bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–04–26
sixty-five papers selected by
Cédric Chaveroux, CNRS
  1. The regulation, function and disease relevance of cytoplasmic tRNAs.
  2. rRNA expansion segments mediate ribosome dimerization as a conserved stress response.
  3. Inhibiting the integrated stress response restores cognition.
  4. Multimodal profiling reveals cell type-specific pseudouridine modification and density-dependent translational regulation.
  5. RNA Modifications: Current Understandings and Future Perspectives.
  6. Conserved and divergent features of human mRNA decapping revealed by biochemical reconstitution.
  7. Sequence and structure of protein binding sites in RNA impact biomolecular condensates.
  8. Dual Role of 3' UTR Length in Modulating Translation Termination Efficiency.
  9. mTORC1 and nuclear ERK spatially control translation in cardiomyocytes through 4EBP1 phosphorylation.
  10. PUS1 Drives Renal Cancer Progression by Preventing Formation of Endogenous Double-stranded RNAs.
  11. The multifunctional, stress-sensitive ribonuclease angiogenin cross-regulates different gene expression processes.
  12. An inhibitor of GCN2 and the integrated stress response directly targets ZAK protein kinase to limit cytotoxicity.
  13. Stress Tested: Aging Rewires Tumors for Metastatic Spread Through Activation of the Integrated Stress Response.
  14. Small RNA-mediated regulation of stress tolerance in Deinococcus radiodurans.
  15. A Nanos3-containing protein complex can activate RNA translation in primordial germ cells in vivo.
  16. Nucleolar expansion: A biomolecular condensate mortality timer.
  17. Bacteria use P-body condensates to attenuate host translation during infection.
  18. The selfish ribosome.
  19. The Human DBR1 Interactome Reveals Coupling Between Intron Lariat Turnover, Pre-mRNA Splicing and RNA Quality Control Pathways.
  20. Temperature-specific regulation of the NDR kinase Orb6 by the MAPK Sty1 to promote heat stress resilience.
  21. Novel Functions and Potential of Ribosomes: From Cellular Transdifferentiation to Applications in Cell-Cultured Foods.
  22. SMG7 and eIF4A constitute a homeostatic module controlling P-body condensation and function of meiotic bodies.
  23. Self-induced dimensional reduction and scaling transition of mRNA in polysomes: A multiscale simulation study.
  24. m6A demethylase FTO promotes the progression of abdominal aortic aneurysm through PDK4-mediated apoptosis.
  25. An optimized translating ribosome affinity purification protocol for low-abundance Drosophila tissues.
  26. A Toolbox for Quantifying Nuclear and Nucleolar Protein Accumulation Using NLS and NoLS Fusion Reporters.
  27. Role of mitochondrial translation in modulating inflammatory disease outcome: current knowledge and future perspectives.
  28. Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress.
  29. Multi-site DMS probing reveals higher-order structure of RNA-protein complexes in living cells.
  30. Long-Term Stress Adaptation as a Highly-Conserved Key Factor in Yeast Aging.
  31. Isoform-specific m6A deposition and coordinated splicing shape mammalian transcriptome evolution.
  32. TOR-dependent regulation of the yeast homolog of the juvenile Batten Disease-associated gene CLN3.
  33. ShapeRNA: an integrated web server for RNA secondary structure, ensemble, and functional analysis.
  34. Computational prediction-combined proteogenomics unveils widespread non-AUG translation initiation events in plants.
  35. m6A epitranscriptomic remodeling links redox stress to mitochondrial quality control and programmed cell death in sepsis-induced myocardial dysfunction.
  36. Depletion of TECPR2 leads to mitochondrial failure associated with neurodegeneration.
  37. Keeping UTRs in Their Place: Clarifying Transcript-Genomic Boundaries.
  38. Interplay between proteostasis pathways and innate immune responses in Caenorhabditis elegans.
  39. A Trojan Horse in the soil: Tetracycline hijacks plant organellar ribosomes to stunt growth and unbalance the rhizosphere microecology.
  40. IGF2BP2 condensates stabilize DOK3 to negatively regulate inflammatory responses.
  41. Pharmacological strategies targeting chaperone-mediated autophagy.
  42. PKR condensation at viral replication complexes initiates its activation.
  43. The m7G RNA modification in gastrointestinal cancers: mechanisms and therapeutic potential.
  44. USP34 modulates mitochondrial function in triple-negative breast cancer cells through the eIf3m/MTCH2 axis.
  45. Direct RNA-seq provides evidence for an antiterminator function of the yeast Hrp1 protein on RNA polymerase II transcripts.
  46. Eigenvalue Ratios Reveal Shared Binding Pocket Shapes in RNA and Protein Structures.
  47. Metaproteome Analysis of Short-Term Thermal Stress in Three Sympatric Coral Species Reveals Divergent Host Responses.
  48. HSP101 Polymorphism Is Related to Heat Tolerance and Seedling Growth in Wild-Type Arabidopsis Accessions From Diverse Geographical Locations.
  49. eEF2K-Mediated Stabilization of PCBP2 Promotes Oncogenic mRNA Programs in Triple-Negative Breast Cancer.
  50. Protective Effects of Murrayafoline A Against Heat-Induced Male Infertility in Drosophila melanogaster: In Vivo Studies and In Silico Evidence for a Potential Interaction With Vasa.
  51. Transcriptomic and Functional Analysis of Fibroid Extracellular Vesicles.
  52. TGF-β/SMAD signaling maintains nucleus pulposus stem cell quiescence to protect against oxidative injury in intervertebral disc degeneration.
  53. Generalizable deep-learning-based mRNA-protein interaction prediction strongly depends on protein diversity.
  54. PIWIL1 activates the R2TP-TELO2-mTORC1 axis independently of piRNA to promote TOP mRNA translation in gastric cancer.
  55. THAP7-AS1 orchestrates IGF2BP3-m6A-dependent CCN2 mRNA stabilization to promote lymphatic metastasis in bladder cancer.
  56. CD133-Guided RNA Nanoparticle Delivery of FTO siRNA Impairs Leukemia Resistance to Tyrosine Kinase Inhibitor Therapy.
  57. Genetic complementation reveals structure-function links in nodavirus RNA replication complex crowns.
  58. Mechanism of YTHDF2-Mediated Epigenetic Modification in the Proliferation and Invasion of Renal Cell Carcinoma Cells.
  59. Enterohemorrhagic Escherichia coli O157:H7 responds to norepinephrine gradients by tRNA reprogramming and codon-biased translation of virulence genes.
  60. Genome-wide identification of the Hsp70 gene family in Atlantic cod (Gadus morhua) and its response to pathogenic stress.
  61. Mettl3-Mediated m6A Methylation of Pdgfrb Regulates the Angiogenesis-Dependent Bone Formation.
  62. Phenotypic cliffs in the RNA genotype-phenotype map.
  63. Cellular plasticity of cancer: roles of biomolecular condensates and ecDNA.
  64. Circular RNA as emerging precision therapeutics: from RNA regulation to peptide translation.
  65. Effects of rok1 gene deletion on mitosis in fission yeast at appropriate and stressful temperatures and the molecular mechanisms.
  1. Nat Rev Mol Cell Biol. 2026 Apr 21.
    The regulation, function and disease relevance of cytoplasmic tRNAs.
    Robin E Stanley, Todd M Lowe, Zoya Ignatova.
      Transfer RNAs (tRNAs) are core components of protein synthesis. Recent studies and technological advances have expanded our understanding of the complexities of tRNA biology. In this Review, we discuss the genomic organization and spatiotemporal expression of human cytoplasmic tRNAs, the quality control pathways that govern their maturation and functionality, and how dysregulation of tRNA biogenesis and function contributes to human pathologies. We also present emerging concepts regarding how tissue-specific tRNA abundance regulates translation velocity and how tRNAs are centrally involved in surveillance and stress signalling pathways, including ribosome-associated quality control and the integrated stress response. We further discuss the potential of tRNA-based therapeutics, highlighting new strategies to address tRNA-associated translation defects. By bridging between molecular tRNA biology and its clinical implications, we emphasize the crucial need to understand the intricacies of tRNA regulation in order to therapeutically target them in a variety of diseases.
    DOI:  https://doi.org/10.1038/s41580-026-00963-3
  2. Nucleic Acids Res. 2026 Apr 13. pii: gkag354. [Epub ahead of print]54(7):
    rRNA expansion segments mediate ribosome dimerization as a conserved stress response.
    Wenhong Jiang, Chen Chen, Xing Wang, Wei Huang, Dawid Krokowski, Ziyao Chen, Jiahao Xie, Zhaoming Su, Maria Hatzoglou, Derek J Taylor, Qiang Guo.
      Inhibition of messenger RNA translation is a common feature in proteostatic stress cellular responses. Puromycin, a widely used compound for studying translation, disrupts protein synthesis by mimicking the 3' end of aminoacyl-transfer RNAs. Despite its extensive use as a research tool to probe the connection between translation activity and various physiological and pathological states, the cellular response associated with puromycin-induced translation stress remains incompletely understood. Here, we used electron tomography and topology analysis to define the effects of puromycin on the translation machinery in situ. We show that puromycin-treated neuronal cells exhibit an accumulation of eIF5A-bound ribosomes in a translationally inactive "idle" state, and thereby defining a broader role of eIF5A in ribosome homeostasis. Additionally, the idle ribosomes formed dimeric complexes mediated by ribosomal RNA expansion segments, suggesting an evolved mechanism involving these regions in translational hibernating and protecting idle ribosomes. We further show that the hibernating disome formation is not unique to puromycin administration but represents a conserved mechanism as a response to different cellular stressors including endoplasmic reticulum stress and amino acid depletion. Collectively, our findings illuminate distinct states of mammalian ribosome hibernation and dimerization, providing new insights into the relationship of cellular stress and the dynamic regulation of ribosomal activity.
    DOI:  https://doi.org/10.1093/nar/gkag354
  3. Nat Rev Drug Discov. 2026 Apr 24.
    Inhibiting the integrated stress response restores cognition.
    Sarah Crunkhorn.
      
    DOI:  https://doi.org/10.1038/d41573-026-00066-w
  4. Nucleic Acids Res. 2026 Apr 13. pii: gkag353. [Epub ahead of print]54(7):
    Multimodal profiling reveals cell type-specific pseudouridine modification and density-dependent translational regulation.
    Caroline A McCormick, Michele Meseonznik, Yuchen Qiu, Oleksandra Fanari, Priyanka Goyal, Mitchell Thomas, Mina Shokoufandeh, Yifang Liu, Dylan Bloch, Cole Greenfield, Isabel N Klink, Miten Jain, Meni Wanunu, Sara H Rouhanifard.
      Pseudouridine (psi) is one of the most abundant mRNA modifications, yet its impact on translation is unclear, in part because existing modification maps are inconsistent, curated comparisons across cell types are lacking, and paired analyses with translation are limited. Using direct RNA nanopore sequencing coupled with our Mod-p ID analytical framework, we mapped psi at single-nucleotide resolution across six immortalized human cell lines. Nanopore sequencing provided single-molecule resolution, enabling quantification of relative modification occupancy and detection of co-occurring modifications. Integrating these psi maps with matched proteomic and ribosome profiling datasets revealed that conserved psi sites installed by the psi synthase TRUB1 are associated with increased protein production. TRUB1 knockout experiments demonstrated a motif-specific reduction in protein abundance, providing direct causal evidence that pseudouridylation enhances protein output. In contrast, transcripts bearing clustered psi sites exhibited reduced protein abundance despite elevated translation efficiency. Controlled in vitro translation experiments confirmed that increasing pseudouridine density within a physiologically relevant range directly reduces protein output, demonstrating a density-dependent effect of pseudouridylation on translation. Together, these findings establish a mechanistic framework in which single-site pseudouridylation enhances protein production, whereas hypermodification impairs translational throughput, revealing pseudouridine density and enzyme specificity as key determinants of proteome output across human cell types.
    DOI:  https://doi.org/10.1093/nar/gkag353
  5. MedComm (2020). 2026 May;7 e70734
    RNA Modifications: Current Understandings and Future Perspectives.
    Shiyu Xiao, Tingwen Xiang, Chuan Yang, Xiaohua Wang, Gang Huang, Fei Luo, Zhao Xie, Yueqi Chen.
      RNA modification has been established as a pivotal field in epitranscriptomics, representing an emerging, dynamic, and precise regulatory layer in gene expression control. N6-methyladenosine (m6A), the most prevalent internal RNA modification, is critical for post-transcriptional regulation of RNA stability, translation, and degradation. In addition to m6A, RNA contains a number of other modifications that play important regulatory roles in RNA metabolism, transport, translation, and stability. Our review uses N4-acetylcytidine (ac4C) modification as a research paradigm to conduct a systematic review of the RNA modification research framework. This article begins with RNA modifications, then discusses several RNA modification-related regulatory enzymes before using ac4C as a detailed research example. Starting with the fundamental functions of ac4C in RNA modifications, it discusses its discovery history, the specific mechanisms of the key acetyltransferase N-acetyltransferase 10 (NAT10) in various RNA modifications, existing detection technologies, and the functional significance of ac4C modification under physiological and pathological conditions. This review systematically explains the multidimensional roles of RNA modifications, represented by ac4C, in health and disease. We point out that RNA modification-related regulatory enzymes, such as NAT10, can serve as prognostic biomarkers and therapeutic targets, thereby advancing disease mechanism research and improving clinical diagnosis and treatment.
    Keywords:  N4‐acetylcytidine; RNA modification; epigenetic modification; homeostasis; pathophysiology
    DOI:  https://doi.org/10.1002/mco2.70734
  6. Nat Commun. 2026 Apr 21. pii: 3697. [Epub ahead of print]17(1):
    Conserved and divergent features of human mRNA decapping revealed by biochemical reconstitution.
    Eric A J Simko, Sowndarya Muthukumar, Tanner M Myers, Anna L Valkov, Eugene Valkov.
      Decapping is a critical step in mRNA decay, but the mechanisms regulating human decapping enzyme DCP2 remain poorly understood. Here, we reconstitute the human decapping network using full-length recombinant proteins and compare it to the yeast system. Unlike in yeast, we find that the C-terminal region of human DCP2 is not autoinhibitory. RNA-binding residues of yeast Dcp2 are not conserved in the human homolog, and we find instead that a charged C-terminal region mediates substrate recognition. Human DCP1 does not stably interact with or directly stimulate DCP2, but mediates activation by the enhancer PNRC2. We also demonstrate that decapping enhancer EDC4 forms tetramers through an extended coiled-coil region, and that both DCP1 and EDC4 homomeric species can further assemble into higher-order oligomers. Furthermore, structural predictions incorporating these findings suggest a model for DCP2 recruitment by EDC4 tetramers. These findings reveal key mechanistic differences between human and yeast decapping regulation and provide insight into the molecular architecture underlying mRNA decay.
