative disorders. By synthesizing available data and identifying critical knowledge gaps, we outline future directions aimed at elucidating their contribution to neuronal dysfunction and disease progression. This work underscores mitochondrial ribosomal proteins as underexplored determinants of neurodegenerative pathology and suggests that their systematic investigation may reveal novel mechanistic insights and therapeutic opportunities.
    Keywords:  Alzheimer's and Parkinson's disease; GEP3; MRPL44; NAM9; mitochondrial disease; mitochondrial genome; nuclear genome; yeast and C. elegans model organisms
    DOI:  https://doi.org/10.3389/fneur.2026.1882474
  11. RNA Biol. 2026 Aug 06.
    Translational repression of 5' TOP mRNAs in chronically activated CD8+ T cells in vitro.
    Erica S Pledger, Navya Ambavaram, Lucas Ferguson, Jamie H D Cate.
      T cell exhaustion is a dysfunctional state that arises during chronic infections and cancer, characterized by impaired effector functions and sustained expression of inhibitory receptors. While transcriptional, epigenetic, and metabolic rewiring have been well documented in exhausted T cells, a comprehensive understanding of how translation is regulated in this state remains incomplete. To address this gap, we performed ribosome profiling and RNA sequencing on in vitro chronically activated human CD8+ T cells to globally assess translational control during a model of T cell exhaustion. Our analyses reveal a marked repression of 5' terminal oligopyrimidine (TOP) mRNAs during chronic activation. Unexpectedly, we demonstrate that this translational repression occurs despite evidence of elevated mTOR activity. These findings uncover a previously unknown layer of translational control in exhausted T cells.
    Keywords:  T cell; TOP mRNAs; chronic activation; exhaustion; mTOR; ribosome profiling; translation regulation
    DOI:  https://doi.org/10.1080/15476286.2026.2715355
  12. Curr Opin Struct Biol. 2026 Aug 03. pii: S0959-440X(26)00129-6. [Epub ahead of print]101 103347
    Probing the complexity of cellular RNA folding: Ensembles, intermediates, and isoforms.
    Anthony M Mustoe, Danny Incarnato.
      RNA molecules populate complex structural landscapes that are continuously reshaped throughout the RNA lifecycle by equilibrium and non-equilibrium processes. Resolving these structural landscapes represents a central challenge in RNA biochemistry. We review recent advances in RNA chemical probing, sequencing, and computational deconvolution technologies that are revolutionizing our ability to measure the complexities of RNA folding in cells and the deep involvement of these complexities in RNA functional mechanisms. We highlight new methods for deconvolving structural ensembles, distinguishing isoform-specific architectures using long-read sequencing, capturing co-transcriptional folding intermediates in vivo, and measuring higher-order RNA structures while also underscoring remaining challenges. We conclude by outlining future directions in probe development, sequencing, and integrative modeling, and discuss how resolving RNA structural ensembles with increasingly high resolution will likely reveal new therapeutic opportunities to selectively target functional RNA heterogeneity.
    DOI:  https://doi.org/10.1016/j.sbi.2026.103347
  13. Proc Natl Acad Sci U S A. 2026 Aug 11. 123(32): e2535921123
    Co-phase separation of KRI1 and NPM1 sustains nucleolar integrity and ribosome biogenesis to fuel liver cancer progression.
    Yu Lu, Lunbiao Gan, Wenxiu Ru, Yujing Guo, Qian Huang, Sha Yin, Fengze Nie, Sijia Di, Siyu Yao, Huanhuan Wan, Fa Yang, Weijun Qin, Weihong Wen.
      Liver cancer is the fourth leading cause of global cancer mortality, with hepatocellular carcinoma (HCC) accounting for most primary liver cancers. The nucleolus, as the primary site of ribosome biogenesis, plays a crucial role in HCC development. Here, we report that the nucleolar protein KRR1 interacting protein (KRI1) is aberrantly overexpressed in HCC tissues and interacts with nucleophosmin 1 (NPM1) via phase separation to maintain nucleolar structure and ribosome biogenesis. Downregulation of KRI1 significantly impairs HCC cell proliferation and increases apoptosis, accompanied by disrupted nucleolar structure and ribosome biogenesis. Moreover, we show that KRI1 phase separation is enhanced by the phosphorylation of three serine residues (S94, S95, and S97) in its N-terminal intrinsically disordered region, and pyruvate kinase M2 (PKM2) is identified as the key kinase. PKM2 inhibitor shikonin markedly attenuates KRI1 phase separation and its interaction with NPM1, disrupts nucleolar structure and ribosome biogenesis, thereby inhibiting HCC progression. This study uncovers the crucial role of KRI1 in HCC progression and provides theoretical and experimental evidence for the development of nucleolar protein-targeted therapeutic strategies for HCC treatment.
    Keywords:  hepatocellular carcinoma; nucleolus; phase separation; phosphorylation
    DOI:  https://doi.org/10.1073/pnas.2535921123
  14. Genes Dis. 2026 Nov;13(6): 102122
    The role, regulatory mechanisms, and therapeutic implications of FTO in gastrointestinal cancer.
    Xinxin Zhang, Yufeng Han, Huimin Yin, Zhenjian Zhuo, Jing He.
      N6-methyladenosine (m6A) is the most common post-transcriptional modification in mRNA, playing a crucial role in cancer development by modulating RNA stability, translation, and nuclear export. As the first discovered m6A demethylase, FTO catalyzes m6A demethylation in a Fe2+/α-KG-dependent manner, functioning as either an oncogene or a tumor suppressor to mediate cancer progression via reducing m6A levels and thereby modulating RNA metabolism. Numerous studies have elucidated the mechanisms by which upstream regulators affect FTO expression, as well as the post-translational modifications that impact its protein stability, translocation, and degradation. Moreover, inhibitors targeting FTO demonstrate significant therapeutic potential. In this review, we summarize recent research on the role and regulatory manner of FTO in gastrointestinal cancer and discuss its potential clinical application in cancer therapy.
    Keywords:  FTO; Gastrointestinal cancer; Inhibitors; Posttranslational modifications; Upstream regulators; m6A
    DOI:  https://doi.org/10.1016/j.gendis.2026.102122
  15. FEBS Open Bio. 2026 Aug 02.
    Yeast Gcn2 retains activity following humanization of its auto-phosphorylation region.
    Reuben A Anderson, Anja H Schiemann, Evelyn Sattlegger.
      The protein kinase Gcn2 is a conserved component of a eukaryotic signaling pathway best known for helping cells cope with amino acid shortage. Upon starvation, Gcn2 auto-phosphorylates and then phosphorylates eIF2α, triggering widespread changes in gene expression. While Gcn2 is gaining attention for its diverse biological roles and links to various diseases, its activation and regulation remain unclear. To date, Saccharomyces cerevisiae remains an important model for dissecting these mechanisms in detail. However, commercial antibodies recognizing phosphorylated Gcn2 are available only for mammalian GCN2. Therefore, we engineered a yeast Gcn2 variant, Gcn2-HsC, recognizable by these antibodies. Gcn2-HsC almost completely complemented a gcn2Δ strain, retained its ability to phosphorylate eIF2α, and is still dependent on Gcn1 for function. Ultimately, our results suggest that Gcn2-HsC serves as a valuable tool for Gcn2-related studies in the highly tractable yeast system.
    Keywords:  Gcn1; Gcn2; ISR; auto‐phosphorylation; protein kinase; stress response
    DOI:  https://doi.org/10.1002/2211-5463.70286
  16. Microbiol Mol Biol Rev. 2026 Aug 05. e0001226
    Biomolecular condensates in fungi: mechanisms and regulatory roles.
    Emma E Blackburn, Xiaorong Lin.
      SUMMARYLiquid-liquid phase separation (LLPS) drives the formation of biomolecular condensates, a conserved phenomenon across eukaryotes. This process governs diverse cellular programs, from stress response and morphogenesis to disease pathology. Over the past two decades, the regulatory impact of biomolecular condensates in fungal biology has become increasingly recognized. In this review, we examine the fundamental molecular mechanisms driving LLPS, evaluate the current evidence for LLPS in macromolecular organization and cellular regulation in fungi, and outline the tools employed to study this phenomenon. Lastly, we highlight the challenges of bridging the gap between the in vitro behavior of biomolecular condensates and their complex regulatory functions in vivo within fungal biology.
    Keywords:  MS2 tagging; RNA-binding proteins; epigenetic; fluorescence in situ hybridization (FISH); fungal pathogen; morphogenesis; phase separation; processing bodies; stress granules; stress response
    DOI:  https://doi.org/10.1128/mmbr.00012-26
  17. Genes Dev. 2026 Aug 06.
    Multiple quality control checkpoints safeguard small nuclear RNA biogenesis and prevent assembly of aberrant spliceosomes.
    Tiantai Ma, Claire Huntington, Zhuoyi Song, Rea M Lardelli, Eric L Van Nostrand, Jens Lykke-Andersen.
      Defective small nuclear (sn)RNAs are produced from hundreds of human snRNA pseudogenes and mutant snRNA genes associated with human developmental disorders. Machineries that prevent defective snRNAs from disrupting pre-mRNA splicing remain poorly defined. Here, we identify multiple checkpoints in snRNA biogenesis monitored by quality control machineries that subject defective snRNAs to degradation and prevent their assembly into spliceosomes. We show that variant U1 snRNAs produced from human pseudogenes, some at rates approaching canonical snRNAs, are impaired in 3' cleavage and targeted for degradation by the NEXT-exosome while failures in subsequent protein assembly steps promote NEXT-exosome- or terminal uridylyl transferase 4/7-mediated degradation. These pathways also repress mutant snRNAs associated with human developmental disorders. Impeding snRNA quality control causes formation of aberrant spliceosomes and altered pre-mRNA splicing. These findings define checkpoints in snRNA biogenesis that safeguard pre-mRNA splicing and represent potential therapeutic targets for human disorders associated with snRNA mutations.
    Keywords:  Integrator; NEXT-exosome; RNA quality control; TUT4; TUT7; neurodevelopmental disorders (NDD); pseudogenes; snRNA; spliceosome; splicing
    DOI:  https://doi.org/10.1101/gad.353690.126
  18. Front Cell Dev Biol. 2026 ;14 1854333
    CNOT11 depletion is associated with autophagy-related responses and IL-6-JAK-STAT signaling in cancer cells.
    Saori Nishijima, Toru Suzuki, Tadashi Yamamoto.
       Introduction: The CCR4-NOT complex is a central regulator of deadenylation-mediated mRNA decay, yet the role of its vertebrate-specific subunit CNOT11 remains unclear.
    Methods: We investigated the role of CNOT11 in cellular stress responses using siRNA-mediated knockdown, immunoblotting, immunoprecipitation, transcriptomic analysis, quantitative RT-PCR, ELISA, cycloheximide chase assays, actinomycin D treatment, and poly(A) tail analysis.
