bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–04–05
47 papers selected by
Cédric Chaveroux, CNRS
  1. Translational control of Toxoplasma gondii differentiation.
  2. 2'-O-Methylation maintains ribosome structural and translation integrity.
  3. Regulatory dynamics of monosomes and polysomes in cellular adaptation.
  4. Epitranscriptomic RNA modifications in human disease: Cooperative networks, molecular mechanisms, and therapeutic opportunities.
  5. Post-transcriptional regulatory networks: The dynamic interplay of RNA-binding proteins.
  6. RNA-based regulation beyond microRNAs: Emerging layers of post-transcriptional control in plants.
  7. G/C-ending and synonymous codon bias define functional translational programs that shape human tissue and cancer proteomes.
  8. METTL14 Promotes the Malignancy of Osteosarcoma by Mediating the m6A Methylation of ITGB3.
  9. Stress granules at the crossroads of retroviral replication and antiviral immunity: mechanisms and therapeutic opportunities.
  10. C/D-box snoRNP assembly and trafficking in plants: organelle-derived insights into 2'-O-methylation.
  11. m6A RNA methylation in neural plasticity, brain aging, and neurodegenerative vulnerability.
  12. A Novel Eukaryotic Ribosome Factor Enables Translation Restart Following Cellular Dormancy.
  13. Polycystin-1 C-Terminus Regulates Protein Synthesis-Related Pathways in Cardiomyocytes.
  14. Dissecting host stress responses for predictable heterologous gene expression in E. coli.
  15. Pharmacological modulation of stress granules via G3BP1/2: A pathway to treat cancer, inflammatory disease, and neurodegeneration.
  16. RNA binding protein Musashi1 interacts with the viral genomic RNA and restricts SARS-CoV-2 infection by repressing translation.
  17. Controlling heterologous protein synthesis through a plant RNA ThermoSwitch.
  18. Decoding m6A: a new frontier in maternal-foetal immunology.
  19. Protein oxidation in crowded environments.
  20. Centriolar satellites regulate CEP350 mRNA localization and centrosome amplification.
  21. How do RNA molecules distinguish self from non-self?
  22. Synthetic circRNAs employ IRES activity for translation in cells and in cell-free translation systems.
  23. The Helicobacter pylori ribosomal silencing factor RsfS is required for low-growth states and chronic infection.
  24. Nitroxoline-O-protected derivatives inhibit MetAP2 and activate ATF4 through mTORC1 to inhibit cancer cell growth.
  25. Mitochondrial translational control in cardiovascular diseases: from mechanisms to therapies.
  26. Multiple mTOR RNA localization signals regulate subcellular protein synthesis and axonal growth.
  27. Chronology of tRNA structural dynamics prior to and during interaction with a pseudouridine synthase.
  28. Activation of the protective arm of renin-angiotensin system enhances mitochondrial turnover improving respiration and decreasing integrated stress response in a human Complex III deficiency model.
  29. Methyltransferase 3 promotes v-set and transmembrane domain-containing 2-like protein expression to intensify ferroptosis-mediated prostate adenocarcinoma progression through the m6A methylation modification.
  30. RNA-Centric Tumour Evolution: Transcriptional Reinforcement, Reversibility, and Clinical Plasticity Beyond Genetics.
  31. Detection of tRNA-Derived Small RNAs in Arabidopsis thaliana via Northern Blotting: Exploring Potential Biomarkers for Phytohormone Analysis.
  32. ATF5 is required for the maintenance of mitochondrial homeostasis and skeletal muscle health during aging.
  33. The PRKN/METTL3/CLDN2 axis promotes colorectal cancer development through epigenetic mechanisms.
  34. Autoregulation of three yeast ribosomal protein genes by splicing inhibition.
  35. Unexpected role of the integrated stress response in cancer immune evasion.
  36. A method of comprehensive sequencing analysis of the small RNA fragmentome (RiboMarker).
  37. Inhibition of eukaryotic translation initiation factor 1 A (eIF1A) and 3B (eIF3B) diminishes the psoriatic phenotype in two mouse models and human 3D model samples.
  38. Pathogenic human mitochondrial tRNA variants impair RNA processing by compromising 5' leader removal.
  39. U2AF regulates the translation and localization of nuclear-encoded mitochondrial mRNAs.
  40. ERN1-dependent regulation of BAG cochaperone 1 expression and the sensitivity to glutamine deprivation in U87MG glioblastoma cells.