    DOI:  https://doi.org/10.1038/s41467-026-72177-2
  7. Mol Biol Cell. 2026 Apr 23. mbcE26020083
    Sequence and structure of protein binding sites in RNA impact biomolecular condensates.
    Sierra J Cole, Scott R Allen, Bryan B Guzmán, Yue Hu, Benjamin M Stormo, Christine A Roden, Joanne Ekena, Vita Zhang, Grace A McLaughlin, Alex W Crocker, Alain Laederach, Daniel Dominguez, Amy S Gladfelter.
      Biomolecular condensates are central to subcellular compartmentalization and RNA regulation. In the multinucleate fungus Ashbya gossypii, condensates composed of Whi3 protein and CLN3 mRNA help ensure nuclear cycle asynchrony in a shared cytoplasm. Here, we investigated how Whi3 protein binding sites within CLN3 mRNA are specified and influence properties of the condensate. We found that Whi3 binds to varied RNA sequences but prefers the five-nucleotide motif UGCGA, which appears at five locations in the CLN3 transcript. Mutating individual UGCGA motifs altered the saturation concentration (Csat) and dense phase concentration of RNA and Whi3 in cell-free reconstitution experiments. These defects were partially rescued by melting and refolding the mRNA, indicating that RNA structure plays a critical role in distinguishing binding sites and determining condensate properties. Lastly, a subset of mutants showed reduced condensate numbers and dysregulation of the cell cycle in cells. These data reveal that the context of otherwise identical mRNA sequences can differentially affect condensate properties.
    DOI:  https://doi.org/10.1091/mbc.E26-02-0083
  8. RNA. 2026 Apr 21. pii: rna.080776.125. [Epub ahead of print]
    Dual Role of 3' UTR Length in Modulating Translation Termination Efficiency.
    Ali Salman, Mikhail Loev, Tatiana Egorova, Alexey V Shuvalov, Anastasia Zharikova, Sergey Dmitriev, Ekaterina Shuvalova, Nikita Biziaev, Elena Alkalaeva.
      The 3' untranslated region of mRNAs are involved in post-transcriptional control, influencing mRNA stability, localization, and translation efficiency through its interaction with various proteins and RNAs. While eukaryotic 3' UTRs are typically several hundred nucleotides long, certain protozoan species possess remarkably short 3' UTRs and have evolved alternative genetic codes where canonical stop codons are reassigned to sense codons. This suggests a potential link between 3' UTR architecture and the efficiency of translation termination. In this study, we investigate how the length and secondary structure of the 3' UTR modulate translation termination efficiency across different species. We demonstrate that shortening of structured 3' UTRs confer a translational advantage for mRNAs bearing UAA stop codons. Using purified pre-termination complexes, we show that 3' UTR secondary structures enhance the termination rate by facilitating the spatial proximity of PABP (bound to the poly(A) tail) to eRF3a on the ribosome. Furthermore, we found that the termination rate at UGA stop codons is highly sensitive to 3' UTR length when assayed with both human and ciliate release factors. Our investigation of stop codon reassignment underscores the primary role of release factor recognition efficiency in this process. Collectively, our findings reveal a dual regulatory mechanism: while long, structured 3' UTRs can sterically hinder stop codon recognition, they simultaneously promote eRF3a-PABP interactions that facilitate the recruitment of release factors to the ribosome. This work establishes 3' UTR length as a key cis-regulatory factor fine-tuning the fundamental process of translation termination.
    Keywords:  3′ UTR; PABP; eRF1; eRF3; ribosome
    DOI:  https://doi.org/10.1261/rna.080776.125
  9. Sci Signal. 2026 Apr 21. 19(934): eadu5769
    mTORC1 and nuclear ERK spatially control translation in cardiomyocytes through 4EBP1 phosphorylation.
    Keita Uchida, Emily A Scarborough, Elizabeth Pruzinsky, Kathlyene R Stone, Hali Hartman, Daniel P Kelly, Jonathan J Edwards, Izhak Kehat, Benjamin L Prosser.
      Cardiomyocytes depend on local translation for growth and can undergo directed growth in length or width in response to different stimuli. Protein synthesis is augmented during concentric hypertrophy, which leads to thickening of the heart muscle by increasing cardiomyocyte width. Protein synthesis is controlled at the translation initiation step, when ribosome loading onto transcripts is regulated by the sequential phosphorylation of the eukaryotic initiation factor 4E-binding protein 1 (4EBP1). Here, we identified a mode of 4EBP1 phosphorylation that was associated with concentric hypertrophy in cultured cardiomyocytes and mouse hearts. Whereas canonical phosphorylation of 4EBP1 by mTORC1 regulates global protein synthesis rates, mTORC1- and nuclear ERK-dependent phosphorylation of 4EBP1 was specifically activated during concentric but not eccentric hypertrophy. Nuclear ERK-dependent phosphorylation of 4EBP1 at Ser64 was necessary and sufficient to relocalize translation initiation sites closer to the nuclei. ERK activation drove redistribution of ribosomes and nascent translation toward the center of the cardiomyocyte without altering global mRNA distribution, leading to spatially enriched deposition of new sarcomeric protein in the cardiomyocyte interior. Together, these findings demonstrate that global protein synthesis can be spatially regulated by the activation of different kinases in distinct subcellular compartments and identify a mechanism that drives concentric hypertrophy.
    DOI:  https://doi.org/10.1126/scisignal.adu5769
  10. Int J Biol Sci. 2026 ;22(7): 3749-3768
    PUS1 Drives Renal Cancer Progression by Preventing Formation of Endogenous Double-stranded RNAs.
    Ziwei Zhu, Zeyi Lu, Fan Li, Zhehao Xu, Ruyue Wang, Yang Li, Haohua Lu, Yiming Ding, Wenqin Luo, Yudong Lin, Yi Lu, Xudong Mao, Mengxuan Li, Ziyuan Wang, Lifeng Ding, Liqun Xia, Gonghui Li.
      Pseudouridine (Ψ) modification is a prevalent epitranscriptomic mark with critical roles in carcinogenesis; however, the function of its catalytic "writer" enzyme, pseudouridine synthase 1 (PUS1), in renal cell carcinoma (RCC) remains elusive. Our analysis revealed that PUS1 mRNA is upregulated in RCC and is associated with an unfavorable prognosis. Strikingly, this transcriptional upregulation results in a concomitant and exclusive increase in the protein abundance of PUS1 isoform 2. Mechanistically, although PUS1 markedly enhances global mRNA translation, this effect is not directly mediated via Ψ modification of either mRNA or tRNA. Instead, PUS1 regulates pre-mRNA splicing, and its deficiency induces elevated intron retention. This, in turn, culminates in the formation of double-stranded RNA (dsRNA), which subsequently activates the innate antiviral immune response and inhibits global translation. Furthermore, depletion of PUS1 in tumor cells significantly sensitizes RCC to immune checkpoint blockade therapy. Collectively, our findings demonstrate that PUS1 shields tumor cells from endogenous dsRNA accumulation and the consequent detrimental innate immune activation, thereby unveiling a novel and promising therapeutic strategy for RCC.
    Keywords:  PUS1; dsRNA; innate immune response; pseudouridine modification; renal cell carcinoma; translation
    DOI:  https://doi.org/10.7150/ijbs.130175
  11. Trends Biochem Sci. 2026 Apr 22. pii: S0968-0004(26)00099-X. [Epub ahead of print]
    The multifunctional, stress-sensitive ribonuclease angiogenin cross-regulates different gene expression processes.
    Ana C de A P Schwarzer, Markus T Bohnsack, Katherine E Bohnsack.
      Ribonucleases shape gene expression by mediating RNA processing and degradation. Angiogenin (ANG) is a prominent ribonuclease implicated in several pathophysiologies that contributes to multiple cellular processes by targeting different RNA substrates in a context-dependent manner. ANG has emerged as a key regulator of ribosomal DNA transcription and a direct modulator of translation. Upon cellular stress, ANG is responsible for the cleavage of tRNAs into fragments that are now recognized as important regulators of different aspects of gene expression, including mRNA stability and translation. In this review, we provide updated perspectives on the mechanisms of gene expression regulation by ANG and highlight the potential of multifunctional ribonucleases for mediating crosstalk between different aspects of gene expression.
    Keywords:  RNase A family; angiogenin; rDNA transcription; ribosome; tRNA fragmentation; translation
    DOI:  https://doi.org/10.1016/j.tibs.2026.03.005
  12. J Biol Chem. 2026 Apr 22. pii: S0021-9258(26)00354-6. [Epub ahead of print] 111482
    An inhibitor of GCN2 and the integrated stress response directly targets ZAK protein kinase to limit cytotoxicity.
    Jagannath Misra, Dan F Spandau, Jonah Z Vilseck, Tracy G Anthony, Kirk A Staschke, Ronald C Wek.
      The integrated stress response (ISR) is a major mechanism protecting cells against environmental and physiological stresses. Central to the ISR is a collection of stress-sensing kinases, such as GCN2 (EIF2AK4). When nutrients are limiting or translating ribosomes stall or collide, activated GCN2 phosphorylates eIF2, lowering global protein synthesis, which conserves resources and confers targeted expression of stress-adaptive genes, such as the transcription factor ATF4. While beneficial during acute stress, chronic GCN2 activation can promote cancer progression and neurological disease, spurring the development of GCN2 inhibitors. However, achieving therapeutic specificity and understanding the pathological context of ISR modulation remains challenging and requires careful evaluation. One of the earliest and most widely used GCN2 inhibitors is GCN2iB. In this study, we report that GCN2iB is a direct inhibitor of the ZAK protein kinase, a critical upstream regulator of stress-activated MAPK signaling that functions in the ribotoxic stress response (RSR). Using biochemical measurements, cell-based assays, and structural modeling, we demonstrate that inhibition of ZAK by GCN2iB dampens stress-induced JNK and p38 activation, thereby masking the cytotoxic consequences normally associated with GCN2 inhibition. While suppression of GCN2 activity may be beneficial in specific disease models, concurrent inhibition of ZAK can negate these effects, obscure its therapeutic benefits, and lead to unanticipated phenotypes. These findings highlight the importance of assessing kinase selectivity in pharmacological studies of ISR modulation and emphasize that dual inhibition of GCN2 and ZAK can yield complex and context-dependent cellular responses.
    DOI:  https://doi.org/10.1016/j.jbc.2026.111482
  13. Cancer Res. 2026 Apr 21.
    Stress Tested: Aging Rewires Tumors for Metastatic Spread Through Activation of the Integrated Stress Response.
    Mitchell E Fane, Daniel J Zabransky.
      Aging is a major risk factor for cancer incidence and mortality, but its effect on tumor evolution and metastatic progression remains incompletely understood. A recent study by Patel and colleagues published in Nature reveals a paradoxical role for aging in cancer biology: while aging constrains primary tumor growth, it simultaneously enhances metastatic spread. Using genetically engineered mouse models and patient-derived data, the authors demonstrate that aging epigenetically reprograms mutant KRAS-driven lung adenocarcinoma through activation of the integrated stress response (ISR). Central to this process is the transcription factor ATF4, which promotes epithelial plasticity and metabolic adaptations, thereby enabling metastasis. This work provides a mechanistic framework linking host aging to tumor cell state transitions that favor distant spread of cancer cells. Importantly, it challenges a long-held assumption that tumor aggressiveness is primarily reflected by primary tumor growth kinetics and properties, and instead, it highlights metastasis as a distinct, age-influenced evolutionary trajectory. The identification of ATF4-driven ISR signaling as a mediator of metastasis highlights new therapeutic vulnerabilities, such as an acquired dependence on glutamine, particularly for older patients who comprise the majority of lung cancer cases. More broadly, this study underscores the need to incorporate aging biology into cancer models and therapeutic strategies, redefining how we conceptualize tumor progression across the lifespan.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-1612
  14. Biochim Biophys Acta Gene Regul Mech. 2026 Apr 16. pii: S1874-9399(26)00019-2. [Epub ahead of print]1869(2): 195153
    Small RNA-mediated regulation of stress tolerance in Deinococcus radiodurans.
    Shiv Narayan Rai, Krishan Kumar.
      Deinococcus radiodurans exhibits exceptional resilience to extreme stressors like ionizing radiation, oxidative damage, and desiccation. This extraordinary resistance stems from a sophisticated regulatory network that enables survival in environments lethal to most organisms. Within this regulatory framework, small RNAs (sRNA) have emerged as key regulators of the stress response. Acting primarily through post-transcriptional regulation, sRNA modulates gene expression by binding target mRNAs to influence their stability or translation, enabling rapid cellular adaptation. Despite significant advances in understanding D. radiodurans' DNA repair capabilities, studies of its RNA-based regulatory pathways are relatively limited. Recent studies have revealed the critical role of sRNAs in D. radiodurans, particularly through advanced RNA sequencing techniques that identified numerous previously unknown sRNAs. These sRNAs act as global regulators, altering the expression of genes involved in the stress response, DNA repair, and metal homeostasis. Mn2+ homeostasis is an important adaptation that enables D. radiodurans to alleviate oxidative stress, a major risk in radiation-rich environments. The role of sRNA in regulating D. radiodurans is more complex than simply responding to the stress. In addition, sRNA controls other bacterial systems, such as quorum sensing and biofilm formation, though these systems are still poorly understood in D. radiodurans. This review focuses on the sRNAs of D. radiodurans and their responses to various stresses. We highlight these riboregulators for their role in one of the most remarkable bacterial survival mechanisms.
    Keywords:  DNA repair; Deinococcus radiodurans; Riboregulators; Stress survival mechanism; sRNA-mediated cell metabolism
    DOI:  https://doi.org/10.1016/j.bbagrm.2026.195153
  15. EMBO Rep. 2026 Apr 24.
    A Nanos3-containing protein complex can activate RNA translation in primordial germ cells in vivo.
    Antra Gupta, Arzu Melsa Basaran, Moritz Ophaus, Shantanu Madiwale, Martin Stehling, Michal Reichman-Fried, Katsiaryna Tarbashevich, Erez Raz.
      Maintaining the germline fate requires tight post-transcriptional control of RNA function. Here, we investigate how primordial germ cell (PGC) identity is maintained in zebrafish and reveal that the conserved RNA-binding proteins Nanos3 and Dead End1 form a complex that safeguards PGC identity. Using transcriptomics and in vivo imaging-based analyses, we show that this complex controls the translational activation and localization of both nanos3 and dead end1 RNAs, establishing a positive feedback loop crucial for regulating their protein expression. These findings uncover a previously unknown layer of control over germline development, where a complex containing Nanos3, a protein associated with the inhibition of RNA translation, acts as an activator by interacting with an eIF3 complex protein to promote translation, thereby maintaining specific RNAs at the periphery of phase-separated germ cell granules. Disrupting the physical interaction between Nanos3 and Dead End1 leads to transdifferentiation of germ cells into somatic lineages. Overall, our findings identify a self-sustaining mechanism of translational activation in vivo, positioning the Nanos3-Dead End1 complex as a central effector of germline fate.