    Results: CNOT11 depletion did not markedly alter the expression of other CCR4-NOT subunits but reduced the association of CNOT10 with the complex. CNOT11 knockdown was associated with LC3-II accumulation, transcriptional upregulation of autophagy-related genes, and changes in AMPK/ULK1 signaling. Increased IL-6 expression and secretion and enhanced STAT1 and STAT3 phosphorylation were also observed. IL-6 knockdown or STAT3 inhibition partially attenuated LC3-II accumulation. Increased IL-6 expression was associated with elevated transcription, without detectable changes in mRNA stability or poly(A) tail length.
    Discussion: These findings suggest that CNOT11 depletion is associated with LC3-II accumulation and other autophagy-related responses, with IL-6-JAK-STAT signaling contributing partially to this phenotype. Definitive assessment of autophagic flux and the causal positioning of IL-6 signaling will require further studies using gold-standard flux assays and IL-6 rescue or neutralization approaches.
    Keywords:  CCR4-NOT complex (CNOT); CNOT11; IL-6; JAK-STAT signaling; autophagy-related responses; lysosome
    DOI:  https://doi.org/10.3389/fcell.2026.1854333
  19. Antimicrob Agents Chemother. 2026 Aug 03. e0068726
    Targeting SARS-CoV-2 programmed -1 ribosomal frameshifting: structural dynamics and RNA-directed antiviral strategies.
    Neha Jeena, Inshad Ali Khan.
      Programmed -1 ribosomal frameshifting (-1 PRF) is a translational recoding mechanism used by many RNA viruses to regulate the expression of viral replication proteins. In coronaviruses, including SARS-CoV-2, -1 PRF is controlled by a conserved frameshift stimulation element containing a three-stemmed RNA pseudoknot located downstream of a slippery sequence. Studies have shown that conformational dynamics, mechanical stability, and structural variability of the pseudoknot influence ribosome pausing and frameshifting efficiency, identifying viral RNA structures as potential antiviral targets. This review outlines the structural organization, mechanistic basis, and conformational dynamics of viral frameshifting pseudoknots, with emphasis on the SARS-CoV-2 frameshift stimulation element. Advances in cryo-electron microscopy, single-molecule biophysics, molecular dynamics simulations, and computational modeling have identified multiple pseudoknot conformations involved in translational recoding and ribosome-RNA interactions. RNA-targeted therapeutic approaches used to suppress or modulate -1 PRF are also discussed, including small-molecule RNA binders, antisense oligonucleotides, peptide nucleic acids, and ribonuclease-targeting chimeras. These approaches act on distinct aspects of RNA structure, conformational flexibility, and stability to inhibit viral translation or promote selective RNA degradation. Major challenges include selective targeting of highly dynamic RNA structures, optimization of intracellular delivery, and minimizing off-target effects. Integration of structural biology, computational modeling, and RNA-targeted therapeutic strategies may support the development of next-generation antivirals targeting conserved viral RNA regulatory elements.
    Keywords:  RNA-targeted therapeutics; SARS-CoV-2 RNA pseudoknot; conformational dynamics; programmed −1 ribosomal frameshifting
    DOI:  https://doi.org/10.1128/aac.00687-26
  20. Planta. 2026 Aug 01. pii: 80. [Epub ahead of print]264(3):
    Adaptive response to long-term high temperatures during the reproductive development in Arabidopsis thaliana.
    Juan Francisco Sánchez López, Marie Štefková, Oussama Guennich, Fen Yang, Ales Pecinka, Hélène S Robert.
       MAIN CONCLUSION: Flowering Arabidopsis plants adapt to long-term high temperature by shortening the flowering period and reducing their fertility. The study also demonstrated that the commonly used hot1-3 mutant is tetraploid. Increasing global temperatures and the rising frequency of heat waves pose a significant threat to plant reproduction. The reproductive phase is particularly sensitive to heat stress, yet the underlying mechanisms regulating thermotolerance during this stage remain insufficiently understood, despite significant advances in its understanding during vegetative growth. Heat stress responses are largely controlled by heat shock factors (HSFs) and their downstream targets, including heat shock proteins (HSPs). Among these, HSP101 is essential for acquired thermotolerance and recovery from stress, while HEAT SHOCK BINDING PROTEIN (HSBP) acts as a negative regulator of HSF activity, modulating the heat shock response. Here, we investigated the impact of elevated temperature regimes on the reproductive development of Arabidopsis thaliana, with a particular focus on pollen development and fertility. Our results show that heat stress negatively affects pollen development in a dose-dependent manner, leading to reduced reproductive success. We confirmed the critical role of HSP101 in reproductive thermotolerance using the hot1-3 mutant, deficient in HSP101. Furthermore, we provide evidence that the hot1-3 mutant is tetraploid. The origin of this event is unknown, but it is tempting to speculate that disruption of heat stress responses and interference with meiotic processes may lead to whole genome duplication. Overall, this study provides new insights into the regulation of plant reproductive development under heat stress and highlights the importance of HSP101 in maintaining fertility. These findings contribute to a better understanding of plant responses to rising temperatures and may inform strategies to enhance crop resilience under climate change.
    Keywords:   hot1-3; Arabidopsis; Flowering; Long-term High temperature; Reproductive development
    DOI:  https://doi.org/10.1007/s00425-026-05108-6
  21. Bioessays. 2026 Aug;48(8): e70168
    Condensates on the Move: Midbody Remnants as Large, Translation-Competent Extracellular Vesicles.
    Ahna R Skop.
      Recent work has expanded understanding of extracellular vesicle (EV) biology by identifying midbody remnants (MBRs) as large, translationally competent vesicles released during mitosis. MBRs contain ribosomes, mitochondria, translation factors, and selected mRNAs and small RNAs concentrated within a condensate‑like ribonucleoprotein core and can support protein synthesis after extracellular release. These features distinguish MBRs from more extensively studied exosomes and microvesicles yet also place them within a broader continuum of large EVs with organelle‑rich, cell‑like properties. This review summarizes current knowledge of MBR biogenesis, molecular organization, and translation competency; contrasts MBRs with canonical EVs and other large EVs; and discusses possible roles in development, tissue homeostasis, disease, and brain function. Particular emphasis is placed on outstanding mechanistic and physiological questions, including how MBR translation is regulated, which recipient cells interact with endogenous MBRs, and whether translation‑competent EVs offer practical advantages over existing EV platforms for therapeutic or biotechnological applications.
    Keywords:  biomolecular condensates; cancer; cytokinesis; extracellular vesicles; intercellular communication; localized translation; midbody; midbody remnant; protein synthesis; stem cells
    DOI:  https://doi.org/10.1002/bies.70168
  22. iScience. 2026 Aug 21. 29(8): 116781
    Spatial control of mRNA translation underlies MKRN3-mediated delay of puberty.
    Dor Shalev, Lilach Pnueli, Amir Argoetti, Tyler Brent de Leon, Gil Golan, Galia Polyak, Tamar Hashimshony, Yael Mandel-Gutfreund, Philippa Melamed.
      Loss-of-function mutations in MKRN3 cause central precocious puberty, but the underlying mechanisms remain unclear, and findings from knockout mice are inconsistent. MKRN3 contains RNA-binding and ubiquitin-ligase domains, so we hypothesized that it regulates GnRH function through RNA and protein interactions. We performed transcriptomic, proteomic, and RNA/protein interactome analyses in GnRH neuronal cells overexpressing Mkrn3. Results indicated predominantly post-transcriptional effects, and the Mkrn3 interactome included the RNA-binding protein Igf2bp2, which is also linked to pubertal timing. Mkrn3 precipitated numerous mRNAs, notably Gnrh1 mRNA. Igf2bp2 also binds this mRNA but in an Mkrn3-dependent manner. Mkrn3 and Igf2bp2 share many mRNA targets, especially nuclear-encoded mitochondrial transcripts, suggesting roles in RNA transport and localized translation. Subcellular fractionation and reporter assays revealed that Mkrn3 alters the localization of proGnRH and Gnrh1 3'UTR-dependent translation and together support a model in which Mkrn3 spatially restricts Gnrh1 mRNA translation, limiting precursor processing and subsequent secretion of the mature peptide.
    Keywords:  GnRH; MKRN3; mRNA localization; neuroendocrine; puberty; reproduction
    DOI:  https://doi.org/10.1016/j.isci.2026.116781
  23. Nucleic Acids Res. 2026 Jul 17. pii: gkag770. [Epub ahead of print]54(14):
    Cytoplasmic RBM20 granules modulate non-RBM20 target splicing through interactions with other splicing factors.
    Yanghai Zhang, Zachery R Gregorich, Chunling Liu, Eli J Larson, Ying Ge, Wei Guo.
      RNA-binding motif protein 20 (RBM20) is a splicing factor that forms discrete nuclear speckles. Certain pathogenic RBM20 variants disrupt its nuclear localization, leading to cytoplasmic granules formation. The composition of RBM20 nuclear speckles and cytoplasmic granules, how these compartments differ from one another, and how they contribute to splicing regulation remain unclear. Here, we employed in situ proximity labeling proteomics and identified 25 and 12 proteins associated with RBM20 nuclear speckles and cytoplasmic granules, respectively. RBM20 nuclear speckles were enriched in proteins involved in splicing and transcriptional regulation, whereas cytoplasmic granules contained proteins commonly found in other cytoplasmic granule populations. Among these, CELF1 and MBNL2 were detected in both RBM20 nuclear speckles and cytoplasmic granules, as confirmed by co-localization and immunoprecipitation experiments. We further showed that CELF1- and MBNL2-regulated splicing events were disrupted in the hearts of mice carrying pathogenic Rbm20 variants but not in animals with Rbm20 loss-of-function that lack cytoplasmic granules. Moreover, reducing cytoplasmic granule burden through RBM20 knockdown in pathogenic variant knock-in mice showed a trend toward partial restoration of MBNL2-mediated splicing defects. Collectively, these findings define the distinct protein compositions of RBM20 nuclear speckles and cytoplasmic granules and suggest that cytoplasmic RBM20 granules affect the splicing of non-RBM20 target genes.
    DOI:  https://doi.org/10.1093/nar/gkag770
  24. J Bacteriol. 2026 Aug 06. e0027026
    Blocked transcription-translation complexes are rescued by transcript release followed by trans-translation.
    Stephanie L Leedom, Kenneth C Keiler.
      Bacterial ribosomes initiate translation while the nascent transcript is still engaged with RNA polymerase, creating a risk that translating ribosomes will become trapped if RNA polymerase is blocked before transcription of the stop codon. Here we show that DNA-binding proteins block RNA polymerase and translating ribosomes in vitro and in vivo. Translating ribosomes are rescued after they trigger the release of the nascent transcript from RNA polymerase. Following the release of the transcript, ribosomes translate to the 3' end of the mRNA and are rescued by trans-translation. This mechanism allows the rescue of all components of blocked transcription-translation reactions.
    IMPORTANCE: Co-transcriptional translation in bacteria provides an efficient means to produce proteins but creates a risk that translating ribosomes could become trapped if RNA polymerase is blocked during transcription. We show that when RNA polymerase is blocked, a translating ribosome triggers the release of the nascent mRNA from the polymerase, and the ribosome is rescued by trans-translation. This mechanism for resolving blocked transcription-translation complexes explains how bacteria avoid detrimental accumulation of stalled ribosomes.