  41. Harnessing viral strategies to reverse cognitive dysfunction through the integrated stress response.
  42. Expanding Biological Roles of Post-translational Arginylation.
  43. Recent Advances in Small-Molecule Modulators Targeting IRE1α.
  44. KREPA6 functions in RNA editing catalytic complex structural organization and gRNA utilization in Trypanosoma brucei.
  45. ATF4 Coordinates Transcriptomic and Structural Adaptations in Aging Muscle.
  46. Muscleblind-like proteins dimerize by forming disulfide bonds to regulate alternative splicing and pathogenic RNA foci formation.
  47. The glp-1 3' untranslated region regulates germline proliferation and promotes reproductive fecundity through multiple mechanisms.
  1. Biosci Rep. 2026 Apr 22. pii: BSR20253672. [Epub ahead of print]46(4):
    Translational control of Toxoplasma gondii differentiation.
    Fengrong Wang.
      Toxoplasma gondii is a globally prevalent protozoan parasite capable of establishing lifelong infections in its host. While acute infection is often asymptomatic, reactivation of latent bradyzoites can cause severe disease, particularly in immunocompromised individuals. Current therapies are ineffective against chronic infection, underscoring critical gaps in our understanding of bradyzoite biology and the molecular mechanisms governing stage conversion. Recent studies have identified translational control as a central regulator of T. gondii differentiation. This review highlights the roles of canonical translation initiation factors (eIF2α, eIF1.2, and eIF4E1), RNA-binding proteins (RBPs; BFD2/ROCY1, Alba1, and Alba2), and RNA modifications (with pseudouridylation representing the best-characterized modification currently linked to differentiation), as well as alternative splicing and non-coding RNAs in shaping stage-specific translational programs. This review further discusses underexplored mechanisms, including non-canonical initiation pathways, upstream open reading frames, transcript-level RNA modifications, ribosome heterogeneity and rRNA modifications, elongation and termination control, uncharacterized RBPs, and post-translational modifications of translation factors, that may coordinate proteome remodeling during differentiation. Together, established translational regulators and these emerging pathways highlight translational control as a central driver of parasite persistence and a promising therapeutic target for chronic toxoplasmosis.
    Keywords:  Alternative splicing; Cell differentiation; Non-coding RNA; RNA editing; RNA-binding proteins; Toxoplasma gondii; Translation; Translation factors
    DOI:  https://doi.org/10.1042/BSR20253672
  2. Mol Cell. 2026 Apr 01. pii: S1097-2765(26)00164-4. [Epub ahead of print]
    2'-O-Methylation maintains ribosome structural and translation integrity.
    Yu Zhao, Jay Rai, Lauren N Cohen, Yuerong Shu, Chong Xu, Hemant Goswami, Xin Chen, Hong Jin, Virginie Marchand, Yuri Motorin, Homa Ghalei, Hong Li.
      In eukaryotic ribosomes, ∼2% of RNA nucleotides undergo 2'-O-methylation, a conserved cellular mechanism thought to be critical for maintaining and regulating translation. Here, we use ribosome profiling, translation assays, proteomics, and high-resolution structural analyses to show that loss of native 2'-O-methylation in yeast ribosomes disproportionally affects the translation of ribosomal protein transcripts, driven by changes in codon usage and recognition of structured RNA. Translation reprogramming by the hypomethylated ribosomes is supported by reduced thermostability and high-resolution evidence of altered ribosomal structures and conformations. Consistent with the roles of the affected proteins in sustaining cellular fitness, hypomethylated ribosomes under stress exhibit a selective loss of downregulated proteins and misassembly associated with methylation loss. Our data provide structural and mechanistic insights into how 2'-O-methylation supports ribosome integrity and mediates cellular stress responses.
    Keywords:  IRES translation; RNA 2′-O-methylation; Ribo-seq; box C/D snoRNPs; fibrillarin; ribosome stability; translation; translation fidelity
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.008
  3. J Biochem. 2026 Apr 01. pii: mvag026. [Epub ahead of print]
    Regulatory dynamics of monosomes and polysomes in cellular adaptation.
    Hirotatsu Imai, Akio Yamashita.