    DOI:  https://doi.org/10.1038/s44319-026-00781-w
  16. Geromedicine. 2026 ;pii: 202524. [Epub ahead of print]2(2):
    Nucleolar expansion: A biomolecular condensate mortality timer.
    J Ignacio Gutierrez, Jessica K Tyler.
      The nucleolus, the largest membraneless organelle in the cell, is a biomolecular condensate that houses ribosomal DNA (rDNA), facilitates ribosomal subunit assembly, and serves as a dynamic reservoir for numerous unrelated proteins. Aging across eukaryotic species is accompanied by nucleolar expansion, raising the question of whether it is a correlate of aging or a driver of cellular aging. Recent studies suggest that nucleolar expansion may drive aging and this may result from age-associated changes in the biophysical properties of the nucleolus. Emerging evidence points to age-driven biophysical changes in the nucleolar condensate, including shifts in size, dynamics, and viscoelasticity, which may occur gradually or through transitions from a liquid-like state to denser gel-like, and in some contexts amyloid-like, assemblies. These transitions remodel two core condensate properties: compartmentalization and partitioning, with consequences for ribosome biogenesis and rDNA stability. Here, we review recent literature on age-driven changes in nucleolar condensation and discuss how these changes may influence nucleolar function and longevity.
    Keywords:  Nucleolus; aging; condensates; lifespan extension; longevity; mortality timer
    DOI:  https://doi.org/10.70401/geromedicine.2026.0017
  17. Sci Adv. 2026 Apr 24. 12(17): eaec4477
    Bacteria use P-body condensates to attenuate host translation during infection.
    Manuel González-Fuente, Nico Schulz, Alibek Abdrakhmanov, Thorben Krüger, Gaiea Izzati, Shanshuo Zhu, Gautier Langin, Paul Gouguet, Mirita Franz-Wachtel, Boris Macek, Anders Hafrén, Yasin Dagdas, Suayib Üstün.
      Pathogens use sophisticated strategies to modulate host protein homeostasis by targeting proteolytic pathways, but their impact on protein synthesis remains elusive. We report that pathogenic bacteria Pseudomonas syringae (Pst) targets ribonucleoprotein condensates, known as processing bodies (P-bodies), to attenuate host translation through two effectors with liquid-like properties. We uncovered a previously unknown link that Pst-mediated repression of the endoplasmic reticulum stress response is required for P-body assembly. Furthermore, we identify a functional link between P-bodies and autophagy, demonstrating that autophagic clearance of P-bodies is crucial for maintaining the balance between translationally active and inactive messenger RNAs. Together, our findings provide insights on how host translation is attenuated by bacteria to dampen plant immunity and uncover unknown connections between ER stress responses and autophagy with P-body dynamics.
    DOI:  https://doi.org/10.1126/sciadv.aec4477
  18. PLoS Biol. 2026 Apr 21. 24(4): e3003780
    The selfish ribosome.
    Mart Krupovic, Eugene V Koonin.
      The ribosome is responsible for protein synthesis in all cells, and is the cell's largest energy consumer. We propose that the ribosome originated as a mutualistic symbiont of an RNA-dependent RNA polymerase ribozyme, supplying peptides that enhanced replication. As life transitioned from the RNA to the RNA-protein world, autonomous replicators became irreversibly addicted to the ribosome for producing replication proteins. Subsequent evolution is construed as a ribosomal takeover, whereby the ribosome evolved to consume most of the cell's resources, while other cellular componentry ensured the propagation of the ribosome, while being fully dependent on it. Under this perspective, the ribosome is a complex symbiont of the cell with pronounced selfish properties.
    DOI:  https://doi.org/10.1371/journal.pbio.3003780
  19. Cell Stress Chaperones. 2026 Apr 16. pii: S1355-8145(26)00034-9. [Epub ahead of print] 100178
    The Human DBR1 Interactome Reveals Coupling Between Intron Lariat Turnover, Pre-mRNA Splicing and RNA Quality Control Pathways.
    Tiffany Barwell, Dipendra Gautam, Nitika, Bo Zheng, Andrew W Truman, Kausik Chakrabarti.
      Pre-mRNA splicing produces intron lariats that must be cleaved at their internal 2'-5' phosphodiester bond by the debranching endonuclease DBR1. While human DBR1 (hDBR1) is established as the lariat debranching enzyme, how it interfaces with broader RNA-metabolc pathways is less clear. Using chemical inhibition of splicing, we show that DBR1 expression correlates with splicing activity. We then mapped the hDBR1 interactome by immunopurification coupled to mass spectrometry using complementary gel-based and on-bead workflows. hDBR1 associates with spliceosome and intron-turnover factors, and with RNA quality-control proteins including UPF1, XRN2, and the RNA helicase DHX29. RNase A treatment identifies an RNA-dependent subnetwork enriched for stress-granule proteins and hnRNPs, linking hDBR1 to RNA surveillance during stress. Comparison with BioGRID indicates that most detected associations were not previously reported. Finally, phosphoproteomic profiling reveals multiple hDBR1 phosphorylation sites, including four residues preferentially detected after RNase treatment, suggesting regulatory modifications that may tune hDBR1 interactions or activity. Together, these data expand the functional landscape of hDBR1 across splicing, intron turnover, and RNA quality control.
    Keywords:  DBR1; Mass Spectrometry; Proteomics; RNA Lariat Debranching Enzyme; Splicing; Stress Granules; mRNA Decay
    DOI:  https://doi.org/10.1016/j.cstres.2026.100178
  20. J Cell Sci. 2026 Apr 15. pii: jcs264507. [Epub ahead of print]139(8):
    Temperature-specific regulation of the NDR kinase Orb6 by the MAPK Sty1 to promote heat stress resilience.
    Laura P Doyle, Robert N Tams, Chuan Chen, Illyce Nuñez, Patrick Roman Haller, Fulvia Verde.
      The cellular response to environmental fluctuations, such as increased temperature, is crucial in promoting cell survival and plays an increasingly recognized role in cancer biology. Important cellular functions altered by heat stress are cell polarization and protein translation. Previous studies have shown that heat stress alters the dynamics of Cdc42, a key regulator of cell polarization in eukaryotes, and promotes ribonucleoprotein (RNP) granule formation, reprogramming protein translation. The biological mechanisms underlying these vast changes are only partially known. Here, we report that the conserved NDR kinase Orb6, a homolog of mammalian STK38, responds to heat stress and regulates heat stress resilience by modulating Cdc42 dynamics and promoting RNP granule assembly in Schizosaccharomyces pombe. Also, we discovered a finely tuned mechanism whereby stress-activated mitogen-activated protein kinase (MAPK) Sty1 negatively regulates Orb6 kinase and Orb6 C-terminal phosphorylation during heat stress. Orb6 inhibition by Sty1 increases the sensitivity of the cell to heat stress in a temperature-specific manner, fostering increased stress resilience and metabolic adaptation. These observations highlight the role of NDR kinase in the process of heat adaptation and thermotolerance during environmental cell exposure to elevated temperatures.
    Keywords:   Schizosaccharomyces pombe ; Cdc42 GTPase; Heat stress; Mitogen-activated protein kinase; NDR kinase; Orb6; RNP granule assembly; Sts5; Sty1
    DOI:  https://doi.org/10.1242/jcs.264507
  21. J Dev Biol. 2026 Apr 09. pii: 17. [Epub ahead of print]14(2):
    Novel Functions and Potential of Ribosomes: From Cellular Transdifferentiation to Applications in Cell-Cultured Foods.
    Shota Inoue, Hiroaki Hatano, Ikko Kawashima, Kunimasa Ohta.
      Ribosomes are widely recognized as large intracellular macromolecular complexes responsible for protein synthesis. However, in recent years, numerous studies have revealed that ribosomal proteins possess non-canonical functions beyond translation, including roles in cell fate regulation, development, and disease. This review outlines emerging concepts surrounding the extracellular functions of ribosomes, with a particular focus on ribosome-induced cellular plasticity and transdifferentiation. Our studies have demonstrated that the incorporation of exogenous ribosomes reprograms somatic cells into a multipotent state and promotes differentiation into multiple lineages. These findings represent an alternative perspective to the conventional view of ribosomes as merely translational components. Furthermore, we discuss the biological significance of factors secreted by ribosome-incorporated cells by integrating the paracrine hypothesis with ribosome-mediated cell fate conversion. Finally, we explore the potential applications of ribosomes in regenerative medicine and cell-cultured food production. By redefining ribosomes as active regulators of cellular identity, this review provides a conceptual framework for understanding ribosome-driven cell fate regulation and its potential applications in sustainable biotechnology.
    Keywords:  cell proliferation; cell-cultured food; chick primary cells; ribosomes; transdifferentiation
    DOI:  https://doi.org/10.3390/jdb14020017
  22. Nat Commun. 2026 Apr 21.
    SMG7 and eIF4A constitute a homeostatic module controlling P-body condensation and function of meiotic bodies.
    Albert Cairo, Neha Shukla, Sofia Kanavorova, Jan Skalak, Pavlina Mikulkova, Anna Vargova, David Potesil, Zbynek Zdrahal, Jan Hejatko, Karel Riha.
      Processing bodies (P-bodies) are ribonucleoprotein condensates that regulate RNA processing and storage. Although constitutively present in most cells, their size and composition change dynamically in response to developmental and environmental cues. However, mechanisms governing P-body assembly and remodeling remain poorly understood. Here we show that in Arabidopsis, SMG7 interacts with the eIF4A helicases and recruits them to P-bodies. eIF4As limit P-body condensation and also restrict stress granule (SG) formation under heat stress. We further identify meiotic bodies (M-bodies) as composite RNP granules with a P-body core surrounded by a SG-like shell. The SMG7-eIF4A module regulates the recruitment of the meiosis-specific protein TDM1 into M-bodies, thereby influencing meiotic exit and plant reproduction. Our findings suggest that SMG7 functions as an adaptor protein that recruits client proteins into P-bodies and, together with eIF4A, forms a regulatory module that controls P-body composition and maintains their size homeostasis.
    DOI:  https://doi.org/10.1038/s41467-026-72218-w
  23. J Chem Phys. 2026 Apr 28. pii: 164907. [Epub ahead of print]164(16):
    Self-induced dimensional reduction and scaling transition of mRNA in polysomes: A multiscale simulation study.
    Hideki Kobayashi, Horacio V Guzman.
      The spatial architecture and mechanical rigidity of polysomes are crucial determinants of translational efficiency and mRNA stability. In this study, we investigate the conformational statistics of an mRNA backbone decorated with high-density ribosomes at varying densities using large-scale, extensive molecular dynamics simulations based on the Kremer-Grest bead-spring model. To address the extreme spatial asymmetry between mRNA monomers and ribosomes, we used an efficient tree-based neighbor list algorithm, enabling the analysis of mRNA chains up to N = 4969. Our results demonstrate that the excluded volume of massive ribosomes induces a significant and robust expansion of the scaling exponent ν from 0.59 to ∼0.7. In the conformation of mRNA, this shift translates to a self-induced dimensional reduction from a three-dimensional random coil toward a stretched, quasi-two-dimensional architecture at biologically relevant scales. Such a transition is further evidenced by a periodic "regain" of the bond-bond correlation function C(n) at ribosome attachment sites, indicating a geometric alignment absent in standard homopolymers. These findings reveal that the geometric crowding of ribosomes itself provides a robust physical prerequisite for the formation of higher-order polysome architectures, bridging the gap between polymer physics and structural properties of mRNA during translation.
    DOI:  https://doi.org/10.1063/5.0320598
  24. Sci Rep. 2026 Apr 18.
    m6A demethylase FTO promotes the progression of abdominal aortic aneurysm through PDK4-mediated apoptosis.
    Wei Gong, Xue Yang, Ning Fan, Han Wang, Shengjie Fu, Yu Tian, Lei Li.
      N6-methyladenosine (m6A) is one of the most abundant methylation modifications in mRNA, regulating different stages of mRNA metabolism, including folding, maturation, export, translation, and decay. However, the role of m6A modification and the m6A demethylase fat mass and obesity-associated (FTO) in abdominal aortic aneurysms (AAAs) remains unclear. We found that FTO expression levels were elevated in both in vitro and in vivo models of abdominal aortic aneurysms, and silencing FTO could partially reverse AngII-induced apoptosis of vascular smooth muscle cells (VSMCs). Integrated RNA-seq and MeRIP-seq analysis further identified pyruvate dehydrogenase kinase 4 (PDK4) as the target gene of FTO-mediated m6A modification. FTO mediates m6A demethylation in the 3' untranslated region (3' UTR) of PDK4 mRNA and induces its degradation through a YTH N6-methyladenosine RNA binding protein 2 (YTHDF2)-dependent mechanism. Overexpression of PDK4-a key enzyme in mitochondrial glucose metabolism and a novel regulator of mitochondria-associated endoplasmic reticulum integrity-reversed the inhibitory effect on apoptosis after FTO silencing. These results suggest that FTO regulates VSMC apoptosis by mediating m6A demethylation of PDK4 mRNA and promoting its degradation in a YTHDF2-dependent manner. Moreover, PDK4 overexpression reverses the apoptosis-inhibitory effect induced by FTO silencing.
    Keywords:  Abdominal aortic aneurysm; Apoptosis;N6-methyladenosine; FTO; Mitochondria; PDK4
    DOI:  https://doi.org/10.1038/s41598-026-47997-3
  25. iScience. 2026 May 15. 29(5): 115530
    An optimized translating ribosome affinity purification protocol for low-abundance Drosophila tissues.
    Leonor Miller-Fleming, Wing Hei Au, Alexander J Whitworth.
      Localized protein translation enables spatially restricted cellular dynamics, particularly in neurons, where specific mRNAs are translated in axons and dendrites far from the cell body. Translating ribosome affinity purification (TRAP) has been used to study axonal translation in rodents and cell-type-specific translation in Drosophila, but existing protocols are not optimized for axons, where material is extremely limited. Here, we present a highly sensitive TRAP protocol for isolating ribosome-bound mRNAs from low-input samples, enabling recovery of axonal mRNAs from Drosophila larval and adult (leg) motor neurons. RNA-seq identified axonally translated transcripts, including mRNAs encoding ribosomal and mitochondrial proteins, similar to those reported in axons of other species, indicating conservation of axonal translation in Drosophila. This low-input method enables analysis of local translation with Drosophila genetics across developmental stages, genetic backgrounds, and disease models, and can be adapted for rare genotypes, other tissues and model systems requiring high sensitivity.