    Keywords:  DNA-binding proteins; ribosomes; transcription; translation
    DOI:  https://doi.org/10.1128/jb.00270-26
  25. Methods Mol Biol. 2026 ;3018 41-56
    Decoding the SUMO Proteome: A Mass Spectrometry Workflow for Site-Specific Identification.
    Chongyang Li, Pierre Thibault.
      Protein SUMOylation is a dynamic post-translational modification that regulates numerous cellular processes, including DNA repair, transcription, and proteostasis. SUMO modifiers are conjugated to lysine residues on substrate proteins via a conserved enzymatic cascade and can form diverse chain architectures that encode specific cellular outcomes. The identification of SUMOylated proteins and their modification sites has historically been challenging due to the low abundance of SUMOylation and the complexity of SUMO remnants after proteolysis. Recent advances in proteomics have led to the development of enrichment strategies and mass spectrometry (MS)-based methods that now enable the site-specific mapping of SUMO modifications. This chapter provides an overview of the biological roles and structural diversity of SUMOylation, and presents an MS-based workflow designed to identify SUMOylation sites with high specificity and depth. These tools offer new opportunities to dissect the SUMO-modified proteome in health and disease.
    Keywords:  Immunoaffinity enrichment; Mass spectrometry; Posttranslational modifications; Proteomics; SUMOylation; Ubiquitin-like proteins (UBLs)
    DOI:  https://doi.org/10.1007/978-1-0716-5166-7_3
  26. Plant J. 2026 Aug;127(3): e71075
    Multilevel genomic constraints shape nuclear tRNA gene organization in plants.
    Guillaume Hummel, David Pflieger, Valérie Cognat, Laurence Drouard, Alexandre Berr.
      Transfer RNAs (tRNAs) are essential components of the translation machinery. Their abundance and diversity shape decoding capacity as well as the efficiency and accuracy of protein synthesis. Because tRNA abundance is encoded in the genome through tDNA copy number, chromosomal organization, and cis-regulatory sequences controlling transcription, these features are expected to influence the translational system. However, the principles governing nuclear tDNA organization remain poorly understood. Here, we analyzed nuclear tDNA repertoires across 53 photosynthetic eukaryotes spanning major Archaeplastida lineages and secondary endosymbionts, along with seven non-plant eukaryotic outgroups, using comparative genomic approaches at sequence, chromosomal, and genome-wide scales. To standardize these analyses and enable interactive exploration of tDNA organization, we developed ShinytRNA (https://nebula.ibmp.unistra.fr/shinytRNA/), a web application for genome-scale analysis of chromosomal tDNA organization. Nuclear tDNA copy numbers vary by more than two orders of magnitude across species, yet the relative representation of tRNA families corresponding to each amino acid remains strikingly conserved across lineages, revealing strong evolutionary constraints on tDNA dosage. Angiosperm tDNAs exhibit coordinated enrichment of cis-regulatory elements involved in RNA polymerase III transcription, including expanded AT-rich upstream regions, positional enrichment of CAA motifs, and extended poly(T) termination stretches. At the chromosomal scale, tDNAs are predominantly dispersed along chromosome arms, with homogeneous spacing that scales with genome size, while also showing non-random chromosomal distribution, exclusion from centromeric regions, and occasional clustering. Together, these patterns reveal conserved yet lineage-specific principles governing nuclear tDNA organization in plants and highlight how multiple genomic constraints shape the evolution of nuclear tDNA repertoires.
    Keywords:  RNA polymerase III; centromeres; chromosomal organization; cis‐regulatory elements; comparative genomics; photosynthetic eukaryotes; tRNA gene clusters; tRNA gene dosage; tRNA genes
    DOI:  https://doi.org/10.1111/tpj.71075
  27. J Proteome Res. 2026 Aug 07. 25(8): 4005-4017
    Novel Insights into the Human Hsc70 Structure by Cross-Linking Mass Spectrometry and Molecular Modeling.
    Aleksandr Melikov, Vsevolod Viliuga, Daniel Kavan, Zdeněk Kukačka, Matthias P Mayer, Petr Novák.
      Heat shock cognate protein 70 (Hsc70) is a 71 kDa molecular chaperone belonging to the Hsp70 family of heat shock proteins. These proteins act as ATP-dependent molecular machines that assist protein folding under both physiological and stress conditions such as hypoxia, heat shock, and pH fluctuations. In addition to general chaperone functions, Hsc70 performs specialized roles, including uncoating clathrin-coated vesicles, facilitating protein transport into organelles, and targeting proteins for lysosomal degradation. Members of the Hsp70 family are known to form dimers and higher oligomers, but the structural organization and functional relevance of these assemblies remain poorly understood. Earlier studies also suggested that J-domain proteins (JDPs) can promote Hsp70 dimerization. In this study, we used chemical cross-linking, high-resolution Fourier transform mass spectrometry (FTMS), 15N isotopic labeling, and advanced data analysis to investigate the structural organization of Hsc70 dimers. Cross-link-derived distance restraints enabled structural modeling of Hsc70 monomers and dimers using AlphaLink2. Our results reveal distinct ATP- and ADP-state dimer conformations that coexist in equilibrium. In the presence of the cochaperone DnaJB1, we observed a shift in the dimer-monomer equilibrium, accompanied by enhanced ATP hydrolysis and formation of intermediate species. These findings demonstrate that the Hsc70 dimer population is structurally heterogeneous and depends on nucleotide state and cochaperone interactions.
    Keywords:  Hsc70; chaperone; homo-oligomerization; mixed isotope cross-linking; protein folding; structural mass spectrometry
    DOI:  https://doi.org/10.1021/acs.jproteome.6c00037
  28. Front Immunol. 2026 ;17 1848357
    Circular RNAs in cervical cancer: from ceRNA networks to epitranscriptomic regulation, immune modulation, and metastatic reprogramming.
    Heying Huang, Lifeng Liu, Yuemei Cui, Fanchen Zhou, Jing Liu, Qianying Chen, Zhengyan Li, Bing Liu.
      Cervical cancer progression is driven not only by persistent high-risk human papillomavirus infection but also by multilayered post-transcriptional regulatory networks that reshape tumor cell behavior and the tumor microenvironment. Among these regulators, circular RNAs (circRNAs) have emerged as pivotal modulators of oncogenic signaling. Initially characterized as competing endogenous RNAs (ceRNAs), circRNAs were shown to promote cervical cancer growth, invasion, and chemoresistance by derepressing key oncogenic targets. However, recent evidence expands this paradigm, revealing that circRNAs are subject to epitranscriptomic modification and function as dynamic scaffolds integrating RNA-binding proteins, translational machinery, inflammatory signaling, and metabolic pathways. In cervical cancer, m6A-dependent regulation and reader-mediated translational control enhance circRNA stability and amplify oncogenic outputs, linking RNA modification to metabolic reprogramming and hypoxia adaptation. Concurrently, circRNAs modulate inflammatory cascades such as IL6/JAK/STAT3 and NF-κB, contributing to immune suppression and tumor microenvironment remodeling. These tumor-intrinsic and immune-extrinsic mechanisms converge on metastatic reprogramming, enabling lipid metabolic flexibility, lymphangiogenesis, autophagy activation, and therapeutic resistance. This review synthesizes current evidence to propose a unified regulatory landscape in which circRNAs function as central nodes connecting ceRNA circuits, epitranscriptomic modulation, immune signaling, and metabolic plasticity. Unlike previous reviews that primarily summarized circRNA-mediated ceRNA networks, canonical oncogenic pathways, or biomarker potential, this review adopts a systems-level perspective and critically integrates epitranscriptomic regulation, RNA-binding protein interactions, immune-inflammatory signaling, metabolic plasticity, and metastatic reprogramming. We further distinguish directly validated cervical cancer mechanisms from emerging or hypothetical regulatory layers, thereby providing a clearer conceptual framework for future mechanistic and translational studies.
    Keywords:  cervical cancer; circular RNAs; epitranscriptomic regulation; immune modulation; metastatic reprogramming
    DOI:  https://doi.org/10.3389/fimmu.2026.1848357
  29. J Pept Sci. 2026 Sep;32(9): e70118
    No Significant Secondary Structural Change of α-Synuclein Monomer by Site-Specific DOPA or Phosphorylation Introduction in Its C-Terminal Region.
    Tatsuhito Matsuo, Isao Suetake, Mariko Kimura, Satoshi Hashimoto, Koichi Matsuo, Sakiko Matsumoto, Shinji Hirotsune, Hironobu Hojo.
      α-Synuclein (αSyn) is a major component of pathogenic Lewy bodies and Lewy neurites and is closely associated with Parkinson's disease. Among the various posttranslational modifications of αSyn, several have been implicated in the degeneration of dopaminergic neurons and are thought to promote Parkinson's disease through enhanced misfolding, aggregation, and accumulation of αSyn. Two such modifications, phosphorylation at Ser129 (S129Phos) and hydroxylation at Tyr136 (Y136DOPA), exert distinct effects on αSyn aggregation: S129Phos has been reported to either inhibit or promote aggregation, whereas Y136DOPA induces the formation of short oligomeric species. To gain insight into the molecular basis underlying the initiation of αSyn multimerization, we semisynthesized αSyn carrying either S129Phos or Y136DOPA and prepared recombinant unmodified full-length αSyn as a control. Vacuum-ultraviolet circular dichroism (VUVCD) spectroscopy revealed that these αSyn variants in their monomeric states possessed essentially identical secondary structures. These results suggest that the modifications themselves do not induce significant secondary structural changes in monomeric αSyn.
    DOI:  https://doi.org/10.1002/psc.70118
  30. Mar Pollut Bull. 2026 Aug 06. pii: S0025-326X(26)00986-0. [Epub ahead of print]233(Pt 1): 120199
    HSP70CA2 is associated with cytoskeletal, membrane repair, and chaperone responses during acute heat shock in Urechis unicinctus.
    Dawei Lin, Yuxin Feng, Wenwen Jiang, Ying Lu, Wenqing Zhang, Long Zhang, Zhifeng Zhang, Yubin Ma.
      Heat shock proteins (HSPs) are essential for cellular homeostasis and thermal adaptation, yet their interaction networks and regulatory mechanisms under high temperature stress remain largely unexplored in aquatic organisms. Here, the expression profiles of HSPs in Urechis unicinctus under high temperature stress were systematically characterized. Among 85 identified HSPs, a member of the HSP70 family, HSP70CA2, was selected for further study due to its sustained and significant differential expression. Sequence analysis revealed that HSP70CA2 has an open reading frame (ORF) of 1917 bp, encoding a 638 amino acid protein. Western blotting confirmed a rapid and significant increase in HSP70CA2 protein levels in both body wall and midgut tissues during early high temperature stress, indicating its active involvement in the initial stress response. Crucially, five novel interacting proteins of HSP70CA2 were screened and identified as cytoskeletal (CIFP), membrane repair (ANXA7), ER-associated (CRT-like), and chaperone (HSP90A1, HSPA8) factors by pull-down assays coupled with LC-MS. These interactions were validated by point to point yeast two-hybrid assays. Our findings suggest that HSP70CA2 acts as an early chaperone related responder associated with cytoskeletal maintenance, membrane repair, and protein folding processes during the acute heat shock response in U. unicinctus. This study provides new evidence for the involvement of a single HSP70 member in multiple cellular protective processes in an aquatic invertebrate, offering fundamental insights into thermal stress adaptation and a potential target for thermotolerance breeding.