    Keywords:  genetics; molecular biology; neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2026.115530
  26. Traffic. 2026 Jun;27(2): e70036
    A Toolbox for Quantifying Nuclear and Nucleolar Protein Accumulation Using NLS and NoLS Fusion Reporters.
    Eugene A Arifulin, Yana R Musinova, Ulyana V Matveeva, Eugene V Sheval.
      Fluorescent proteins that are fused to nuclear localization signals (NLSs) or nucleolar localization signals (NoLSs) are commonly used to investigate the accumulation of proteins within the nucleus and nucleolus. These reporters allow for the in vivo evaluation of signal sequence function, independent of the surrounding protein context. Here, we present a standardized protocol for measuring nuclear and nucleolar accumulation using NLS- and NoLS-fusion reporters. The workflow integrates plasmid construction, transfection, expression control, imaging and computational analysis to minimize artifacts and enhance reproducibility. This framework provides a robust basis for the reliable quantification of NLS- and NoLS-mediated localization and allows for the comparison of nuclear transport mechanisms across studies.
    Keywords:  cytoplasm; importins; live‐cell imaging; nuclear localization signal (NLS); nucleolar localization signal (NoLS); nucleolus; nucleus
    DOI:  https://doi.org/10.1111/tra.70036
  27. J Biol Chem. 2026 Apr 16. pii: S0021-9258(26)00327-3. [Epub ahead of print] 111455
    Role of mitochondrial translation in modulating inflammatory disease outcome: current knowledge and future perspectives.
    Swarnali Basu, Rukshar Khan, Shiva Sharma, Priyanka Prajapati, Veena Ammanathan, Sumit Rungta, Amit Lahiri.
      Mitochondrial translation is crucial for maintaining cellular respiration, energy balance, calcium signaling, apoptosis, immune surveillance, and the regulation of inflammatory responses. This specialized process, involving mitochondrial rRNAs, tRNAs, mitoribosomes, and nuclear-encoded translation factors, ensures the synthesis of mitochondrially encoded proteins that support oxidative phosphorylation. The mitochondrial translation cycle is tightly regulated by RNA-binding proteins, mitochondrial unfolded protein response, and stress-responsive pathways such as mTOR, particularly during metabolic shifts and immune activation. Emerging evidence highlights mitochondrial translation as a critical modulator of inflammation. In this review, we describe the alteration in mitochondrial-specific translation dynamics in immune cells, its adaptation to stress, and its interplay with organelle-wide signaling via mito-nuclear and mito-cytosolic communication. We focus on the alterations in mitochondrial translation machinery including mitoribosomal proteins, rRNA, tRNA synthetases or other regulatory factors linked to inflammatory diseases, including neurodegeneration, IBD, metabolic and cardiovascular disorders. We further examine how mitochondrial translation influences immune responses through mitochondrial DNA/RNA release, activation of mitochondrial damage-associated molecular patterns, and inflammasomes such as NLRP3. Collectively, mitochondrial translation functions as an immune centric-checkpoint that presents promising therapeutic target for intervention in inflammation-driven diseases.
    DOI:  https://doi.org/10.1016/j.jbc.2026.111455
  28. PLoS One. 2026 ;21(4): e0345890
    Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress.
    David K Sidibe, Erin M Smith, Maeve L Spivey, Maria C Vogel, Sandra Maday.
      Sequestosome 1/p62 (hereafter referred to as p62) is a multifunctional protein that orchestrates various cellular stress response pathways including autophagy, proteasome-mediated degradation, antioxidant defense, nutrient sensing, and inflammatory signaling. Mutations in distinct functional domains of p62 are linked with the neurodegenerative disease amyotrophic lateral sclerosis (ALS), underscoring its importance in neural cells. Neurons and astrocytes, two key cell types in the brain, perform distinct roles in brain physiology and thus encounter a unique landscape of cellular stress. However, how p62 is regulated in these cell types in response to various stress modalities remains largely unexplored. Several functions for p62 depend on its engagement with ubiquitinated substrates. Thus, we investigated how the regulation of p62-ubiquitin conjugates differs between neurons and astrocytes exposed to two stress modalities: lysosomal membrane damage and metabolic stress. Lysosomal damage triggered ubiquitin-dependent assembly of p62 puncta in both neurons and astrocytes. In contrast, nutrient deprivation elicited different responses between neurons and astrocytes. Neurons formed p62-ubiquitin structures more prominently and displayed a greater dependence on ubiquitin for p62 clustering. Together, these findings reveal cell-type-specific and stress-specific regulation of p62-ubiquitin conjugates, indicating that neurons and astrocytes can deploy distinct quality control strategies.
    DOI:  https://doi.org/10.1371/journal.pone.0345890
  29. Mol Cell. 2026 Apr 21. pii: S1097-2765(26)00205-4. [Epub ahead of print]
    Multi-site DMS probing reveals higher-order structure of RNA-protein complexes in living cells.
    Irfana Saleem, Thomas Miller, Lucas Kearns, Anthony Hoang, Joshua Meehan, Ritwika Bose, David Mitchell, David H Price, Calla M Olson, Chase A Weidmann, Anthony M Mustoe.
      Identifying tertiary structures and protein binding sites in RNA molecules remains a key challenge in RNA biology. We describe multi-site dimethyl sulfate (DMS)-mutational profiling (MaP) (msDMS-MaP), a strategy that enables simultaneous measurement of RNA secondary, tertiary, and quaternary structures via a single DMS chemical probing experiment. Optimized reverse transcription decodes typically invisible DMS N7-methylguanine (N7-G) modifications via a tautomer-induced mutational signature concurrent with N1 and N3 modifications. We show that N7-G reactivity reports on higher-order RNA structures, revealing key functional motifs such as pseudoknots and protein binding sites. Using msDMS-MaP, we find that E. coli ribosomal RNAs encode numerous independently folding tertiary structures that coincide with binding sites for primary assembly proteins. We further apply msDMS-MaP to define the quaternary structural ensemble of the 7SK small nuclear ribonucleoprotein particle (snRNP), revealing that each of the three 7SK structural isoforms possesses distinct protein binding profiles in cells. msDMS-MaP represents a broadly applicable strategy for enhanced RNA functional motif discovery and characterization.
    Keywords:  7SK; RNA binding proteins; RNA folding; RNA motif discovery; RNA structure; RNA tertiary structure; RNP; ribosome assembly; structure modeling
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.029
  30. Aging Cell. 2026 May;25(5): e70513
    Long-Term Stress Adaptation as a Highly-Conserved Key Factor in Yeast Aging.
    Yanzhuo Kong, Damola Adejoro, Christopher Winefield, Stephen L W On, Philip A Wescombe, Arvind Subbaraj, Andrew Saunders, Venkata Chelikani.
      Aging is commonly viewed as a passive consequence of accumulated damage; however, emerging evidence suggests that it may also represent an adaptive response to environmental stress. Here, we combined transcriptomic and metabolomic profiling of Saccharomyces cerevisiae to investigate how short-term, long-term, and recovery phases of stress exposure shape cellular physiology and lifespan. Short-term stress-induced protective pathways and longevity-associated metabolites, including trehalose and 5'-methylthioadenosine, consistent with enhanced stress resilience and proteostasis. In contrast, prolonged stress activated heat shock proteins and epigenetic regulators, coupled with metabolic signatures associated with loss of proteostasis, reduced energy homeostasis, and shortened chronological lifespan. Upon recovery, beneficial metabolites such as S-adenosylhomocysteine were restored, highlighting the reversibility of stress-induced aging trajectories. Phylogenetic analysis demonstrated conservation of these stress- and aging-related genes across eukaryotes and prokaryotes, suggesting an evolutionary basis for aging as a long-term stress adaptation. Together, these findings suggest that aging-associated molecular changes are closely linked to conserved stress response pathways, with implications for understanding the hallmarks of aging.
    Keywords:  cell aging and yeast biology; cell survival; stress adaptation; stress response
    DOI:  https://doi.org/10.1111/acel.70513
  31. Nat Commun. 2026 Apr 21.
    Isoform-specific m6A deposition and coordinated splicing shape mammalian transcriptome evolution.
    Gabriela Santos-Rodriguez, Akanksha Srivastava, Agin Ravindran, Favour O Oyelami, Chi Kin Ip, Pallavi Gupta, Jeanette Villanueva, Helen E King, Abigail Grootveld, Alexandra Sneddon, James Blackburn, Ishaan Gupta, Helaine Graziele Santos Vieira, Nikolay E Shirokikh, Eduardo Eyras, Robert J Weatheritt.
      Alternative isoform usage and RNA modifications are fundamental to transcriptome evolution. Among these, N6-methyladenosine (m6A), the most abundant internal mRNA modification, plays a key role in gene regulation. However, due to the limitations of short-read technology, the evolutionary conservation and phenotypic impact of transcript isoforms and m6A modifications remain incomplete. Here we present a comparative evolutionary analysis using direct-RNA long-read sequencing of six tissues from species representing three major clades within Mammalia, along with an avian outgroup. We find that although 71% of transcript isoforms are species-specific, they contribute less than 3% to total mRNA gene expression, whereas 18% of mammalian-conserved isoforms account for the majority of mRNA gene expression. We also identify that 14.2% of m6A modification sites, present in 39% of genes, are conserved across mammals, with enrichment in 3'-untranslated regions and stop codon-proximal regions. Notably, 27.3% of conserved m6A sites display isoform-specific deposition, supporting a role for epitranscriptomic regulation in maintaining functional transcript diversity. Finally, we uncover widespread conservation of coordinate splicing, in which exon co-regulation compensates for frameshift-inducing changes in individual exons, suggesting a buffering mechanism in isoform regulation. Together, these findings provide insight into how post-transcriptional regulation shapes phenotypic diversity and evolutionary adaptation in mammals.
    DOI:  https://doi.org/10.1038/s41467-026-72124-1
  32. Microb Cell. 2026 ;13 131-147
    TOR-dependent regulation of the yeast homolog of the juvenile Batten Disease-associated gene CLN3.
    Vijaykumar Pillalamarri, Samuel W M Gatesy, Amanda E Grassel, Lucienna Wolf, Justin P Whalley, David M Mueller.
      The Juvenile form of Batten disease is a neurodegenerative disease with symptoms starting in the first decade and ending in death in the third decade of life. The gene defective in this form of Batten disease, CLN3, is conserved in eukaryotes, suggesting that the gene product serves a basic function in the cell, though the function is unknown. We have investigated the expression and regulation of the yeast homolog BTN1. Reanalysis of publicly available gene expression data suggests that transcription of BTN1 increases in response to oxidative stress, treatment with rapamycin or arsenate, amino acid starvation, and sporulation conditions. Similar to GCN4, there are upstream open reading frames (uORF) in front of BTN1, suggesting translational regulation. We developed reporter strains in which the HIS3 open reading frame replaced that of the BTN1 gene, with and without the uORFs. These reporters show that one or more of the uORFs decrease the expression of the HIS3 reporter. When expressed in the reporter strain using a high copy vector, GCN3, tRNA Arg , and tRNA Leu , increase expression, suggesting the involvement of the TORC1 pathway. BIT61 abuts BTN1 but is encoded on the opposite strand; 3' RACE analysis indicates that the mRNA of BIT61 overlaps with that of BTN1. BIT61 is involved in the TORC2 pathway, which interacts with the TORC1 pathway, suggesting a possible cis-acting mechanism of co-regulation. Lastly, we demonstrate that a yeast strain with a null mutation in BTN1 is sensitive to selective amino acid starvation, further supporting the association of BTN1 with TORC1.
    Keywords:  BTN1; Batten Disease; CLN3; amino acid starvation; translational regulation
    DOI:  https://doi.org/10.15698/mic2026.03.872
  33. Nucleic Acids Res. 2026 Apr 23. pii: gkag387. [Epub ahead of print]
    ShapeRNA: an integrated web server for RNA secondary structure, ensemble, and functional analysis.
    Jialu Liang, Minghao Zhou, Mingyi Xie, Qianqian Song.
      RNA secondary structure plays a critical role in gene regulation, yet existing computational and experimental tools for structure analysis are often fragmented across prediction, ensemble modeling, and functional interpretation workflows. Here, we present ShapeRNA, a user-friendly web server for integrated RNA secondary structure prediction, ensemble inference, and structure-aware regulatory annotation. ShapeRNA supports three complementary analytical workflows, including sequence-based structure prediction, reactivity-guided modeling using SHAPE or DMS data, and sequencing-guided ensemble inference from high-throughput probing experiments. The platform integrates multiple established prediction algorithms and provides standardized data processing, ensemble clustering, and visualization. In addition, ShapeRNA enables mapping of RNA modification sites, microRNA target regions, and RNA-binding protein interaction motifs onto predicted RNA structures and representative ensemble conformations. We demonstrate the utility of ShapeRNA through applications including analysis of mutation-associated structural changes in MAPT exon 10, characterization of conformational heterogeneity in the HIV-1 Rev Response Element, and regulatory annotation of the oncogenic long non-coding RNA HULC. ShapeRNA provides an accessible and extensible platform for investigating RNA structural heterogeneity and regulatory mechanisms. This website is free and open to all users, and there is no login requirement. The server is accessible at https://shaperna.com.
    DOI:  https://doi.org/10.1093/nar/gkag387
  34. Nucleic Acids Res. 2026 Apr 13. pii: gkag303. [Epub ahead of print]54(7):
    Computational prediction-combined proteogenomics unveils widespread non-AUG translation initiation events in plants.
    Yuqian Zhang, Baiyang Chang, Shunxi Wang, Lei Tian, Huina Zhao, Weiwei Luo, Hanxue Zhang, Shoudong Zhang, Shubiao Wu, Liuji Wu.
      Non-AUG translation initiation can generate N-terminally extended proteoforms, contributing to proteome complexity and regulatory diversity. While well characterized in mammals, its identification in plants remains limited, hindering both functional investigations and cross-species comparisons. Here, we applied a computational prediction-combined proteogenomic strategy to systematically explore non-AUG translation initiation events in the monocots maize and rice and the dicot soybean, identifying 879 transcripts potentially producing 3 938 N-terminally extended proteoforms. These events exhibited both conserved and lineage-specific mechanistic features, including stable RNA secondary structures flanking upstream translation initiation sites (uTISs), codon and sequence context preferences between monocot and dicot species, and a lack of evolutionary conservation. Plant N-terminal extensions were predicted to encode diverse targeting signals, implicating them in subcellular localization and functional diversification. Comparative analysis revealed both conserved trends and plant-specific features relative to humans. Collectively, this study provides a foundational resource and conceptual framework to advance understanding of plant non-AUG translation within a cross-kingdom evolutionary context. It also offers new opportunities to elucidate the roles of non-AUG translation in regulatory networks, proteome diversification, and adaptive biological functions across eukaryotic systems.
    DOI:  https://doi.org/10.1093/nar/gkag303
  35. Redox Biol. 2026 Apr 19. pii: S2213-2317(26)00176-X. [Epub ahead of print]93 104178
    m6A epitranscriptomic remodeling links redox stress to mitochondrial quality control and programmed cell death in sepsis-induced myocardial dysfunction.
    Meilian Chen, Binlan Fu, Qiaomin Wu.
      Sepsis-induced myocardial dysfunction (SIMD) is a major contributor to sepsis-related mortality and is characterized by excessive oxidative stress, mitochondrial dysfunction, and heterogeneous forms of programmed cell death. However, how cardiomyocytes interpret redox stress and commit to distinct death pathways remains incompletely understood. Increasing evidence suggests that N6-methyladenosine (m6A), the most abundant internal RNA modification, functions as a dynamic post-transcriptional regulator linking redox signaling to mitochondrial homeostasis and cell fate decisions. This review summarizes recent advances indicating that m6A-dependent regulatory networks integrate mitochondrial reactive oxygen species (mtROS), mitochondrial quality control (MQC), and downstream cell death pathways in SIMD. Under septic conditions, sustained inflammation and oxidative stress perturb the balance of m6A writers, erasers, and readers, leading to maladaptive remodeling of mitochondrial dynamics, mitophagy, and biogenesis. Such epitranscriptomic dysregulation is associated with mtROS accumulation, impaired mitochondrial renewal, and a shift from adaptive redox compensation toward irreversible cardiomyocyte injury. Importantly, emerging evidence suggests that m6A remodeling does not uniformly activate cell death but modulates redox signal processing in a context-dependent manner. Preferential amplification of inflammatory sensing and inflammasome signaling may bias mtROS toward pyroptotic execution, whereas compromised antioxidant capacity, iron handling, and lipid metabolism may increase vulnerability to ferroptosis. On this basis, we propose the m6A-ROS-MQC axis as a unifying, hypothesis-driven framework for understanding SIMD pathogenesis, in which m6A acts as a redox-responsive epitranscriptomic regulator coordinating mitochondrial adaptation and programmed cell death decisions.
    Keywords:  Ferroptosis; Mitochondria; Oxidative stress; Pyroptosis; Sepsis; m6A
    DOI:  https://doi.org/10.1016/j.redox.2026.104178
  36. Autophagy. 2026 Apr 23. 1-15
    Depletion of TECPR2 leads to mitochondrial failure associated with neurodegeneration.
    Madhuri Chaurasia, Milana Fraiberg, Nemanja Subic, Oren Shatz, Kamilya Kokabi, Olee Gogoi, Olena Trofimyuk, Bat Chen Tamim-Yecheskel, Saskia Freud, Alik Demishtein, Ekaterina Kopitman, Inna Goliand, Sabita Chourasia, Yoav Peleg, Elena Ainbinder, Nili Dezorella, Zvulun Elazar.
      HSAN9 is a rare progressive neurodegenerative disease in children linked to bi-allelic loss-of-function mutations in the TECPR2 gene. TECPR2 is a multi-domain protein harboring N-terminal WD repeats and C-terminal TECPR repeats, followed by a functional LIR motif that serves in phagophore targeting. Here, we demonstrate that the absence of TECPR2 results in impaired mitophagy, which can be restored by expressing its C-terminal domain. Accordingly, we uncover severe mitochondrial dysfunction and accumulation of mitochondrial content in primary fibroblasts derived from an HSAN9 patient, as well as in embryonic fibroblasts and dorsal root ganglia derived from an HSAN9 mouse model. Notably, these mitochondrial defects are mediated by mitochondrial stress through the activation of the integrated stress response (ISR), whereas mitochondrial function is restored by pharmaceutical or genetic suppression of ISR. Our findings establish a new connection between mitophagy and ISR in maintaining mitochondrial homeostasis during neurodegeneration.Abbreviations: Baf. A1: bafilomycin A1; CYCS: cytochrome c, somatic; HSAN9: hereditary sensory and autonomic neuropathy IX; ISR: integrated stress response; OA: oligomycin + antimycin A; ROS: reactive oxygen species; TECPR2: tectonin beta-propeller repeat containing 2.
    Keywords:  HSAN9; TECPR2; integrated stress response; mitophagy; neurodegeneration; unfolded protein response
    DOI:  https://doi.org/10.1080/15548627.2026.2660850
  37. Physiol Plant. 2026 Mar-Apr;178(2):178(2): e70899
    Keeping UTRs in Their Place: Clarifying Transcript-Genomic Boundaries.
    Batoul M Ibrahim, Rahmat Ali, Zhixin Xie.
      Untranslated regions (UTRs) are defining features of mature messenger RNAs (mRNAs), yet a brief, non-exhaustive survey of recent literature reveals numerous instances of conceptually significant conflation between transcript-defined UTRs and genomic DNA segments. Because UTRs arise only after transcription initiation, RNA processing, and transcript maturation, applying UTR terminology directly to promoter-proximal or downstream flanking regions of a protein-coding gene obscures the fundamental distinction between genomic coordinates and the RNA molecules they encode. In this Viewpoint, we highlight this recurring conceptual drift and use the well-characterized Arabidopsis thaliana PHOSPHATE2 (PHO2) locus to illustrate how transcript, cDNA, and genomic representations differ and why they must not be interchanged. Representative examples from plant biology and related fields suggest that this misapplication has spread across otherwise credible studies and is now appearing in the secondary literature. Although such errors rarely alter empirical conclusions, they undermine terminological clarity, complicate genome annotation and figure labeling, and hinder the training of early-career researchers. Reinforcing the transcript-specific definition of UTRs is therefore essential for maintaining precision and coherence in scientific communication.
    Keywords:  cis‐regulatory elements; coding sequence (CDS); genomic flanking regions; transcript‐genome boundaries; untranslated regions (UTRs)
    DOI:  https://doi.org/10.1111/ppl.70899
  38. Infect Immun. 2026 Apr 21. e0003726
    Interplay between proteostasis pathways and innate immune responses in Caenorhabditis elegans.
    Annesha Ghosh, Jogender Singh.
      Microbial pathogens frequently manipulate host protein homeostasis to undermine immunity by targeting protein synthesis, folding, trafficking, and degradation. Conversely, effective immune responses themselves impose substantial proteostatic demands, as the rapid production of antimicrobial effectors increases the burden on cellular quality-control systems. This bidirectional pressure has likely driven the evolution of surveillance mechanisms that sense disruptions in protein homeostasis as indicators of infection. Using Caenorhabditis elegans as a genetically tractable model, recent studies have revealed that perturbations in proteostasis across multiple cellular compartments, including the cytosol, endoplasmic reticulum (ER), mitochondria, proteasome, and extracellular space, are actively integrated with innate immune signaling. Stress-response pathways such as the heat shock response, translational regulation, and the unfolded protein responses of the ER and mitochondria function not only to restore proteome integrity but also to directly shape immune gene expression and pathogen resistance in a context-dependent manner. This review highlights proteostasis as an evolutionarily conserved immune surveillance system, linking cellular stress sensing to host defense and offering broader insights into the coupling of stress adaptation, immunity, and organismal health.
    Keywords:  C. elegans; endoplasmic reticulum; mitochondria; proteasome; unfolded protein response
    DOI:  https://doi.org/10.1128/iai.00037-26
  39. J Hazard Mater. 2026 Mar 15. pii: S0304-3894(26)00770-3. [Epub ahead of print]510 141792
    A Trojan Horse in the soil: Tetracycline hijacks plant organellar ribosomes to stunt growth and unbalance the rhizosphere microecology.
    Wei Han, Yuan Liu, Xinying Liang, Jiaxin Liu, Qun Jiang, Congyu Zhang, Ying Zhang.
      Tetracycline, a widely used antibiotic, accumulates in agricultural soils and poses significant risks to crop development and soil health. This study elucidates novel mechanisms of TC phytotoxicity by demonstrating its specific binding to the structurally conserved A-site of ribosomal small subunit RNA (SSU rRNA) in plant mitochondria and chloroplasts-organelles of prokaryotic origin. Through integrated physiological, transcriptomic, and structural analyses, we show that TC disrupts ribosomal function, induces oxidative stress, and impairs photosynthesis and antioxidant defense in soybean, and unbalances the SSU/LSU (ribosomal large subunit RNA) rRNA ratio. We further developed a comprehensive Ecological Risk Index (ERI) framework that integrates soil physicochemical properties, enzyme activities, microbial metabolism, and community structure to evaluate soil microecological shifts under TC stress. Metagenomic analysis uncovered functional adaptations in microbial nitrogen/phosphorus cycling and emphasized the role of multidrug resistance genes-rather than tetracycline-specific resistance-via mobile genetic elements, including those from ssDNA viruses. Our findings provide unprecedented insights into the evolutionary conservation of ribosomal targets of antibiotics and establish a holistic framework for assessing the ecological impact of antibiotic residues in agroecosystems.
    Keywords:  Phytotoxicity; Ribosome RNA; Soil microecology; Tetracycline
    DOI:  https://doi.org/10.1016/j.jhazmat.2026.141792
  40. J Immunol. 2026 Apr 15. pii: vkag067. [Epub ahead of print]215(4):
    IGF2BP2 condensates stabilize DOK3 to negatively regulate inflammatory responses.
    Jian Chen, Weixin Chen, Xiaojing Shan, Peng Lu, Zhangyi Sun, Siyun Chen, Bo Liu, Chenglei Wu, Bing Lu.
      Negative regulators are crucial for maintaining immune homeostasis, yet the complexities of their regulatory mechanisms are not fully elucidated. In this study, we reveal that IGF2BP2, an m6A reader protein, orchestrates the formation of phase-separated condensates dependent on G3BP1, acting as a pivotal negative regulator of bacterial-induced inflammation. The absence of IGF2BP2 amplifies the production of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β, whereas its overexpression attenuates these inflammatory responses. Mechanistically, IGF2BP2 depletion enhances NF-κB signaling by diminishing DOK3 expression upon bacterial stimulation. Restoration of DOK3 expression in IGF2BP2-deficient cells markedly mitigates this hyper-inflammatory phenotype. Additionally, we identify m6A modifications at nucleotides 1056 and 1101 on DOK3 mRNA that facilitate its binding and stabilization by IGF2BP2. These insights provide a novel understanding of how IGF2BP2 modulates immune responses via m6A-dependent stabilization of DOK3 mRNA and highlight potential therapeutic avenues for treating inflammatory diseases.
    Keywords:  IGF2BP2; biomolecular condensates; immune regulation; inflammation; m6A modification
    DOI:  https://doi.org/10.1093/jimmun/vkag067
  41. Trends Pharmacol Sci. 2026 Apr 20. pii: S0165-6147(26)00084-2. [Epub ahead of print]
    Pharmacological strategies targeting chaperone-mediated autophagy.
    Eva Berenger, Alice Maestri, Daniel R Vaz, Elena Kochetkova, Erik Norberg, Vitaliy O Kaminskyy, S Joseph Endicott, Helin Vakifahmetoglu-Norberg.
      Chaperone-mediated autophagy (CMA) is a selective lysosomal protein degradation pathway that regulates proteostasis, metabolism, and stress adaptation. Genetic- and disease-model studies show that altered CMA activity contributes to diverse human disorders, including neurodegenerative, metabolic, inflammatory, and malignant diseases. However, pharmacological targeting has remained challenging due to a limited understanding of its regulatory architecture and a lack of criteria to distinguish pathway-selective from indirect modulation. Recent advances in mapping CMA regulatory checkpoints and the in vivo validation of CMA-biased compounds have revealed discrete, mechanistically defined control nodes that render CMA pharmacologically tractable. In this review, we synthesize these advances and introduce a mechanistic classification of CMA-modulating compounds by level of action, distinguishing physiological inducers, permissive potentiators, and proximal activators to clarify pathway selectivity and guide translational drug discovery.
    Keywords:  LAMP-2A; chaperone-mediated autophagy; pharmacological modulation; proteostasis; therapeutic targeting
    DOI:  https://doi.org/10.1016/j.tips.2026.03.008
  42. Cell Rep. 2026 Apr 22. pii: S2211-1247(26)00368-2. [Epub ahead of print]45(5): 117290
    PKR condensation at viral replication complexes initiates its activation.
    Ebba K Blomqvist, Nicole Bracci, Helena Winstone, J Monty Watkins, Susan R Weiss, James M Burke.
      Protein kinase R (PKR) is a critical component of mammalian intracellular antiviral immunity. Here, we examine the process of PKR activation in response to Middle East respiratory syndrome coronavirus (MERS-CoV) and Zika virus (ZIKV) using super-resolution confocal microscopy, proximity ligation assay, immunogold transmission electron microscopy, and live-cell imaging. Our data support that PKR activates upon condensation on double-stranded RNA (dsRNA) exposed at membrane-associated viral replication complexes. Subsequently, p-PKR condensates disassociate from dsRNA and dissolve, releasing activated PKR molecules into the cytosol, where they phosphorylate eIF2α to initiate the integrated stress response (ISR). Importantly, the disassociation of p-PKR from dsRNA allows for the exchange of inactive PKR monomers, thus promoting robust PKR activation from limited exposed viral dsRNA substrates. MERS-CoV NS4a prevents PKR activation via competitive condensation on viral dsRNA. These findings establish a comprehensive model for PKR activation in response to positive-strand RNA viruses that replicate within membrane-associated complexes.
    Keywords:  CP: microbiology; CP: molecular biology; DRIF; MERS-CoV; NS4a; PKR; Zika virus; condensation; dsRNA; innate immunity; nsp15; viral antagonist proteins
    DOI:  https://doi.org/10.1016/j.celrep.2026.117290
  43. Cancer Biol Med. 2026 Apr 16. pii: j.issn.2095-3941.2025.0698. [Epub ahead of print]
    The m7G RNA modification in gastrointestinal cancers: mechanisms and therapeutic potential.
    Rui Li, Xiaoqing Lu, Zhiyu Guan, Xianli Shi, Rongxin Zhang.