    Keywords:  HSP70CA2; High temperature stress; Multi-pathway protective network; Urechis unicinctus
    DOI:  https://doi.org/10.1016/j.marpolbul.2026.120199
  31. Nucleic Acids Res. 2026 Jul 17. pii: gkag755. [Epub ahead of print]54(14):
    MiaA-mediated tRNA modifications couple tryptophan attenuation and changes in tRNA abundance to complex phenotypes in Pseudomonas aeruginosa.
    Yannick N Frommeyer, Janne G Thöming, Nicolas O Gomez, Svenja Grobe, Matthias Preusse, Alejandro Arce-Rodríguez, Kerstin Neubauer, Benedikt Kennepohl, Tim Kirk, Raimo Franke, Mark Brönstrup, Meina Neumann-Schaal, Mathias Müsken, Daniel P Depledge, Heike Bähre, Andreas Pich, Susanne Häussler.
      Transfer RNA (tRNA)-modifying enzymes are emerging as key regulators of bacterial physiology. MiaA, a tRNA isopentenyltransferase, is well studied in model organisms, but its role in the opportunistic pathogen Pseudomonas aeruginosa remains unclear. Using LC-MS, nanopore tRNA sequencing, as well as transcriptional, translational, and proteomic profiling, we mapped MiaA-dependent tRNA modifications and revealed unexpected effects of MiaA loss. Impaired translation of MiaA-sensitive codons reduced quorum-sensing-controlled virulence gene expression and attenuated pathogenicity in Galleria mellonella. Ribosome stalling at trp codons in miaA mutants overrides the attenuation-controlled repression of tryptophan biosynthesis, causing overproduction of tryptophan, along with upregulation of cognate tRNAs, thereby linking translation to global metabolic adaptation. MiaA is tightly regulated and is so central to bacterial physiology that its expression level correlates directly to virulence in clinical isolates, highlighting its role as a hub connecting translation, transcription, metabolism, and pathogenicity. These findings position MiaA as a key integrator of cellular processes critical for pathogen fitness and host interactions.
    DOI:  https://doi.org/10.1093/nar/gkag755
  32. J Biol Chem. 2026 Aug 05. pii: S0021-9258(26)02267-2. [Epub ahead of print] 113395
    The Evolutionarily-conserved C-terminal tail of the Dib1 Protein is Required for Spliceosome Efficacy and Dib1 Protein Stability.
    Bryce Dye, Richard Dunn, Kathryn Wheeler, Grace Lee, Nicholas Pittner, Corina Maeder.
      The spliceosome catalyzes pre-messenger RNA splicing by facilitating two transesterification reactions that excise introns and ligate exons together. To accomplish this process, the spliceosome assembles and rearranges its components through a series of sequentially regulated steps. A key step in this pathway is the transition to the catalytically active Bact complex. In the course of its catalytic activation, the spliceosome must release Dib1, an essential, conserved 143 amino acid protein that resides in the U4/U6-U5 tri-snRNP complex. However, the mechanism of Dib1 departure is not fully characterized. To further this understanding, this study determined the importance of the flexible C-terminus of Dib1 in the spliceosome. The C-terminus of Dib1 sits in proximity to the catalytic regions of both U5 and U6 snRNAs and interacts with Prp8 and Prp31 in the spliceosome. We find that the length of Dib1's C-terminus is critical for the stability of the protein and its removal results in loss of cell viability and splicing capabilities. Additionally, we have identified residues in Dib1's C-terminal tail that we postulate are part of stabilizing protein-protein interactions in the spliceosome, including key areas between Dib1 and Prp8. Together, these findings further our understanding of a critical step in spliceosome assembly and activation.
    Keywords:  RNA splicing; U5 snRNP; mRNA; protein stability; ribonuclear protein (RNP); spliceosome; spliceosome assembly
    DOI:  https://doi.org/10.1016/j.jbc.2026.113395
  33. Dokl Biochem Biophys. 2026 Aug 03.
    Local RNA Structure, not Primary Sequence, Governs the Binding Specificity of PCID2 in Drosophila melanogaster.
    Y A Vdovina, S G Georgieva, D V Kopytova.
      Nuclear export of mRNA is one of the key stages of gene expression in eukaryotes. A wide range of mRNAs is exported by the TREX-2 complex, which includes the PCID2 RNA-binding protein. Previously, we showed that PCID2 is responsible for specific recognition of transcripts, and we identified its binding site on the Drosophila ras2 gene mRNA within the 3'-non-coding region. However, the interaction was not localized for other mRNAs, which makes it impossible to identify the general patterns of PCID2 interaction with mRNA. In this work, we investigated the interaction of PCID2 with the mRNA of the kruppel gene of Drosophila melanogaster. In the EMSA experiments, we showed that PCID2 binds to two fragments of kruppel mRNA, from the 5' non-coding and coding mRNA regions. Thus, the PCID2 binding site can be located not only in the 3'-non-coding region, as in the case of the ras2 mRNA, but also in other mRNA regions. PCID2 has a lower affinity for binding sites in the kruppel mRNA than in the ras2 mRNA. Our analysis of the mRNA structure at three binding sites led to a general interaction model, in which a hairpin-type conformation emerges as the most probable structural motif at these sites.
    Keywords:  EMSA; PCID2; mRNA export
    DOI:  https://doi.org/10.1134/S1607672926600399
  34. Microbiol Mol Biol Rev. 2026 Aug 06. e0001726
    Translation factors that keep the ribosome Pro-active.
    Heather A Feaga.
      SUMMARYRibosomes produce the staggering array of proteins that perform the structural and enzymatic feats of the cell. Therefore, most of the cell's energy goes toward producing ribosomes and the work performed by them. The work of the ribosome is relatively simple-decode mRNA codons and catalyze the formation of peptide bonds. By marching iteratively along the length of an open reading frame, a complete peptide is produced. Ribosomes catalyze the formation of peptide bonds at a rate of approximately 15 amino acids per second. However, bonds between amino acids do not form with equal efficiency, and ribosomes can become stalled at difficult-to-translate sequences. Proline is unique among the amino acids in that its side chain is covalently bonded to the peptide backbone to form a rigid ring. The rigidity of proline, and especially tracts of proline, makes it a difficult substrate for peptide bond formation, but it is also an essential motif in many protein structures. Elongation factor P (EF-P) is the star player for facilitating translation of polyproline tracts. However, recently identified factors play an important supporting role, and loss of these factors incurs a severe fitness defect in the absence of EF-P. These factors include an EF-P paralog, EfpL, as well as the ABCF ATPase YfmR/Uup and YebC2. The abundance and partial redundancy of factors that prevent ribosome stalling at polyprolines highlights the structural importance of polyproline tracts and the need to facilitate their translation. Here, we review recently identified translation factors that prevent ribosome stalling at polyprolines in bacteria.
    Keywords:  bacteria; ribosome; translation
    DOI:  https://doi.org/10.1128/mmbr.00017-26
  35. J Chem Phys. 2026 Aug 07. pii: 055101. [Epub ahead of print]165(5):
    Potential structure induced effects of the hairpin motif in RNA to form the phase separated droplet like associate in different solution condition.
    Manas Mondal, Maodong Li, Yi Qin Gao.
      Reversible associations of RNAs among themselves, or with RNA binding proteins through the process of phase separation, are found to be important in many different cellular contexts, including cellular responses to stress, gene regulation, development, and disease. Short RNA repeat sequences, which are mostly linked with many repeat expansion neurodegenerative diseases, are found to undergo phase separation and yield protein-free biomolecular condensates in vitro and in cells. However, the physicochemical principles governing phase separation of RNAs considering both sequence and structural aspects, especially for short RNAs, remain elusive. It is intriguing, as well as challenging, to characterize the RNA phase behavior at a submolecular resolution. Based on atomistic enhanced sampling simulations, here we report potential dynamic structural effects in the mutual association properties of a tetra loop containing 14-mer hairpin RNA. We show that the folded and unfolded conformations of the hairpin fragment lead to different energetic barriers for the formation of an associated pair. Unfolded conformation leads to the formation of gel like energetically stable associated phases spontaneously; the folded hairpin motif is found to yield droplet like associated phases accompanying by cations in solution. Overall, our findings illustrate that dynamic association/dissociation is energetically more favorable for folded RNA hairpins, and the presence of additional salt in solution assists the formation of dense droplet like associated phases, while ionic concentration plays a critical role in the formation and stability of the droplet like associated phase. These observations open avenues for exploring structure-based phase separation mechanisms of RNAs in the context of RNA mediated functional biomolecular condensate formation within cells and designing RNA based novel biomaterials.
    DOI:  https://doi.org/10.1063/5.0334014
  36. J Proteome Res. 2026 Aug 07. 25(8): 3965-3986
    Profiling of Yeast Saccharomyces cerevisiae Mitochondrial AMPylome Reveals a Regulation of OXPHOS Coupling through ATP Synthase Subunit Delta.
    Chiranjit Panja, Aneta Wiesyk, Suchismita Masanta, Katarzyna Niedzwiecka, Emilia Baranowska, Dominik Cysewski, Marta Sipko, Anna Anielska-Mazur, Agata Malinowska, Roza Kucharczyk.
      Protein adenylation (AMPylation) is a post-translational modification in which an adenosine monophosphate (AMP) group is covalently attached to target proteins by AMPylases using ATP as a donor. In metazoans, two conserved AMPylase families are known: FIC-domain proteins and SelO. The yeast Saccharomyces cerevisiae lacks a FIC-domain enzyme; its only known AMPylase is the mitochondrial SelO homologue, Fmp40, involved in redox signaling. We conducted the first comprehensive screen for AMPylated proteins in the mitochondrial proteome of S. cerevisiae analyzing both wild-type and fmp40Δ cells using quantitative mass spectrometry. We identified 124 AMPylated mitochondrial proteins in wild-type and 41 in fmp40Δ mitochondria, suggesting the existence of additional AMPylase(s) in yeast. Among the modified targets, seven ATP synthase subunits were AMPylated, many at sites also phosphorylated, underscoring complex PTM regulation of the enzyme. We demonstrated that substitutions of one such residue, serine 29 in the δ subunit (Atp16), to alanine or glutamic acid, altered ATP synthase activity and oxidative phosphorylation coupling under both fermentative and respiratory conditions. This regulation is crucial for maintaining mitochondrial membrane potential. Our study provides the first catalog of AMPylated mitochondrial proteins in yeast, establishing a foundation for future studies on mitochondrial AMPylation.