      The N7-methylguanosine (m7G) modification, an epigenetic transcriptional regulatory mechanism, plays a crucial role in the development of gastrointestinal malignant tumors. This modification, mediated by enzyme complexes such as methyltransferase-like 1 (METTL1)/WD repeat domain 4 (WDR4) and williams-beuren syndrome chromosome region 22 (WBSCR22)/tRNA methyl transferase activator subunit 11-2 (TRMT12), is widely distributed in messenger RNA (mRNA), transfer RNA (tRNA), ribosomal RNA (rRNA), and non-coding RNA. Its abnormal expression is closely associated with the pathogenesis of various gastrointestinal tumors, including hepatocellular carcinoma, colorectal cancer, pancreatic cancer, and esophageal cancer. The METTL1/WDR4 complex enhances the translation efficiency of oncogenes by promoting tRNA m7G modification, thereby facilitating tumor cell proliferation, metastasis, and chemotherapy resistance. More importantly, the m7G modification significantly influences tumor cell resistance to chemotherapy, targeted therapy, and radiation therapy by regulating the epidermal growth factor receptor (EGFR) signaling pathway, autophagy processes, and DNA repair mechanisms. Therefore, m7G modification has dual potential as both a prognostic biomarker and a therapeutic target, and may provide a molecular basis for precision medicine in the treatment of gastrointestinal tumors.
    Keywords:  Gastrointestinal cancers; METTL1/WDR4; WBSCR22/TRMT112; drug resistance; m7G modification
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2025.0698
  44. J Histotechnol. 2026 Apr 23. 1-13
    USP34 modulates mitochondrial function in triple-negative breast cancer cells through the eIf3m/MTCH2 axis.
    Peng-Fei Qian, Yi Zeng, Wang-Jing Zhong.
      Triple-negative breast cancer (TNBC) represents a particularly aggressive form of breast tumors. Mitochondrial dysfunction represses the proliferation of TNBC cells. Ubiquitin-specific proteases 34 (USP34) has been predicted to be abnormally overexpressed in TNBC. This research examined the role of USP34 in the mitochondrial function modulation of TNBC. Herein, cell proliferation was evaluated by the 5-ethynyl-2'-deoxyuridine assay. Mitochondrial membrane potential was detected employing the JC-1 assay. Mitochondrial superoxide was measured utilizing MitoSOX Red assay. Mito‑Tracker Red CMXRos staining was selected to monitor mitochondrial network structure. The relationship among USP34, eukaryotic translation initiation factor 3 m (eIF3m), and mitochondrial carrier homolog 2 (MTCH2) was validated by co-immunoprecipitation, GST-pull down, RNA immunoprecipitation and RNA-pull down analysis. We found that USP34 silencing inhibited cell proliferation by inducing mitochondrial dysfunction in TNBC cells. USP34 maintained the stability of the eIF3m protein through deubiquitination. Overexpression of eIF3m countered the mitochondrial dysfunction induced by USP34 silencing. Furthermore, eIF3m upregulated the MTCH2 level by directly binding to its 5'UTR region. MTCH2 overexpression reversed the damaging effect of eIF3m silencing on mitochondrial function. Collectively, USP34 maintained the stability of eIF3m protein through deubiquitination; the upregulated eIF3m bound to the 5'UTR of MTCH2 mRNA to promote MTCH2 expression, thereby maintaining mitochondrial function and promoting the malignant progression of TNBC.
    Keywords:  MTCH2; TNBC; USP34; eIF3m; mitochondrial function
    DOI:  https://doi.org/10.1080/01478885.2026.2648740
  45. RNA. 2026 Apr 22. pii: rna.080781.125. [Epub ahead of print]
    Direct RNA-seq provides evidence for an antiterminator function of the yeast Hrp1 protein on RNA polymerase II transcripts.
    Emma C Goguen, Kylie A Zawisza, David A Brow.
      Hrp1/Nab4 is an essential nuclear RNA-binding protein that was first identified in the yeast Saccharomyces cerevisiae as a cleavage and polyadenylation factor for mRNAs, CF1B, but was later shown to promote termination of some short, noncoding transcripts via the "NNS" termination pathway. Hrp1 binds (UA)n repeats found in both mRNA 3'-UTRs and short noncoding RNA terminators, but its function in 3'-end formation is not fully understood. Our past microarray transcriptome analysis of the heat-sensitive hrp1-7 allele suggested Hrp1 functions in antitermination of RNA polymerase II (RNAP II) on protein-coding genes. The hrp1-7 allele has four substitutions and one, M191T, was shown to be primarily responsible for NNS terminator readthrough. Here we show that Hrp1-7 protein has a three-fold and Hrp1-M191T a 1.5-fold decreased affinity for (UA)4 in vitro. We used nanopore direct RNA sequencing to assess the transcriptome-wide effects of hrp1-7 and hrp1-M191T, which identified new examples of Hrp1-dependent small nucleolar RNA terminators and mRNA attenuators (regulatory terminators in the 5'-UTR and ORF). For some genes, including HRP1, attenuated transcript reads outnumber the corresponding mRNA reads in exponentially growing wildtype cells. We also observed widespread changes in mRNA polyA site selection. In the hrp1-M191T strain the polyA site shifts are mostly downstream, while in the hrp1-7 strain upstream and downstream shifts are more similar in frequency. Our results are consistent with a model in which one or more of the four substitutions in hrp1-7 weaken the affinity of Hrp1 for the RNAP II elongation complex, promoting premature termination, while others interfere with its recognition of terminator sequences, promoting terminator readthrough.
    Keywords:  RNA Polymerase II; polyadenylation; transcription; transcription termination; yeast hnRNP proteins
    DOI:  https://doi.org/10.1261/rna.080781.125
  46. Comput Struct Biotechnol J. 2026 ;35(1): 0022
    Eigenvalue Ratios Reveal Shared Binding Pocket Shapes in RNA and Protein Structures.
    Leïla Ziani, Anne Badel, Léa Dufay, Delphine Flatters, Leslie Regad, Anne-Claude Camproux.
      Molecular recognition in drug design relies on accurate characterization of ligand-binding pockets on macromolecular targets such as proteins and RNA. While protein binding sites have been extensively described, the geometric organization of RNA pockets remains comparatively underexplored. Here, we introduce a unified and size-independent geometric framework to describe and compare RNA and protein binding pocket shapes. Pocket geometry is captured using size-independent and residue-agnostic measures of global anisotropy, enabling direct comparison across RNA and protein binding pockets without introducing macromolecule-specific assumptions. This approach defines 4 interpretable pocket shape archetypes: sphere-like, rod-like, disk-like, and strongly anisotropic. Application to balanced datasets of 300 RNA and 300 protein binding pockets reveals a largely shared geometric landscape, with substantially overlapping shape descriptors within each archetype. However, archetype frequencies differ: Sphere-like pockets are more frequent in proteins, whereas disk-like and strongly anisotropic pockets are enriched in RNA, while rod-like pockets occur at comparable frequencies. Notably, strongly anisotropic pockets lacking a dominant symmetry axis represent a substantial fraction of pockets in both datasets. By organizing diverse binding sites into a small number of reproducible geometric regimes, this framework reduces structural heterogeneity and provides a transferable geometrical reference for comparative analysis of RNA and protein pocket architectures, thereby supporting the exploration of RNA pocket accessibility in structure-based studies.
    DOI:  https://doi.org/10.34133/csbj.0022
  47. Ecol Evol. 2026 Mar;16(3): e73275
    Metaproteome Analysis of Short-Term Thermal Stress in Three Sympatric Coral Species Reveals Divergent Host Responses.
    Shrinivas Nandi, Timothy G Stephens, Erin E Chille, Samantha Goyen, Line K Bay, Debashish Bhattacharya.
      Anthropogenic climate change has contributed to the accelerating loss of coral reefs worldwide. This crisis has led to a myriad of studies aimed at understanding the basis of coral resilience to support reef conservation. Here, we compare physiological, proteomic, and metabolomic responses to acute thermal stress to identify both diverged and conserved stress response strategies and molecular markers of bleaching susceptibility in three different coral species. We find species-specific responses with the thermally sensitive Acropora hyacinthus exhibiting a rapid decline in endosymbiont physiology (~19% decline in photosynthetic efficiency and a -1.88 fold change in abundance), coupled with one-third of proteins showing a reduction in abundance. In contrast, Porites lobata displayed a delayed physiological and proteomic (~5% initial; ~14% prolonged) response to stress, suggesting greater resilience. Stylophora pistillata initially showed shifts in the proteome (~11%) followed by colony "bail-out", that is, rapid tissue loss. Overall, we observed markedly different responses in most biochemical pathways in the three coral species. Nonetheless, some known biomarkers of stress, including heat-shock proteins, showed conserved, cross-species responses to thermal stress with differences in temporal abundance reflecting bleaching resistance. Metabolomic profiling revealed an increase in stress-associated dipeptides and free amino acids in all three species, although species-specific and temporally variable responses occurred. Our results underscore the species-specific nature of coral responses to thermal stress and highlight proteomic signatures associated with symbiosis breakdown, offering mechanistic insights into coral bleaching susceptibility and resilience. Overall, these findings enhance our ability to identify early-warning indicators of bleaching and underscore the challenges associated with the development of universal coral stress biomarkers.
    Keywords:  coral bleaching; great barrier reef; holobiont; metaproteomics; protein abundance; stony corals; thermal stress
    DOI:  https://doi.org/10.1002/ece3.73275
  48. Physiol Plant. 2026 Mar-Apr;178(2):178(2): e70895
    HSP101 Polymorphism Is Related to Heat Tolerance and Seedling Growth in Wild-Type Arabidopsis Accessions From Diverse Geographical Locations.
    Gayatri Tripathi, Neelam K Sarkar, Anil Grover.
      HSP101 is vital in resolving protein aggregates formed under heat stress. However, the role of this protein has not been adequately analyzed in larger populations considering their variation in growth and survival under non-heat stress, heat stress, and post-heat stress recovery conditions. Employing 29 Arabidopsis thaliana accessions representing diverse locations of the globe, we analyzed the natural variations in the amino acid sequence of HSP101, expression levels of HSP101 protein, and the thermotolerance response. Taking the HSP101 amino acid sequence of Col-0 ecotype as a reference point, the HSP101 sequence of the analyzed accessions showed significant variations in terms of deletions and substitutions of amino acids. The HSP101 protein level was variable under non-heat stress, heat stress, and post-heat stress recovery conditions amongst the accessions. The seedling basal thermotolerance response was likewise variable among the accessions, and importantly, HSP101 levels showed a positive correlation with the survival of the seedlings during the post-heat stress recovery conditions. The HSP101 levels and the growth of the seedlings showed a negative correlation, indicating that there is a trade-off between the HSP101 levels and the growth of the seedlings.
    Keywords:  Arabidopsis; HSP101; heat stress; natural accessions; natural variations; seedling development; thermotolerance
    DOI:  https://doi.org/10.1111/ppl.70895
  49. Int J Biol Sci. 2026 ;22(7): 3714-3730
    eEF2K-Mediated Stabilization of PCBP2 Promotes Oncogenic mRNA Programs in Triple-Negative Breast Cancer.
    Yueying Cheng, Ting Jiang, Wenqian Zhu, Linhao He, Zongling Chen, Hang Li, Ruigang Zhao, Shilong Jiang, Yan Cheng.
      Triple-negative breast cancer (TNBC), characterized by the absence of effective therapeutic targets, remains a major clinical challenge with poor prognosis. The identification of novel molecular targets is therefore crucial for developing effective treatment strategies. Eukaryotic elongation factor 2 kinase (eEF2K) is highly expressed in TNBC and known to promote tumor progression; however, the precise mechanisms underlying its oncogenic role remain elusive. In this study, we identified poly(rC)-binding protein 2 (PCBP2) as a previously unrecognized downstream substrate of eEF2K. Analysis of clinical TNBC specimens revealed a positive correlation between eEF2K and PCBP2 protein expression levels. Further studies demonstrated that site-specific phosphorylation of PCBP2 at serine 189 (Ser189) markedly promoted the malignant phenotype of TNBC cells. Mechanistically, eEF2K-mediated phosphorylation at Ser189 stabilized PCBP2 by preventing its ubiquitin-proteasome-dependent degradation. This phosphorylation-dependent stabilization, in turn, enabled PCBP2 to promote the mRNA stability of pro-oncogenic genes, including TNC, SOX5, and ITGB3, thereby driving TNBC progression. Collectively, these findings not only reveal PCBP2 as a critical downstream effector of eEF2K, but also highlight the eEF2K-PCBP2 signaling axis as a promising therapeutic target for TNBC.
    Keywords:  PCBP2; eEF2K; mRNA stability; triple-negative breast cancer; ubiquitin-proteasome degradation
    DOI:  https://doi.org/10.7150/ijbs.127111
  50. Chem Biodivers. 2026 Apr;23(4): e02512
    Protective Effects of Murrayafoline A Against Heat-Induced Male Infertility in Drosophila melanogaster: In Vivo Studies and In Silico Evidence for a Potential Interaction With Vasa.
    Nguyen Viet Phong, Hyo-Sung Kim, Yan Zhao, Eunbyul Yeom, Seo Young Yang.
      Male infertility, often caused by disruptions in spermatogenesis-the differentiation of diploid germline stem cells into mature spermatozoa-is a global concern. Vasa, a DEAD-box RNA helicase, plays a crucial role in this process, particularly in Drosophila melanogaster, where it regulates mRNA translation essential for germline development. Murrayafoline A (MurA), a carbazole alkaloid from Glycosmis stenocarpa, shows therapeutic potential for the treatment of various diseases. Therefore, this study aims to investigate the protective effects of MurA against heat-induced male infertility in Drosophila in vivo assays and computational simulations. Heat stress significantly reduced egg-hatching rates and impaired spermatogonia integrity, while MurA supplementation strongly improved these outcomes. Molecular docking revealed that MurA binds strongly to Vasa within the ATP-binding pocket, forming hydrogen bonds and hydrophobic interactions with a binding affinity of -8.67 kcal/mol. Molecular dynamics simulations confirmed stable Vasa-MurA interactions over 100 ns, with conserved residues and hydrophobic contacts stabilizing the complex. These findings, supported by in vivo rescue of fertility and germline integrity together with computational simulations, suggest a plausible mechanism of action for MurA that warrants further experimental investigation.
    Keywords:  Drosophila melanogaster; Murrayafoline A; Vasa; male infertility; molecular dynamics
    DOI:  https://doi.org/10.1002/cbdv.202502512
  51. Clin Sci (Lond). 2026 Apr 20. pii: CS20250814. [Epub ahead of print]
    Transcriptomic and Functional Analysis of Fibroid Extracellular Vesicles.
    Tsai-Der Chuang, Abigail Wiseman, Gabriela Alfaro, Shawn Rysling, Nhu Ton, Daniel Baghdasarian, Omid Khorram.