    Keywords:  AMPylation; ATP synthase; Fmp40; mitochondria; yeast
    DOI:  https://doi.org/10.1021/acs.jproteome.5c01273
  37. J Yeungnam Med Sci. 2026 ;43 51
    Vitamin B deficiency and sarcopenia: an integrated narrative review of metabolic, inflammatory, endoplasmic reticulum stress, and myokine signaling pathways.
    Kisang Kwon, Sangmin Lee, Jenny Kwon, Seung Whan Kim.
      Sarcopenia is an age-related skeletal muscle disorder characterized by progressive decline in muscle mass, strength, and physical performance, leading to frailty, disability, falls, and increased mortality. Although its pathogenesis is multifactorial, growing evidence indicates that vitamin B complex deficiency contributes to muscle deterioration through interconnected metabolic and signaling pathways. This narrative review summarizes current evidence regarding the roles of B vitamins in skeletal muscle biology and their potential contribution to sarcopenia. Vitamin B deficiency impairs mitochondrial energy metabolism by reducing cofactor availability and adenosine triphosphate production, thereby increasing oxidative stress and chronic inflammation. These disturbances may trigger endoplasmic reticulum stress and the integrated stress response, leading to activating transcription factor 4 (ATF4)-dependent induction of growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21) expression. Collectively, these changes disrupt protein homeostasis, suppress anabolic signaling, impair neuromuscular function, and alter myokine secretion by reducing anabolic mediators while increasing catabolic and inflammatory myokines, thereby accelerating muscle loss and functional decline. Current evidence is the strongest for vitamins B6, B9, and B12, whereas mechanistic and clinical data for B2, B3, B5, and B7 remain limited. Overall, vitamin B deficiency can be viewed as a modifiable biological contributor to sarcopenia. Well-designed prospective studies and randomized clinical trials are required to clarify causality, validate biomarkers, and determine whether targeted vitamin B supplementation can enhance exercise- and nutrition-based strategies for preserving muscle health in older adults.
    Keywords:  Muscle protein metabolism; Myokines; Older adults; Sarcopenia; Vitamin B complex
    DOI:  https://doi.org/10.12701/jyms.2026.43.51
  38. PLoS One. 2026 ;21(8): e0355681
    Dual regulatory mechanisms of YGP1 expression in response to glucose availability in Saccharomyces cerevisiae.
    Megumi Sato, Kaoru Irie, Yasuyuki Suda, Tomoaki Mizuno, Kenji Irie.
      Cells adapt to fluctuating nutrient conditions by dynamically regulating gene expression, ensuring survival under stress. Ygp1, a secretory yeast glycoprotein, is one such gene that is induced by nutrition deprivation, particularly glucose starvation. In this study, we investigated the regulatory mechanisms underlying nutrition-deprivation-responsive changes in gene expression, focusing on YGP1 expression. Under glucose-rich conditions, YGP1 expression was positively regulated by the RNA-binding protein Puf5, a member of the Puf family. This regulation ensured rhythmic YGP1 expression during M phase of the cell cycle. The Puf5-mediated control targeted a specific 60-nucleotide region in the YGP1 promoter (-600 to -540 from the start codon), and this regulation was partly mediated by the acid stress-responsive transcriptional activator Haa1. In addition, upon glucose exhaustion (diauxic shift), YGP1 expression was strongly induced by the stress-responsive transcription factors Msn2 and Msn4 through the stress-response elements in the YGP1 promoter. Further analysis of the physiological significance of YGP1 expression revealed that the Puf5-mediated regulation contributes to the acid stress responses, and YGP1 expression supports cell survival in the puf5Δ background. In summary, YGP1 expression is regulated by two distinct factors in a glucose availability-dependent manner: Puf5 under glucose-rich conditions and the Msn2/Msn4 during glucose starvation. Especially, Puf5-mediated regulation contributes to the acid stress responses and subsequently supports long-term cell survival.
    DOI:  https://doi.org/10.1371/journal.pone.0355681
  39. Nature. 2026 Aug 05.
    ZFP36L2 orchestrates stress-adaptive plasticity in regeneration and cancer.
    Qingwen Jiang, Manisha S Raghavan, Aileen M Rodriguez, Morgan Lallo, Cyrus L Tam, Saskia Hartner, Britney Forsyth, Ahmed Mahmoud, Fabian Zincke, Huiyong Zhao, Andrew Moorman, Sasha Balkaran, Kathleen Luckett, Jura Pintar, Yevgeniy Romin, Eric Chan, Anthony Santella, Bernadette Mödl, Farheen Shah, Ilyes Baali, Michael G Kharas, Elisa de Stanchina, Nil Urganci, Jinru Shia, Dana Pe'er, Francisco Sanchez-Vega, Richard Koche, Quaid Morris, Joseph M Chan, Karuna Ganesh.
      Phenotypic plasticity is a hallmark of cancer1; however the molecular switches required for cell-fate reprogramming are poorly understood. During intestinal wound-healing and colorectal cancer (CRC) metastasis, differentiated cells can dynamically dedifferentiate into an intestinal stem cell (ISC) state to drive epithelial regeneration and metastatic outgrowth2-10. Here we show that the RNA-binding protein ZFP36L2, which is mutated in 5-10% of CRC11-15, is a pivotal stress-responsive orchestrator of dynamic dedifferentiation. In mouse colon regeneration models, ZFP36L2 ablation inhibits dedifferentiation, ISC gene expression and function and impairs intestinal regeneration. In human CRC, loss of ZFP36L2 function abrogates metastatic seeding and the outgrowth of LGR5+ canonical metastases while promoting lineage plasticity and non-canonical differentiation into heterogeneous cell states. Mechanistically, ZFP36L2 binds to stress-associated mRNAs that contain AU-rich 3' untranslated regions, which induces the formation of dynamic biomolecular condensates associated with mRNA degradation and termination of the stress response. Together, these data show that ZFP36L2 acts as an important molecular switch that couples stress sensing with phenotypic plasticity. This in turn drives cellular dedifferentiation essential for re-establishing the ISC state during wound healing and metastasis. In ZFP36L2-deficient CRC, the inability to re-enter the LGR5+ state during metastatic outgrowth promotes non-canonical lineage plasticity, which is associated with poor clinical outcomes.
    DOI:  https://doi.org/10.1038/s41586-026-10890-0
  40. Microlife. 2026 ;7 uqag027
    The CRISPR/Cas-associated scaRNA modulates efeUOB expression and stress responses in Neisseria meningitidis.
    Denise Pytlik, Milan Gerovac, Thorsten Bischler, Andreas Schlosser, Jörg Vogel, Christoph Schoen.
      Neisseria meningitidis is a human-adapted commensal pathogen that must continuously balance nutrient acquisition with stress tolerance. Here, we identify a type II-C CRISPR/Cas-associated small RNA (scaRNA) as a posttranscriptional regulator of the efeUOB operon and oxidative stress responses. Using in vitro RNA binding and structure probing assays, we show that the scaRNA interacts with the 5' untranslated region of efeO mRNA, leading to reduced translation of this component of the ferrous iron transporter EfeUOB. Consistent with this, efeO translational fusions demonstrate repression by the scaRNA, whereas a ΔscaRNA mutant shows increased reporter expression. We further show that meningococcal Cas9 (Nme1Cas9) is able to cleave scaRNA in vitro, but in vivo phenotypes are primarily scaRNA-dependent, indicating that Nme1Cas9 contributes, at most, indirectly to this regulation. In line with this observation, comparative proteomics revealed overlapping but distinct roles of scaRNA and Nme1Cas9 in oxidative stress adaptation, energy metabolism, and ion transport. While steady-state protein abundances did not capture all scaRNA-dependent effects, functional assays confirmed that scaRNA inactivation reduces survival under oxidative stress. Together, our results identify scaRNA-mediated repression of efeO as a novel posttranscriptional mechanism that contributes to stress adaptation in meningococci. These findings expand the functional repertoire of CRISPR-associated elements and suggest a role for small RNA-based regulation in iron-related stress adaptation in a major human pathogen.
    Keywords:  CRISPR/Cas; Neisseria meningitidis; iron; oxidative stress; scaRNA; virulence
    DOI:  https://doi.org/10.1093/femsml/uqag027
  41. Mol Cell Biochem. 2026 Aug 07.
    METTL3 promotes proliferation and invasion and inhibits ferroptosis in hepatocellular carcinoma by mediating m6A methylation modification of NUPR1.
    Yushan Zhao, Zhiyu Nan, Haojie Feng, Dong Wang.
      N6-methyladenosine (m6A) methylation modification plays an essential role in cancer development. This study focused on the mechanism exploration of m6A methyltransferase 3 (METTL3) and its downstream target gene nuclear protein-1 (NUPR1) in hepatocellular carcinoma (HCC). Detection of mRNA and protein was completed using real-time quantitative polymerase chain reaction and Western blot. Cellular behaviors were evaluated by CCK-8, EdU, flow cytometry and transwell assay. Ferroptosis was analyzed via Fe2+ level and oxidative indicators. Methylated RNA immunoprecipitation (MeRIP) was performed for validating m6A modification. RIP and dual-luciferase reporter assay were used to confirm METTL3 and NUPR1 combination. Animal research was implemented for METTL3 and NUPR1 analysis in vivo. METTL3 was overexpressed in HCC. METTL3 silencing suppressed HCC cell proliferation and invasion, while enhancing apoptosis and partially inducing ferroptosis. METTL3 downregulation reduced NUPR1 level. METTL3 induced m6A modification of NUPR1 in an IGF2BP2-dependent manner. Tumor-inhibitory effects of METTL3 knockdown were counteracted by NUPR1 overexpression. METTL3 promoted HCC tumor growth and suppressed ferroptosis in vivo by regulating NUPR1. These findings suggested that METTL3 facilitated cell invasion and partially inhibited ferroptosis through catalyzing m6A methylation modification of NUPR1, validating the specific regulatory axis METTL3/NUPR1 in HCC progression.
    Keywords:  Hepatocellular carcinoma; Methyltransferase 3; N6-methyladenosine (m6A) methylation; Nuclear protein-1
    DOI:  https://doi.org/10.1007/s11010-026-05679-8
  42. Mol Biol Cell. 2026 Aug 05. mbcE26030142
    Centriolar satellites regulate CEP350 mRNA stability and centrosome amplification.
    Abraham Martinez, Chad G Pearson.
      Messenger RNAs (mRNAs) accumulate at centrosomes in mitosis and interphase, yet the mechanisms governing their localization and their functional significance remain poorly understood. Here, we identify a centriolar satellite - RNA-binding protein (RBP) pathway that regulates CEP350 mRNA localization and stability to support centriole overduplication. We find that CEP350 mRNA localizes to centrosomes in S phase in a microtubule (MT)-dependent manner. The RBP, UNK and centriolar satellite protein, CEP131 stabilize CEP350 mRNA and promote its steady-state levels and centrosomal protein accumulation. CEP350 is required for PLK4-induced centriole overduplication but has limited effects on canonical centriole duplication. Disrupting the centriolar satellite - RBP pathway reduces centriole overduplication in triple-negative breast cancer cells, indicating CEP131 and UNK are potential therapeutic targets for reducing centriole overduplication.