      Exosomes were isolated from cultures of fibroid explants and matched myometrial explants, and their RNA cargo was analyzed by next-generation sequencing to profile both long and short RNA species. Fibroid-derived exosomes (Fib-EXO) expressed the canonical EV markers CD81 and CD63, and their size distribution (30-200 nm) was consistent with exosomal vesicles. The RNA cargo of Fib-EXO generally reflected that of its tissue of origin, although selective enrichment of specific transcripts, such as piR-1398740 and piR-333378, suggested active loading mechanisms. Long RNA sequencing identified differential expression of protein-coding genes and lncRNAs involved in RNA binding, cytoplasmic translation, exosome pathways, and PI3K/AKT and focal adhesion signaling. qPCR validation confirmed increased IGF2, HOXA10, and decreased IGFBP6 mRNA expression in Fib-EXO. Among lncRNAs, MSC-AS1, PART1, and H19 were overexpressed in Fib-EXO. Small RNA sequencing revealed differential expression of multiple sncRNA classes, including piRNAs, miRNAs, snRNAs, snoRNAs, and tRNAs. KEGG analysis showed that miRNAs were primarily associated with PI3K/AKT signaling, proteoglycans in cancer, interleukin signaling, and transcriptional regulation. Functionally, Fib-EXO were internalized by myometrial cells and promoted their proliferation with no effects on apoptosis. Furthermore, Fib-EXO enhanced angiogenesis in HUVECs. Fib-EXO increased the expression of vimentin, EZH2, DNMT1, TGF-β3, and c-MYC, and phosphorylated p65 protein, reduced COL1A1 and COL3A1 expression, and decreased miR-133a, miR-29, and miR-200c while increasing miR-21 in cultured MSMC, mirroring changes observed in fibroids. These findings indicate that Fib-EXO reprogram myometrial cells toward a fibroid-like phenotype characterized by increased proliferation, inflammation and fibrotic features thus contributing to fibroid propagation.
    Keywords:  Exosome; Fibroid; Leiomyoma; lncRNA; miRNA; piRNA
    DOI:  https://doi.org/10.1042/CS20250814
  52. Stem Cell Res Ther. 2026 Apr 20.
    TGF-β/SMAD signaling maintains nucleus pulposus stem cell quiescence to protect against oxidative injury in intervertebral disc degeneration.
    Qi Chen, Xiaolong Chen, Qu Yang, Xinxin Miao, Jinghong Yuan, Shuihua Ding, Rui Ding, Shenghao Cai, Bin Li, Xigao Cheng.
       BACKGROUND: Intervertebral disc degeneration (IVDD) is characterized by progressive nucleus pulposus cell loss and extracellular matrix degradation, in which persistent oxidative stress plays a critical pathogenic role. Transplantation of nucleus pulposus-derived stem cells (NPSCs) is a promising therapeutic strategy, yet the hostile oxidative microenvironment severely compromises cell survival. Although cellular quiescence has been suggested to enhance stress tolerance, its regulatory mechanisms and relevance in NPSCs remain largely unexplored.
    METHODS: Oxidative stress was evaluated in human degenerated disc tissues, a rat needle-puncture degeneration model, and tert-butyl hydroperoxide-treated NPSCs in vitro. Proliferating and quiescent NPSCs were compared for reactive oxygen species (ROS) levels, apoptosis, viability, and transcriptomic profiles. Pathway enrichment analyses were performed to identify critical signaling mechanisms. Recombinant transforming growth factor-beta 3 (rhTGF-β3) was used to activate the pathway, while small interfering RNA targeting the transforming growth factor-beta receptor type 2 (Tgfbr2) and the pharmacological inhibitor SB431542 were applied for pathway suppression. Functional assays, organ culture, and in vivo transplantation were conducted to assess cell survival and regenerative effects.
    RESULTS: Elevated oxidative stress was consistently observed across clinical, animal, and cellular models of disc degeneration. Quiescent NPSCs demonstrated enhanced resistance to oxidative injury, with reduced ROS accumulation, decreased apoptosis, and improved survival. Transcriptomic analyses revealed suppression of metabolic and P53-mediated apoptotic pathways, alongside marked activation of TGF-β/SMAD signaling. Activation of this pathway induced quiescence, reduced ROS levels, inhibited mitochondrial apoptotic signaling, and protected NPSCs from oxidative injury, whereas pathway inhibition abolished these protective effects. In both organ culture and in vivo transplantation models, quiescent and TGF-β-activated NPSCs exhibited superior survival and significantly improved disc structural preservation compared with proliferating or pathway-blocked cells.
    CONCLUSION: Activation of the TGF-β/SMAD pathway induces NPSC quiescence and enhances oxidative stress tolerance by suppressing P53-dependent mitochondrial apoptosis. Pharmacological induction of quiescence represents a potential strategy to improve stem cell-based therapies for intervertebral disc degeneration.
    Keywords:  Apoptosis; IVDD; Nucleus pulposus stem cells; Oxidative stress; P53; Quiescence; TGF-β/SMAD signaling
    DOI:  https://doi.org/10.1186/s13287-026-05031-3
  53. J Cheminform. 2026 Apr 21.
    Generalizable deep-learning-based mRNA-protein interaction prediction strongly depends on protein diversity.
    Yu-Huai Yu, Han-Ting Hong, Tzu-Hsien Yang.
       BACKGROUND: Proteins regulate diverse biological processes through interactions with other molecules, including RNAs. RNA-binding proteins (RBPs) are essential regulators of gene expression, forming specific mRNA-protein interactions (mRPIs) that influence mRNA processing, translation, and stability. Recently, deep-learning models have been proposed to predict mRPIs using only sequence information, with some reporting near-perfect accuracy. However, such performance appears inconsistent with the biological complexity of RNA recognition by proteins, which is often influenced by protein tertiary structures that are computationally challenging to predict. In related fields such as protein-protein interaction prediction, data leakage, particularly caused by overlapping proteins between training and test sets, has been shown to substantially inflate performance metrics. Nevertheless, whether similar issues affect mRPI prediction has not yet been systematically investigated.
    RESULTS: We constructed an mRPI benchmark dataset from CLIP experiments and implemented two data partitioning schemes: a random interaction-level split and an RBP-aware split in which pairs of all test RBPs were excluded from training. Three RBP sequence encoding strategies were evaluated within an attention-based deep-learning framework under both partitioning settings: sequence-based one-hot encoding, language model-derived encoding, and structure-aware encoding. Across all models, performance remained high only when test RBPs were also present in the training data. When predicting interactions for unseen RBPs, performance dropped substantially, indicating limited generalization. Even replacing RBPs with their most similar counterparts from the training set did not meaningfully improve generalization. These results suggest that additional protein features beyond sequence information are required to achieve robust mRPI prediction. Overall, our study demonstrated that existing mRPI prediction models are largely overfitted to their original training RBPs and fail to generalize to unseen proteins.
    CONCLUSIONS: Overall, we provided a curated benchmark dataset, a rigorous evaluation framework, and an attention-based model that achieves the best generalization performance among currently available methods, with an approximately 8.5% auROC improvement over existing tools. These resources will facilitate the development of more reliable and broadly applicable mRPI prediction tools.
    SCIENTIFIC CONTRIBUTION: This work presented the first systematic investigation of data leakage and generalization in mRNA-protein interaction prediction, demonstrating that most reported near-perfect performance is largely driven by RBP overlap between training and test sets. By introducing an RBP-aware evaluation framework and a benchmark dataset, we revealed that most sequence-based models fail to generalize to unseen RBPs, even when enhanced with protein language model-derived and structure-aware encodings. Our study established a more rigorous evaluation standard for mRNA-protein interaction prediction, highlighting the critical need for protein diversity and beyond-sequence features to advance reliable mRNA-protein interaction prediction.
    Keywords:  Deep learning; Model generalization; RNA-protein interaction
    DOI:  https://doi.org/10.1186/s13321-026-01197-3
  54. Oncogene. 2026 Apr 22.
    PIWIL1 activates the R2TP-TELO2-mTORC1 axis independently of piRNA to promote TOP mRNA translation in gastric cancer.
    Tianqu Fan, Jiangsha Zhao, Ling Li, Meihua Cui, Jiawei Zhang, Tian Chi, Shuo Shi.
      PIWI proteins, a subfamily of the PAZ-PIWI domain (PPD) protein family, are traditionally regarded as germline factors that partner with PIWI-interacting RNAs (piRNAs) to silence transposons and regulate gene expression. However, growing evidence implicates PIWI proteins as oncogenic drivers in diverse somatic cancers, often acting through piRNA-independent mechanisms that remain incompletely understood. Here, we integrate transcriptomic, translatomic, and proteomic profiling of wild-type versus PIWIL1-knockout gastric cancer cells to uncover a non-canonical, translational role for PIWIL1, one of the four human PIWI proteins. We find that PIWIL1 selectively enhances the translation of 5'-terminal oligopyrimidine (TOP) mRNAs by activating mTOR complex 1 (mTORC1). Mechanistically, PIWIL1 interacts with the R2TP chaperone complex (RUVBL1-RUVBL2-RPAP3-PIH1D1) and promotes its association with TELO2, facilitating mTOR-RAPTOR assembly and mTORC1 activation. Functionally, PIWIL1 deficiency sensitizes gastric cancer cells to mTOR inhibition, and in clinical samples, PIWIL1 expression positively correlates with mTORC1 pathway activity. Together, these findings define a novel piRNA-independent mechanism through which PIWIL1 contributes to tumor progression, extend PIWI-mediated translational control from the germline to human cancers, and establish PIWIL1 as a potential therapeutic target for gastric cancer in synergy with mTOR inhibition.
    DOI:  https://doi.org/10.1038/s41388-026-03791-z
  55. Am J Cancer Res. 2026 ;16(3): 1215-1230
    THAP7-AS1 orchestrates IGF2BP3-m6A-dependent CCN2 mRNA stabilization to promote lymphatic metastasis in bladder cancer.
    Qiuyan Li, Junjie Bai, Shiwen Zheng, Jiaxuan Liao, Zesong Yang, Wanghai Cai, Jiexiang Lin, Liefu Ye.
      Lymphatic dissemination is a major cause of treatment failure in muscle-invasive bladder cancer (MIBC), yet the RNA circuits linking post-transcriptional regulation to lymphatic metastasis remain incompletely defined. Here, we identify THAP7-AS1 as a predominantly cytoplasmic long noncoding RNA that is markedly upregulated in lymph node (LN) metastatic bladder cancer (BCa) and is associated with poor clinical outcome. Functionally, THAP7-AS1 promotes invasion and transendothelial migration in vitro and enhances LN metastasis in vivo. Mechanistically, THAP7-AS1 interacts with the m6A reader IGF2BP3 and facilitates IGF2BP3 association with CCN2 mRNA, thereby promoting m6A-dependent stabilization of CCN2 transcripts and increasing CCN2 protein abundance. Genetic depletion of IGF2BP3 or CCN2 abrogates THAP7-AS1-driven invasive and metastatic phenotypes, whereas CCN2 re-expression partially rescues the effects of THAP7-AS1 silencing. Collectively, these findings define a THAP7-AS1-IGF2BP3-m6A-CCN2 axis that couples post-transcriptional mRNA stabilization to lymphatic metastasis and nominate THAP7-AS1 as a potential biomarker and therapeutic target in BCa.
    Keywords:  CCN2; IGF2BP3; Lymphatic metastasis; N6-methyladenosine (m6A); THAP7-AS1
    DOI:  https://doi.org/10.62347/WGQA3188
  56. RNA Nanomed. 2025 Apr;2(1): 70-88
    CD133-Guided RNA Nanoparticle Delivery of FTO siRNA Impairs Leukemia Resistance to Tyrosine Kinase Inhibitor Therapy.
    Huiqin Bian, Changli Zhou, Hiroaki Koyama, Wen Gao, Sicheng Bian, Tao Cheng, Xiaonan Han, William Tse, Alexander Miron, Shujun Liu.
      Despite the initial responses to the tyrosine kinase inhibitor (TKI) for cancer therapy, many patients often relapse with no curative regimens available. Further, the ability to target therapeutic agents to cancer cells with appropriate doses remains challenging in the clinic, especially for leukemia. Here, we show that naïve CML cells are dynamically heterogeneous in colony formation. Larger clones expand while smaller ones diminish and eventually disappear. Compared to resistant cells, parental populations, including CD44+ stem cells, form a greater number of larger, solid spheroids. Upregulation of fat mass and obesity associated protein (FTO), an RNA N 6 -methyladenosine demethylase, and stem cell markers (e.g., CD44, CD133, CD25) is more obvious in resistant cells compared to parental cells. FTO inhibitors (e.g., CS1, FB23-2) appreciably impair the growth of resistant cells either alone or in combination with nilotinib. FTO protein expression is unexpectedly upregulated by CS1 or FB23-2 treatment in multiple leukemia cell lines. We then constructed RNA nanoparticles encapsulating FTO siRNAs and conjugated with anti-CD133 RNA aptamers. We showed that, compared to negative control, these nanoparticles were taken up much more efficiently by resistant cells that highly express CD133. Treatment with the CD133-guided FTO siRNA nanoparticles efficiently silenced FTO expression in resistant cells, which leads to a significant reduction in their colony and spheroid formation. These findings offer new insights into cancer drug resistance and advance the application of RNA nanotechnology for treating leukemia. The research provides a foundation for developing novel, targeted therapies for resistant leukemia.
    Keywords:  CD133; FTO; Heterogeneity; Leukemia; RNA nanoparticles; colonies; drug resistance; leukemia stem cell; m6A; spheroids; tyrosine kinase inhibitors
    DOI:  https://doi.org/10.59566/isrnn.2025.0201e
  57. PLoS Pathog. 2026 Apr;22(4): e1013802
    Genetic complementation reveals structure-function links in nodavirus RNA replication complex crowns.
    Johan A den Boon, Helena Jaramillo-Mesa, Mark Horswill, Adam Jochem, Megan Bracken, Hong Zhan, Paul Ahlquist.