    DOI:  https://doi.org/10.1091/mbc.E26-03-0142
  43. Circ Res. 2026 Aug 07.
    CDK5RAP3-Mediated Mitochondrial RQC Alleviates Pathological Cardiac Hypertrophy.
    Yazhi Peng, Wenwen Cai, Tailai Du, Yi Zheng, Yiling Yao, Gang Dai, Jialing Wu, Yan Li, Jiangui He, Yugang Dong, Jing-Song Ou, Chen Liu, Xin He, Zhan-Peng Huang.
       BACKGROUND: Recent studies have revealed heterogeneity among ribosomes. Pathological cardiac hypertrophy is characterized by profound alterations in translation. However, how ribosome heterogeneity contributes to this process remains largely unclear.
    METHODS: We used translating ribosome affinity purification coupled with mass spectrometry to profile ribosome-interacting proteins. Cardiomyocyte-specific gene manipulation was achieved through either genetic knockout or adeno-associated virus-mediated overexpression. Pathological cardiac hypertrophy was induced by transverse aortic constriction surgery in vivo and by phenylephrine stimulation in vitro.
    RESULTS: The cardiomyocyte-specific ribosome proteomics indicated dynamic alterations in ribosome-interacting proteins during pathological hypertrophy. Notably, multiple proteins associated with ribosome stalling were detected in the ribosome-interactome of hypertrophic hearts. Among these, we verified that CDK5RAP3 (CDK5 regulatory subunit-associated protein 3) exhibited the most specific ribosome binding in hypertrophic hearts. CDK5RAP3 was upregulated and recruited to ribosomes during pathological hypertrophy. It promoted RPL26 (ribosomal protein L26) UFMylation and ribosome-associated quality control on the mitochondrial surface. In vitro, CDK5RAP3 knockdown exacerbated cardiomyocyte hypertrophy induced by phenylephrine, whereas its overexpression attenuated it. In vivo, cardiomyocyte-specific CDK5RAP3 knockout promoted, while adeno-associated virus-mediated overexpression suppressed pathological cardiac hypertrophy induced by transverse aortic constriction. Mechanistically, ribosome stalling on the mitochondrial surface was exacerbated in hypertrophic hearts of both humans and mice, which was associated with impaired mitochondrial protein import. CDK5RAP3 enhanced ribosome-associated quality control, alleviated ribosome stalling, and restored mitochondrial protein import, thereby improving mitochondrial function. Notably, mitochondrial import of PDP1 was maintained by CDK5RAP3-mediated ribosome-associated quality control. Knockdown of PDK (pyruvate dehydrogenase kinase) 1/2, functional antagonists of PDP1, reversed cardiomyocyte hypertrophy caused by CDK5RAP3 deficiency.
    CONCLUSIONS: This study identifies CDK5RAP3-mediated ribosome-associated quality control on the mitochondrial surface as a critical protective mechanism that preserves protein import and mitochondrial function during pathological cardiac hypertrophy.
    Keywords:  cardiomegaly; endoplasmic reticulum; heart failure; mitochondria; pyruvate kinase
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.328184
  44. Cancer Sci. 2026 Aug 04.
    tRNA-Derived Small RNAs in Digestive Cancers: From Translational Regulation to Immune and Extracellular Communication.
    Wang Xitan, Li Han.
      Transfer RNA-derived small RNAs (tsRNAs), comprising tRNA-derived fragments (tRFs) and stress-induced tRNA halves (tiRNAs), have increasingly been recognized as an important regulatory class in gastric cancer (GC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), and pancreatic cancer/pancreatic ductal adenocarcinoma (PC/PDAC). Research in this field has expanded from expression profiling and liquid biopsy to non-canonical translational control, metabolic adaptation, therapy resistance, immune-associated remodeling, and extracellular-vesicle (EV)-related communication. The most intensively studied and mechanistically developed area currently lies at the intracellular level. In digestive system tumors, tsRNAs can act through EIF4 displacement, AGO2/RISC-dependent silencing, direct target repression, and ribosome-associated interactions, with some of these mechanisms validated in animal models. Beyond direct regulation of gene expression, tsRNAs can also influence tumor metabolic state and thereby contribute to chemo- and radio-resistance. By contrast, studies directly examining the effects of tsRNAs on immune-cell populations remain relatively limited, and work on EV-mediated systemic propagation still largely focuses on vesicle association and biomarker value. Functional delivery and recipient-cell effects require further clarification. Among the currently summarized studies, pancreatic-derived signaling that conditions the hepatic niche represents one of the few examples approaching a cross-organ functional model. This review discusses the major functional layers of tsRNAs in digestive system tumors, beginning with the relatively mature intracellular mechanisms and then extending to emerging immune, extracellular/systemic, and host-microbe research. We also identify key unresolved problems, including nomenclature standardization, modification-aware sequencing, criteria for EV functional delivery, causal validation of microbiota-derived tsRNAs, and prospective biomarker validation against benign and inflammatory disease controls.
    Keywords:  colorectal cancer; extracellular vesicles; gastric cancer; hepatocellular carcinoma; liquid biopsy; pancreatic cancer; tRF; tRNA halves; tRNA‐derived small RNAs; tumor microenvironment
    DOI:  https://doi.org/10.1111/cas.70494
  45. J Pineal Res. 2026 Sep;78(5): e70158
    Promoter-Level Regulation of Melatonin Biosynthesis in Plant Stress Responses: A Framework for Climate-Resilient Crop Improvement.
    Muhammad Hafeez Ullah Khan, Ali Muhammad, Lijie Li, Daijing Zhang, Meixue Zhou, Baohong Zhang, Zhiyong Zhang, Quanyong Liu.
      Climate change increasingly exposes crops to overlapping abiotic and biotic stresses, creating a need for regulatory strategies that improve stress tolerance without imposing unnecessary fitness costs under favorable conditions. Melatonin has been widely associated with plant responses to drought, salinity, temperature extremes, oxidative stress, and pathogen challenge, where it contributes to redox balance, hormone crosstalk, and stress-responsive gene regulation. However, the benefits of melatonin appear to depend strongly on when, where, and to what extent it is produced. In this review, we examine melatonin biosynthesis and function from a promoter-centered perspective, focusing on how stress-associated signals may regulate the core biosynthetic genes TDC, T5H, SNAT, and ASMT/COMT across tissues and stress contexts. Because direct functional validation of specific promoter architectures in plant melatonin biosynthesis genes remains limited, this review presents the promoter-centered model as a hypothesis-generating framework rather than a fully established regulatory mechanism. Here, we argue that the melatonin-mediated stress tolerance depends primarily on regulated, context-dependent pathway activation rather than constitutive pathway enhancement. We therefore discuss how current knowledge of stress signaling, cis-regulatory organization, and genome editing can be used to frame future efforts in promoter engineering of melatonin biosynthesis genes. Throughout, we distinguish established findings from forward-looking hypotheses and highlight key experimental questions that must be addressed before these concepts can be translated into crop improvement.
    Keywords:  cis‐regulatory control; climate‐resilient crops; melatonin biosynthesis; promoter editing; stress memory; stress‐responsive promoters
    DOI:  https://doi.org/10.1111/jpi.70158
  46. Angew Chem Int Ed Engl. 2026 Aug 05. e3238473
    Generalizable Strategies for the Synthesis of Cereblon-Recruiting PROTAC Prodrugs.
    Aiden X Wang, Bin Liu, Elise M Ackerman, Yichen Xiang, Hung V-T Nguyen, Yivan Jiang, Angela N Koehler, Jeremiah A Johnson.
      Cereblon (CRBN)-recruiting PROTACs (proteolysis-targeting chimeras) are among the most clinically advanced degraders but remain challenging to chemically modify for translation to prodrug-based delivery strategies. Here, we report three orthogonal approaches-triazole quaternization, tertiary-amine alkylation, and installation of a hydroxyl linker-that enable chemoselective, high-yielding syntheses of CRBN-recruiting PROTAC prodrugs. These strategies allow incorporation of self-immolative linkers whose cleavage kinetics can be predictably tuned to release the parent PROTAC, which is demonstrated in the context of PEGylated macromonomer and bottlebrush prodrug macromolecular scaffolds. In multiple myeloma models, representative PROTAC-bottlebrush prodrugs (PROTAC-BPDs) induce cellular potency profiles that follow the designed PROTAC release rates, confirming that the observed protein degradation and cytotoxicity arise from effective prodrug linker cleavage. Collectively, this work establishes generalizable approaches for constructing prodrugs of CRBN-based PROTACs, expanding the synthetic space for targeted protein degradation and providing new design principles for controlling degrader activation, selectivity, and in vivo delivery.
    Keywords:   cytotoxicity; alkylation; cereblon; chemistry; combinatorial chemistry; linker; macromonomer; prodrug; protein degradation
    DOI:  https://doi.org/10.1002/anie.3238473
  47. Hum Cell. 2026 Aug 04. pii: 120. [Epub ahead of print]39(8):
    Exploring the role of CaMKII in exercise-induced cardioprotection.
    Yongchang Xu, Ziyu Liu, Xiaofeng Li.
      Regular physical exercise can induce a multifaceted cardioprotective phenotype characterized by improved Ca2⁺ handling, mitochondrial resilience, redox buffering, autonomic regulation, and resistance to ischemia-reperfusion injury. Ca2⁺/calmodulin-dependent protein kinase II (CaMKII), particularly cardiac CaMKIIδ, is positioned at the intersection of these adaptive and maladaptive responses because it couples repetitive Ca2⁺ oscillations to excitation-contraction coupling, ion-channel regulation, transcriptional remodeling, mitochondrial stress signaling, and cell-death pathways. Current evidence indicates that CaMKII is not intrinsically protective or harmful; rather, its biological output depends on activation magnitude, duration, post-translational modification, isoform or splice-variant composition, and subcellular localization. Within physiological exercise contexts, transient and compartmentalized CaMKII signaling may support rate adaptation, phospholamban phosphorylation, sarcoplasmic reticulum Ca2⁺ reuptake, and contractile reserve. In contrast, chronic oxidative, inflammatory, catecholaminergic, or metabolic stress promotes autonomous CaMKII activation, RyR2-mediated Ca2⁺ leak, late Na⁺ current, mitochondrial dysfunction, arrhythmogenesis, and adverse remodeling. Exercise training appears to normalize this pathological signaling environment by improving redox and metabolic homeostasis, mitochondrial quality control, nitric oxide bioavailability, and autonomic balance, while preserving physiological CaMKII-dependent cardiac reserve. In this review, we synthesize current evidence on CaMKII as a context-dependent mediator of exercise-induced cardioprotection and discuss its implications for cardiovascular disease mechanisms, biomarker development, exercise prescription, and selective CaMKII-targeted therapy.
    Keywords:  Calcium signaling; Calcium-calmodulin-dependent protein kinase type 2; Exercise; Myocardial ischemia; Myocardial reperfusion injury
    DOI:  https://doi.org/10.1007/s13577-026-01425-w
  48. Front Immunol. 2026 ;17 1861781
    Reader-dependent functional duality of FTO: a context-switching node at the intersection of immune evasion and therapeutic resistance.
    WenJie Tian, Bin Xie, Peng Zhan.
      The fat mass and obesity-associated protein (FTO), an RNA demethylase acting on both internal m6;A and cap-proximal m6;Am, functions in cancer as a context-dependent epitranscriptomic regulator whose net effect cannot be reduced to an oncogene-tumor-suppressor dichotomy. Its biological output is shaped by tumor lineage, subcellular localization, upstream signaling, and competing m6;A reader activities, predominantly YTHDF2-mediated decay and IGF2BP-mediated stabilization, although both reader families display additional non-canonical functions and are themselves modulated by post-translational modifications. Building on the now well-established context-dependence of FTO biology, which we do not claim as a novel observation, this review synthesizes current evidence on FTO's roles at the intersection of tumor immune contexture, immune checkpoint regulation, metabolic reprogramming, and therapeutic resistance. We examine how FTO may contribute to immune exclusion through metabolic competition, exosomal signaling, and stromal reprogramming; modulate PD-L1 expression through direct and indirect mechanisms; and influence response to chemotherapy, targeted therapy, radiotherapy, and CNS-directed treatment. Emerging FTO inhibitors, FTO-degraders, and combination strategies with immune checkpoint blockade, ferroptosis inducers, or glycolytic inhibitors are evaluated against their underlying preclinical evidence base. The contribution of this review lies less in proposing a new framework than in three forms of integration typically addressed in isolation: explicit calibration of mechanistic claims to evidence tier, systematic separation of tumor-intrinsic from immune-cell-intrinsic FTO functions across lymphoid and myeloid compartments, and translation of reader-network biology into biomarker-stratified trial design. Technical limitations of epitranscriptomic methods are addressed as constraints on inference. To our knowledge, no FTO-targeted strategy has yet entered Phase I oncology evaluation; current combination rationales therefore remain preclinically supported rather than clinically established.
    Keywords:  FTO; immune checkpoint regulation; metabolic reprogramming; therapeutic resistance; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1861781
  49. Cell Chem Biol. 2026 Aug 05. pii: S2451-9456(26)00279-5. [Epub ahead of print]
    An ER stress-responsive RNA rheostat for programmable gene and mRNA therapies.
    Roza Ogurlu, Eliya B Sanchez, Joshua A Hull, Sophia M Fergione, Vivian Yudistyra, Gabriela M Webb, Helen L Wu, Cleiton T Pessoa, Matthew C Humkey, Sofia K Potter, Alan Rosales, Heather A Vincent, Jonah B Sacha, Aravind Asokan.
      Therapeutic protein overexpression can overwhelm endoplasmic reticulum (ER) folding capacity, trigger unfolded protein response (UPR) signaling, and compromise the safety of gene and mRNA therapies. Here, we engineer stress-responsive RNA rheostats that couple transgene expression to endogenous ER stress sensing. Short RNA elements derived from X-box-binding protein 1 (XBP1) mRNA undergo inositol-requiring enzyme 1α (IRE1α)-dependent splicing under ER stress, inducing a frameshift that attenuates downstream protein expression. XBP1 switches function across DNA and mRNA delivery platforms and regulate the expression of fluorescent reporters, coagulation factor VIII, and Leronlimab, a therapeutic anti-CCR5 monoclonal antibody. Switch activation reduces ER stress markers while preserving expression under homeostatic conditions. We further demonstrate the regulation of Leronlimab expression in vivo using recombinant adeno-associated virus vectors. Together, these findings establish programmable RNA feedback control as a strategy for linking cellular proteostasis to therapeutic protein expression and improving the safety of gene and mRNA therapies.
    Keywords:  ER stress; RNA splicing; RNA switches; endoplasmic reticulum stress; gene therapy; mRNA therapy; protein overexpression; rheostat; unfolded protein response
    DOI:  https://doi.org/10.1016/j.chembiol.2026.07.006
  50. Mol Biol Rep. 2026 Aug 06. pii: 1351. [Epub ahead of print]53(1):
    eIF6 affects the occurrence and development of esophageal cancer.
    Cong-Gai Huang, Xin Zhou, Ran Huang, Hui-Ling Zhang, Chen-Xi Li, Fei Du, Hong Lei, Qiong Dai, Zhi-Hui Yang.
       OBJECTIVE: Esophageal cancer (EC) ranks 11th in incidence and 7th in mortality among malignancies globally. The role of eukaryotic translation initiation factor 6 (eIF6) in esophageal squamous cell carcinoma (ESCA) progression, including its involvement in tumor development, invasion, and epithelial-mesenchymal transition (EMT), remains to be fully characterized.
    METHODS: Bioinformatic and immunohistochemistry (IHC) analyses of 114 ESCA cases demonstrated eIF6 upregulation, which was associated with lower tumor differentiation. Elevated eIF6 expression in ESCA cell lines (KYSE150, TE-1) relative to normal esophageal epithelial cells (HEEC) was verified by reverse transcription-quantitative PCR and western blotting. eIF6 silencing via short hairpin RNA (shRNA) attenuated ESCA cell proliferation, migration, and colony formation in vitro, as assessed by Cell Counting Kit-8, wound healing, and Transwell assays.
    RESULTS: Bioinformatic analysis and IHC results showed that eIF6 protein was up-regulated in ESCC, and its expression level was inversely correlated with tumor differentiation degree. eIF6 knockdown was associated with reduced proliferation, migration, and colony formation of ESCC cells, accompanied by shifts in EMT markers, including increased E-cadherin and decreased N-cadherin and Vimentin levels. In addition, eIF6 depletion was accompanied by decreased phosphorylation of AKT (p-AKTSer473) and mTOR (p-mTOR), both key components of the PI3K/AKT/mTOR pathway.
    CONCLUSION: These findings indicate an association between eIF6 upregulation and ESCA aggressiveness, along with concomitant changes in the PI3K/AKT/mTOR signaling pathway.
    Keywords:  EMT; Esophageal cancer; Esophageal squamous cell carcinoma; Eukaryotic translation initiation factor 6; PI3K/AKT/mTOR
    DOI:  https://doi.org/10.1007/s11033-026-12268-x
  51. Science. 2026 Aug 06. 393(6811): 601-606
    A molecular switch for coordinating kinesin and dynein transport of mitochondrial cargo.
    Christina Gladkova, Maria G Paez-Segala, William P Grant, Mark Kittisopikul, Samuel A Myers, Yuxiao Wang, Ronald D Vale.
      The cellular distribution of mitochondria in response to stress and local energy needs is governed by the relative activities of the microtubule-based molecular motors kinesin and dynein. The mechanism for switching between these two opposite-polarity microtubule motors remains unknown. In this study, we coupled a cellular synthetic cargo transport assay with AlphaFold2-guided mutagenesis to identify a regulatory helix in the mitochondrial adaptor protein [trafficking kinesin-binding protein (TRAK)] that mediates switching between kinesin- and dynein-driven transport. Differences in the helix sequence explained why two near-identical TRAK isoforms transported mitochondria in predominantly opposite directions. Phosphorylation of the regulatory helix by stress-activated kinases caused the activation of dynein and dissociation of kinesin. Our results reveal a molecular mechanism for coordinating the directional transport of mitochondria in response to intracellular signals.
    DOI:  https://doi.org/10.1126/science.aeh1475
  52. Methods Mol Biol. 2026 ;3018 227-238
    Purification of Protein-Free and Protein-Linked Poly(ADP-Ribose) from Biochemical Reactions and from Human Cells.
    Marie-France Langelier, Manija Mirhasan, John M Pascal.
      Poly(ADP-ribose) or PAR regulates multiple aspects of cell biology, both as an independent signaling molecule and as a modification on biomolecules. As a posttranslational modification, PAR can modulate the biochemical properties of target proteins. Isolated free PAR molecules function in cellular signaling. This chapter describes two methods to isolate and purify free PAR and protein-linked PAR from biochemical reactions, one using chemical fractionation and another using physical separation. A method to isolate free PAR and protein-linked PAR from human cells is also presented. These methods allow monitoring of free PAR and protein-linked PAR levels under different biochemical conditions or in response to different cellular stimuli.
    Keywords:  Biochemical assays; Cellular analysis; Free PAR; PARP1; PARP2; Poly(ADP-ribose) (PAR); Protein-linked PAR; Tankyrases (TNKS)
    DOI:  https://doi.org/10.1007/978-1-0716-5166-7_15
  53. Comput Methods Programs Biomed. 2026 Aug 01. pii: S0169-2607(26)00330-5. [Epub ahead of print]286 109581
    Meta-PseU: A meta-classifier for robust prediction of RNA pseudouridine modification sites from long sequences.
    Takumi Suto, Md Harun-Or-Roshid, Hiroyuki Kurata.
       BACKGROUND AND OBJECTIVES: Pseudouridine (Ψ) represents one of the most abundant and conserved RNA modifications. Ψ provides an additional hydrogen-bond donor that enhances RNA structural stability and modulates translation. It participates in diverse biological processes, including RNA-protein interactions, splicing, translational control, and stress responses. Aberrant pseudouridylation is implicated in cancer, neurodegenerative disorders, and autoimmune diseases. Despite its biological importance, experimental identification of Ψ sites remains time-consuming and costly, limiting the feasibility of transcriptome-wide profiling. Computational approaches have therefore become essential complements to experimental techniques. However, state-of-the-art machine-learning and deep-learning predictors often suffer from limited generalizability due to small training datasets. To overcome these issues, we aim at constructing new long-sequence datasets and developing a novel Ψ site predictor.
    METHODS: New long-sequence datasets were constructed as benchmarks for RNA Ψ-site prediction. The Ψ modification sites in RMBase 3.0 were mapped to the reference genomes across three species of human, mouse, and yeast, and the RNA sequences with a length of 201 were generated by extending the upstream and downstream from the mapped, central sites. To eliminate sequence redundancy, the sequences were clustered using CD-HIT with a 70% sequence identity threshold. We developed Meta-PseU, a logistic regression-based meta-classifier that considered 118 machine learning and deep learning classifiers. The datasets and programs are freely accessible at https://github.com/kuratahiroyuki/MetaPseU.
    RESULTS: By optimizing model configuration, we proposed the Meta-PseU model stacking 32 machine learning and deep learning classifiers out of 118 classifiers. Meta-PseU substantially improved model generalizability, overcoming a key limitation of existing approaches. It greatly outperformed state-of-the-art predictors and achieved increasing accuracy with increasing sequence length.
    CONCLUSIONS: Long-sequence datasets were newly constructed as benchmarks for RNA Ψ-site prediction. Meta-PseU offers a new framework for robust Ψ-site identification by using long sequences.