      Positive-strand RNA viruses replicate their RNA genomes in virus-induced, membrane-bounded organelles. As first found for nodaviruses, the necked cytosolic portals of these organelles bear ringed "crown" complexes of viral RNA replication proteins that drive synthesis, capping and release of new RNA genomes. Nodavirus crowns contain two 12-mer rings of viral protein A with C-proximal polymerase domains stacked. In the basal ring, protein A's N-proximal RNA capping domains form a central, toroidal floor, while in the apical ring these domains extend radially outward. A third protein A conformation provides a putative central Pol domain interacting with the viral dsRNA replication intermediate in a vesicle beneath the crown. Protein A's multiple conformations likely differentially contribute to crown assembly, RNA template recruitment, (-) and (+) strand synthesis, RNA capping, and progeny RNA release. Protein A's high copy numbers may provide robustness to these processes. To test such concepts, we combined mutational, complementation and functional analyses. Strong complementation between null mutants in protein A's polymerase and RNA capping active sites showed that they operate in independent protein A copies, likely at distinct sites. Thus, neither function is required in all protein A copies, nor are both required in any single copy. Lack of complementation between mutants in distinct RNA capping steps implied that major RNA capping steps must be performed in the same protein. Although RNA polymerase and capping activity were not required in all protein A subunits, none of a series of deletions across these domains were complementable, showing the importance of structural and other requirements for crown assembly, etc.. Surprisingly, RNA replication was more sensitive to depleting the fraction of subunits retaining protein A's C-terminal intrinsically disordered region than polymerase or capping activity. These and other results reveal and illuminate the cooperative, interdependent nature of protein A's diverse functions.
    DOI:  https://doi.org/10.1371/journal.ppat.1013802
  58. Biofactors. 2026 Mar-Apr;52(2):52(2): e70099
    Mechanism of YTHDF2-Mediated Epigenetic Modification in the Proliferation and Invasion of Renal Cell Carcinoma Cells.
    Xiaomeng Zhang, Yan Zhang, Xin Yang, Ye Fan, Yingying Zhu.
      Renal cell carcinoma (RCC) ranks as the most prevalent form of urogenital cancer. This research aims to investigate the role of YTHDF2 in the RCC progression and identify new therapeutic targets for RCC. YTHDF2, E2F2, and CORO6 were assayed via qRT-PCR and Western blot. YTHDF2 was downregulated in RCC cells, while E2F2 and CORO6 were upregulated. After overexpressing YTHDF2 in RCC cells, cell viability, proliferation, invasion, and migration were measured. m6A levels were assessed. The binding of YTHDF2 to E2F2 was detected. The E2F2 mRNA stability was detected. The binding of E2F2 to the CORO6 promoter was analyzed. Overexpression of E2F2 or CORO6 was combined with YTHDF2 overexpression to validate the mechanism. Tumor growth and metastasis were observed. Results confirmed that YTHDF2 overexpression decreased cell proliferation, invasion, and migration. YTHDF2 bound to the m6A sites on E2F2 mRNA, promoted E2F2 degradation, and inhibited E2F2 expression. E2F2 bound to the CORO6 promoter to enhance CORO6 expression. Overexpression of E2F2 or CORO6 partially reversed the suppressive effects of YTHDF2 overexpression on RCC cell proliferation and invasion. YTHDF2 overexpression suppressed tumor growth and metastasis. In conclusion, YTHDF2 overexpression suppresses RCC progression by inhibiting E2F2 expression and reducing CORO6 expression via m6A modification.
    Keywords:  CORO6; E2F2; YTHDF2; m6A modification; proliferation; renal cell carcinoma
    DOI:  https://doi.org/10.1002/biof.70099
  59. mSystems. 2026 Apr 22. e0141825
    Enterohemorrhagic Escherichia coli O157:H7 responds to norepinephrine gradients by tRNA reprogramming and codon-biased translation of virulence genes.
    Abigail E McShane, Chi-Kong Chan, Ruixi Chen, Michael S DeMott, Thomas J Begley, Peter C Dedon.
      Enterohemorrhagic Escherichia coli O157:H7 (EHEC) is a low-infectious-dose foodborne pathogen that uses norepinephrine gradients in the gut to locate sites for colonization and activate expression of virulence factors. Here, we identified features of transfer RNA (tRNA) reprogramming and codon-biased translation that play a role in this infectious process. Multivariate statistical analysis of genome-wide codon usage patterns revealed five gene clusters with unique codon biases, with one cluster containing all Locus of Enterocyte Effacement virulence genes that are all strongly biased for A/U-ending codons. EHEC cultures were then exposed to a norepinephrine gradient to induce type III secretion, as well as chemotaxis and flagellar motility, followed by a multi-omic interrogation of changes in tRNA modifications, tRNA abundance, and the proteome. We observed altered levels of multiple tRNA wobble modifications involved in G/C- versus A/U-ending codon recognition and a corresponding shift in the proteome toward genes enriched in A/U-ending codons. Our studies suggest EHEC can alter its tRNA pool in response to cues from the host, fine-tuning translational efficiency of its virulence program.IMPORTANCERegulation of microbial physiology and virulence during environmental changes has typically been ascribed to transcriptional mechanisms. Using convergent multi-omic technologies, we have discovered mechanisms of translational regulation of gene expression that regulate cell phenotype. Here, we applied these technologies to define mechanisms of translational regulation in the Escherichia coli O157:H7 response to norepinephrine exposure known to induce virulence.
    Keywords:  EHEC; norepinephrine; tRNA; translational regulation; type III secretion; virulence
    DOI:  https://doi.org/10.1128/msystems.01418-25
  60. J Fish Biol. 2026 Apr 22.
    Genome-wide identification of the Hsp70 gene family in Atlantic cod (Gadus morhua) and its response to pathogenic stress.
    Miao Zhu, Xinran Li.
      Heat shock protein 70 (Hsp70) is a critical molecular chaperone in most eukaryotes and prokaryotes, significantly contributing to several physiological and biochemical processes and regulating stress response to external stimuli. Gadus morhua is a fish species with exceptionally high nutritional value and significant economic importance, making it highly meaningful to study its response strategies under pathogenic stress. However, systematic analyses of Hsp70 in G. morhua have yet to be performed. In this study, we identified 24 family members of Hsp70 genes from G. morhua and analysed their protein properties, chromosomal distribution, phylogenetic relationships, gene structure and conserved motifs. We observed that some hsp70 members exhibited significantly differential expression under the stress of pathogenic bacteria and worm, suggesting that these genes could be involved in regulating pathogenic immunity. Overall, these findings provide useful information for studying cod Hsp70 gene function and evaluating its role in pathogenic immunity regulation.
    Keywords:  Gadus morhua; Hsp70; biotic stress; heat shock protein; pathogenic immunity
    DOI:  https://doi.org/10.1111/jfb.70459
  61. FASEB J. 2026 Apr 30. 40(8): e71817
    Mettl3-Mediated m6A Methylation of Pdgfrb Regulates the Angiogenesis-Dependent Bone Formation.
    Shijie Zhou, Yihua Zhu, Li Yun, Muzhe Li, Tianchi Zhang, Taxi Wumiti, Qinfeng Zhou, Shuangliu Chen, Yue Hu, Zhitao Han, Chunlei Zhang, Kai Tong, Yafeng Zhang, Yong Ma, Yang Guo, Lining Wang.
      CD31hiEMCNhi (type H) vessels orchestrate the bone metabolic microenvironment, yet the epigenetic control of their endothelial identity remains unclear. N6-methyladenosine (m6A), catalyzed by Mettl3, is essential for mRNA fate and emerging as a regulator of skeletal homeostasis. After isolating and validating type H bone microvascular endothelial cells (H-BMECs) from mouse femora, we used lentiviral shRNA and endothelial-specific Cdh5-Cre;Mettl3fl/fl mice to silence Mettl3 in vitro and in vivo. m6A-seq and RNA-seq pinpointed downstream targets; qPCR, Western blot, MeRIP-qPCR, RNA stability, migration, and tube formation assays dissected mechanisms. Local platelet-derived growth factor-BB (PDGF-BB) administration was employed to rescue Mettl3-null phenotypes. Mettl3 expression and global m6A levels were reduced in ovariectomy-induced osteoporosis. Knock-down or genetic deletion of Mettl3 decreased m6A methylation within the 3'UTR of Pdgfrb, accelerated Pdgfrb mRNA decay, blunted PI3K/AKt signaling and impaired H-BMEC proliferation, migration and tube formation. Consequently, type H vessels and trabecular bone mass were markedly diminished. PDGF-BB ligand delivery restored Pdgfrb abundance, reactivated PI3K/AKt, and fully reversed vascular and skeletal defects in Mettl3-null mice. Mettl3-mediated m6A methylation preserves Pdgfrb mRNA stability in bone endothelial cells and is associated with the maintenance of type H vessels, thereby coupling angiogenesis to bone formation. Targeting the Mettl3-m6A-Pdgfrb/PI3K-AKt axis may represent a potential therapeutic strategy for estrogen-deficiency-induced bone loss.
    Keywords:  Mettl3; Pdgfrb; angiogenesis; m6A methylation; osteoporosis
    DOI:  https://doi.org/10.1096/fj.202504396R
  62. J R Soc Interface. 2026 Apr 22. pii: 20251028. [Epub ahead of print]23(237):
    Phenotypic cliffs in the RNA genotype-phenotype map.
    Paula García-Galindo, Sebastian Ahnert.
      Point mutations of a genotype can leave the phenotype unchanged, or change it, in some cases radically. The extent of this phenotypic change can critically impact fitness. To investigate the range of possible phenotypic changes that result from point mutations, we analyse the structure of the well-established RNA genotype-phenotype (GP) map for sequences of length 12 by developing a general phenotypic distance framework. Our analysis reveals that phenotypes are more likely to be surrounded by similar phenotypes than would be expected by chance. Furthermore, we see that generalized versions of the GP map metrics of frequency, robustness and evolvability that take phenotypic distance into account still exhibit the same fundamental structural relationships that are observed in many GP maps. We also develop site-specific quantities for robustness, evolvability and accessible phenotypic distance, which reveal a key insight: RNA secondary structure sites that are more likely to be neutral and access fewer new phenotypes tend to produce larger changes in phenotype when a change does occur. Robust sites, therefore, produce cliffs in the landscape (flat in some directions, steep in others), whereas non-robust sites give rise to more gently undulating landscapes.
    Keywords:  RNA secondary structure; genotype–phenotype map; phenotypic distance
    DOI:  https://doi.org/10.1098/rsif.2025.1028
  63. Jpn J Clin Oncol. 2026 Apr 21. pii: hyag065. [Epub ahead of print]
    Cellular plasticity of cancer: roles of biomolecular condensates and ecDNA.
    Yohei Sugimoto, Yihao Zhang, Takeru Kachi, Koichi Ogami, Hiroshi I Suzuki.
      Cancer is characterized not only by malignant transformation driven by genomic alterations but also by remarkable cellular plasticity that enables adaptation to environmental and therapeutic stress. Cancer cell plasticity frequently involves extensive remodeling of gene regulatory and transcriptional networks arising from complex interactions between genetic alterations and nongenetic regulatory mechanisms. The regulatory sources of cancer cell plasticity include changes in RNA molecules, such as microRNAs, alterations in RNA processing, epigenetic reprogramming, and higher-order cellular organization. In particular, biomolecular condensates-membraneless organelles formed through phase separation-and extrachromosomal DNA (ecDNA) have gained attention as important regulators of gene expression and cellular heterogeneity in cancer. Alterations in biomolecular condensates in cancer cells are frequently associated with dysregulated gene regulation and cell signaling. In addition, ecDNA represents an emerging mechanism that mediates high-level oncogene transcription, tumor heterogeneity, and drug resistance in cancer. This review summarizes recent advances in understanding how biomolecular condensates and ecDNA contribute to the regulation of cancer cell plasticity and discusses their implications for tumor evolution and therapeutic resistance. We also outline the usefulness of several CRISPR-based methods to test the roles of ecDNA, including generation of ecDNA-like circular DNA as model systems, optimization of Cas9 activity for prevention of Cas9-induced ecDNA loss and efficient ecDNA knock-in, and CRISPR interference-based perturbations.
    Keywords:  biomolecular condensate; cancer; ecDNA; phase separation; super-enhancer
    DOI:  https://doi.org/10.1093/jjco/hyag065
  64. Precis Clin Med. 2026 Jun;9(2): pbag011
    Circular RNA as emerging precision therapeutics: from RNA regulation to peptide translation.
    Nan Wu, Jeremiah Amalraj, Burton B Yang.
      Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs characterized by a covalently closed-loop structure. Although initially regarded as splicing byproducts, circRNAs are now recognized as essential regulators of gene and protein expression and play important roles in various human diseases. In recent years, growing evidence has indicated that a subset of circRNAs can be translated through cap-independent mechanisms to produce bioactive peptides or proteins. These findings expand the functional scope of circRNAs and offer new opportunities for RNA therapy. This review summarizes recent advances in circRNA biology, with an emphasis on their potential in diagnosis and treatment. We also review the therapeutic strategies targeting circRNAs at both the RNA and protein levels and the delivery systems that support circRNA-directed therapies. After we discuss how circRNA therapeutics may be integrated into precision medicine, we further highlight the current clinical progress and key challenges for advancing circRNA-based therapies toward clinical application.
    Keywords:  RNA biology; circRNA; circular RNA; oncogenesis; therapy
    DOI:  https://doi.org/10.1093/pcmedi/pbag011
  65. Exp Ther Med. 2026 Jun;31(6): 151
    Effects of rok1 gene deletion on mitosis in fission yeast at appropriate and stressful temperatures and the molecular mechanisms.
    Jiayi He, Mengnan Liu, Jiani Xu, Xiang Ding, Yiling Hou.
      The rok1 gene encodes the ATP-dependent RNA helicase Rok1, which is involved in regulating the maturation of small subunit ribosomal RNA and thus ribosome biogenesis. However, the regulation of cellular mitotic dynamics by the rok1 gene deletion is currently unclear. In the present study, fluorescent protein labeling and live cell imaging techniques were used to investigate the effects of rok1 deletion on the dynamics of microtubules, actin and kinetochores during mitosis at 25 and 37˚C, and RNA-sequencing and bioinformatics analyses were used to reveal the key genes. Analysis of the live cell imaging results revealed that, in mitosis, the initiation length and contraction length of actin rings were both shortened and the contraction rate was decreased at 25 and 37˚C. The separation process of kinetochores was inhibited at 25 and 37˚C, and the inhibition was more severe at the higher temperature of 37˚C. Analysis of RNA sequencing results showed that upregulation of myo51 and blt1 resulted in delayed actin ring assembly and slowed actin ring contraction in the rok1Δ strain. In addition, psm1 and psc3 were upregulated and are key genes affecting the ability of kinetochores to move on the spindle and the cohesion of sister chromatids. The present study revealed that the Rok1 protein not only influences the actin polymerization process, participate in the regulation of actin ring assembly and contraction, and cytoplasmic division, but also affects the migration ability of kinetochores on the spindle and participate in the regulation of the formation and maintenance of cohesion between sister chromatids, which provides a certain scientific basis for further exploring the function of the Rok1 protein in cell division.
    Keywords:  RNA-sequencing; Schizosaccharomyces pombe; high-temperature stress; mitosis; rok1 gene
    DOI:  https://doi.org/10.3892/etm.2026.13145
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