    Keywords:  Bioinformatics; Deep learning; Ensemble; Machine learning; Meta-classifier; Pseudouridine; RNA modification; Sequence; Stacking model
    DOI:  https://doi.org/10.1016/j.cmpb.2026.109581
  54. Oncogene. 2026 Aug 07.
    IGF2BP3-mediated regulation of the RNA isoform and modification landscape in pancreatic cancer.
    Sandra Margielewska-Davies, Wayne Croft, Hayden Pearce, Natalie To, Fouzia Zayou, Falguni Meghrajani, Jing Zhang, Claudia M A Pinna, Laura Bills, Andrew D Beggs, Soumyajit Mallick, Sarah F Powell-Brett, Rachel Brown, Jianmin Zuo, Keith J Roberts, Paul Moss.
      The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing but clinical outcomes remain poor and new treatments are required. IGF2BP3 is an oncofetal m6A-reading RNA regulatory protein whose expression is commonly observed in PDAC and which may represent an important therapeutic target. IGF2BP3 protein is expressed in >95% of primary tumours whilst RNA expression ranges from 3 to 3000-fold above normal epithelium. siRNA knockdown reveals IGF2BP3 to strongly support expression of gene programs related to DNA replication, cell cycle and apoptosis, TNF signalling and epithelial-mesenchymal transition. Direct sequencing of native RNA further reveals IGF2BP3-mediated enhancement of 863 RNA isoforms with suppression of 389 isoforms. m6A, m5C and pseudouridine (ψ) RNA modifications were seen in 97% of transcripts within the PDAC transcriptome and enriched within MYC gene targets. IGF2BP3 regulated the pattern of RNA modification with a substantial impact on m5C modifications of miRNA and scRNA, and genes associated with regulation of TNF signalling. Knockdown of IGF2BP3 expression in primary tumour organoid cultures suppressed proliferation and elicited apoptosis, indicating a critical requirement for IGF2BP3 within malignant stem cells. These data show that IGF2BP3 is expressed consistently in PDAC, plays a dominant role in regulation of RNA splicing and modification, and supports cancer stem cell proliferation and survival. IGF2BP3 therefore occupies a critical position within the RNA regulon of PDAC and represents an important therapeutic target in this tumour of unmet need.
    DOI:  https://doi.org/10.1038/s41388-026-03933-3
  55. Exp Mol Med. 2026 Aug 04.
    METTL14-dependent N6-methyladenosine modification of FGF16 participates in IGFBP5 deficiency-enhanced angiogenesis.
    Fei Song, Yu Hu, Yi-Xiang Hong, Shan-Shan Zhao, Hui-Zhu Huang, Yutian Wang, Le Zhang, Wei-Yin Wu, Yan Wang, Gang Li.
      N6-methyladenosine (m6A) RNA modification plays critical roles in physiological and pathological processes. Our prior study demonstrated that IGFBP5 expression is upregulated in the ischemic limb, whereas endothelial-specific IGFBP5 knockout (Igfbp5EKO) protects against hind limb ischemia by enhancing angiogenesis. Here, we show that IGFBP5 deficiency elevates global m6A levels and upregulates the expression of m6A methyltransferase complex components METTL3, METTL14 and WTAP in endothelial cells. We further identified a direct interaction between IGFBP5 and the MT-A70 domain of METTL14. Knockdown of METTL14, METTL3 or WTAP attenuated the pro-angiogenic effects of IGFBP5 deficiency in vitro. In vivo, endothelial knockdown of METTL14 abolished the improved hind-limb ischemia recovery in Igfbp5EKO mice. Methylated RNA immunoprecipitation sequencing revealed that IGFBP5 depletion in endothelial cells increases both m6A modification and mRNA abundance of FGF16. Notably, METTL14 or METTL3 silencing suppressed IGFBP5-dependent FGF16 upregulation. Enhanced translational efficiency of FGF16 in IGFBP5-deficient cells was reversed by METTL14 knockdown, indicating that IGFBP5 regulates FGF16 translation via m6A modification. Mechanistically, IGFBP5 modulates FGF16 m6A modification via interaction with the m6A reader protein IGF2BP2, targeting the m6A site at position 255 of FGF16 mRNA. In summary, our study establishes METTL14-mediated m6A modification of FGF16 as a key mechanism underlying IGFBP5-driven angiogenesis. Targeting the IGFBP5-METTL14-m6A-FGF16 axis may offer novel therapeutic strategies for ischemic disease.
    DOI:  https://doi.org/10.1038/s12276-026-01788-y
  56. Immunol Cell Biol. 2026 Aug 04.
    The Emerging Role of UCHL1 in Neurological and Musculoskeletal Diseases.
    Ru Feng, Xiu Zhong, Jianjun Li, Adrian A Achuthan.
      Ubiquitin C-terminal hydrolase L1 (UCHL1) is a highly conserved deubiquitinating enzyme that has transitioned from being viewed as a "brain-specific" protein to a global regulator of cellular proteostasis and signal transduction. As a key component of the ubiquitin-proteasome system (UPS), UCHL1 maintains the intracellular free ubiquitin pool through its C-terminal hydrolase activity, while also exhibiting atypical ligase-like functions and acting as a molecular scaffold for signaling complexes. Beyond its classical role in neurons, increasing evidence suggests that UCHL1 participates in diverse pathological conditions including neurodegeneration, cancer, cardiovascular and metabolic diseases, as well as musculoskeletal disorders. Through regulation of protein turnover, oxidative stress, inflammatory signaling, and cell survival, UCHL1 emerges as a context-dependent regulator with dual protective and pathogenic roles. This review explores the sophisticated multi-level regulation of UCHL1, ranging from transcriptional control to epigenetic silencing and posttranslational modifications, summarizes the recent research progress of UCHL1 in various systems, and elaborates on its mechanism of action in various conditions, including neurological and musculoskeletal disorders.
    Keywords:  UCHL1; cancer; deubiquitinating enzyme; inflammation; musculoskeletal conditions; neurological disorders; signaling pathways
    DOI:  https://doi.org/10.1111/imcb.70151
  57. Carcinogenesis. 2026 Jul 07. pii: bgag039. [Epub ahead of print]47(3):
    Neddylation pathway promotes the ubiquitinated degradation of FBXO21 in lung cancer cells.
    Ying Zhang, Meng Li, Tiangeng Dong, Yunyang Zhou, Wenjuan Zhang, Gaili Chang, Mingsong Wang, Lijun Jia, Lihui Li.
      SCF (Skp1-Cullin1-Fbox protein) is a multi-subunit RING-type E3 ligase and plays critical roles in various pivotal physiological and pathological processes by mediating the ubiquitination and degradation of key proteins. F-box proteins directly bind substrates, thereby determining their specificity, stability, and function. However, the regulatory mechanisms of FBXO21 degradation in human cancers remain largely elusive. In this study, we demonstrated that Neddylation-ROC1 E3 ligase regulates the protein level of FBXO21. Mechanistic studies revealed that Neddylation-ROC1 targeted FBXO21 for ubiquitination and degradation. Moreover, we found that FBXO21 depletion increased p53 protein stability by delaying its degradation, followed by increasing the transcriptional level of p21. Taken together, our findings reveal a previously unrecognized mechanism by which FBXO21 is regulated by Neddylation modification and regulates the p53-p21 signaling pathway.
    Keywords:  FBXO21; lung cancer; neddylation
    DOI:  https://doi.org/10.1093/carcin/bgag039
  58. Food Res Int. 2026 Oct 01. pii: S0963-9969(26)01323-2. [Epub ahead of print]241 119640
    Lactation-stage profiles of rRNA-derived small RNAs in human milk exosome-enriched fractions: Compositional features and relevance to infant nutrition.
    Xinping Chen, Xiaoyu Liu, Ying Meng, Yutong Hu, Ze Guan, Xiqing Yue, Mei Yang.
      Human milk exosome-enriched fractions contain exosome-like vesicles and bioactive molecules, yet the compositional features of rRNA-derived small RNAs (rsRNAs) and their variation across lactation stages remain unclear. In this study, exosome-enriched fractions were isolated and characterized from human colostrum (HC) and mature milk (HM) collected from healthy lactating mothers, and small RNA sequencing was used to systematically profile the rsRNA landscape, differential patterns, and positional origin distribution in these fractions. The results showed that human milk exosome-enriched fractions contained diverse rsRNAs, mainly derived from 18S, 28S, 5.8S, and 5S rRNAs. Compared with HM, rsRNAs in HC-derived exosome-enriched fractions exhibited marked differences in compositional proportion, length distribution, and abundance, indicating lactation-stage-associated variation. Coverage analysis further showed that most rsRNAs were not evenly distributed across full-length precursor rRNAs but were concentrated in specific regions, which is consistent with non-random enrichment patterns. Target prediction and functional enrichment analyses of representative differential rsRNAs suggested possible associations with pathways related to immune-related signaling, epithelial barrier function, and cell growth; however, these results should be interpreted as hypothesis-generating and require further experimental validation. Collectively, this study reveals the compositional characteristics and lactation-stage-associated profiles of rsRNAs in human milk exosome-enriched fractions, expands current understanding of milk-borne bioactive small RNA systems, and provides candidate molecular information for future studies on stage-specific bioactive components relevant to infant nutrition.
    Keywords:  Bioactive small RNAs; Exosome-enriched fractions; Human milk; Infant nutrition; Lactation stage; rRNA-derived small RNAs
    DOI:  https://doi.org/10.1016/j.foodres.2026.119640
  59. Nat Commun. 2026 Aug 07. pii: 8011. [Epub ahead of print]17(1):
    Vitamin B12 alleviates spliceosomopathy via phospholipid remodeling.
    Jonathan Kölschbach, Hormos S Dafsari, Emily Baum, Anna Löhrke, Chun Kew, Ivan Dikic, Wenming Huang, Adam Antebi.
      mRNA splicing represents a fundamental level of gene regulation that alters proteomic diversity and cellular state. Its dysfunction can profoundly rewire metabolism, yet underlying mechanisms remain elusive. Here, we investigate Verheij syndrome, caused by mutations in core splicing factor PUF60, using a Caenorhabditis elegans model, human cell lines, and patient-derived samples. We demonstrate that RNP-6/PUF60 deficiency disrupts splicing of genes governing one-carbon metabolism and phospholipid remodeling, impairing S-adenosylmethionine/S-adenosylhomocysteine cycling and phosphatidylcholine synthesis. These perturbations trigger the integrated stress response and compromise mTORC1 signaling, causing developmental growth defects. Vitamin B12 supplementation restores metabolic balance by reactivating S-adenosylmethionine-dependent phospholipid remodeling and mTORC1 activity, effectively rescuing Verheij-like phenotypes. Similar responses arise from perturbing another splicing factor, PRP-19. Mechanistically, intron retention of nhr-114/HNF4 transcription factor drives these phenotypes, while restoring its splicing rescues them. Our findings implicate vitamin B12-dependent one-carbon metabolism as a metabolic modulator with therapeutic potential to mitigate Verheij syndrome and other spliceosomopathies.
    DOI:  https://doi.org/10.1038/s41467-026-76295-9
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