      Cytosolic 80S ribosomes have long been considered a uniform translation apparatus, with the only distinction being that they exist as either monosomes or polysomes. However, emerging evidence has revealed that monosomes and polysomes exhibit distinct translational profiles, contributing to selective protein synthesis and localized messenger RNA (mRNA) translation in specific subcellular compartments in mammals. When mammalian cells encounter environmental or metabolic stress, global gene expression is dynamically reprogrammed, accompanied by a marked shift in the monosome-to-polysome ratio, suggesting context-dependent roles for monosome- and polysome-mediated mRNA translation in cellular adaptation. In parallel, accumulating evidence indicates that distinct types of eukaryotic non-translating monosomes are formed under various biological conditions. Moreover, monosomes participate in the first round of mRNA translation on newly synthesized mRNAs, a process coupled with several early events such as nonsense-mediated mRNA decay and messenger ribonucleoprotein (mRNP) remodeling. In this review, we summarize current advances in understanding the roles of monosomes as crucial regulatory layers that shape the proteome across diverse physiological conditions in mammals.
    Keywords:  mRNA translation; monosome; polysome; ribosome
    DOI:  https://doi.org/10.1093/jb/mvag026
  4. Biochem Biophys Res Commun. 2026 Mar 25. pii: S0006-291X(26)00437-7. [Epub ahead of print]815 153673
    Epitranscriptomic RNA modifications in human disease: Cooperative networks, molecular mechanisms, and therapeutic opportunities.
    Omar Eladl, Alaa Abdelhady, Moustafa A Tageldein.
      Epitranscriptomic RNA modifications form a dynamic regulatory layer that shapes gene expression and cellular function. While N6-methyladenosine (m6A) has been extensively studied, other modifications-including m5C, m1A, m3C, m7G, and Ψ-play critical roles in RNA folding, stability, translation, and stress responses. Initially, studies focused on each RNA modification individually, but recent evidence has revealed that these modifications often occur together, forming interconnected networks in which each modification can influence others, ultimately determining transcript fate and cellular states. In this review, we synthesize insights across the full spectrum of RNA modifications, highlight combinatorial regulation, and examine technological advances that enable mechanistic dissection and translational exploration. By emphasizing how modifications cooperate rather than act alone, this review aims to shift the field toward a holistic, network-based understanding of epitranscriptomic regulation in human disease.
    Keywords:  Epitranscriptomic; Human disease mechanisms; Noncoding RNAs; Post-transcriptional regulation; RNA modifications
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153673
  5. FEBS J. 2026 Apr 01.
    Post-transcriptional regulatory networks: The dynamic interplay of RNA-binding proteins.
    Lena A Street, Marko Jovanovic, Eugenio F Fornasiero.
      Post-transcriptional regulation of gene expression is orchestrated by RNA-binding proteins (RBPs), which regulate key aspects of the RNA life cycle including splicing, localization, translation, and decay. Although RBPs have been initially considered as isolated regulators, it is becoming clear that RNA molecules are commonly bound by several RBPs whose coordination directs their fate. These combinatorial interactions produce complex, context-dependent post-transcriptional regulatory networks (PTRNs) whose outcomes are difficult to predict. RBPs may also switch function depending on cell state, subcellular localization, or post-translational modification, adding further complexity to RNA regulation. This review focuses on recent technological advances expanding our ability to map and interpret PTRNs. Multiplexed methods allow profiling of the RNA-binding patterns of several RBPs in parallel, whereas deeper interaction proteomics studies reveal protein-protein connections and changes in distinct biological settings. Complementary RNA-targeting pulldown and single-molecule imaging strategies enable real-time and single-cell-resolution visualization of ribonucleoprotein assembly and dynamics, while functional high-throughput screens allow assignment of first order functions for these RBPs. Overall, these approaches set the stage for comprehensive decoding of the spatiotemporal structure of PTRNs and reveal how RBP interactions coordinate sets of RNAs to collectively regulate them in response to physiological demands. In addition to describing these systems-level approaches, we outline key future analytical and experimental innovations that could transform our understanding of RBP function. We believe that a systems-level understanding of RBPs as dynamic, integrated components of multiscale regulatory regimes is required to fully understand the complexity of gene expression control and its disruption in disease.
    Keywords:  RNA‐binding proteins; RNA–protein interactions; RNP complex dynamics; post‐transcriptional regulation; systems biology of RNA regulation
    DOI:  https://doi.org/10.1111/febs.70524
  6. Plant Sci. 2026 Mar 27. pii: S0168-9452(26)00149-4. [Epub ahead of print]367 113121
    RNA-based regulation beyond microRNAs: Emerging layers of post-transcriptional control in plants.
    Bhagyashri Rathod, Sachin Puri.
      Plant gene expression is regulated by multilayered post-transcriptional mechanisms that extend beyond the well-characterized microRNA pathway. Although miRNAs play central roles in controlling mRNA stability and translation, recent advances in transcriptomics and RNA biology have uncovered additional regulatory layers that significantly expand the complexity of plant PTR. These include long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), diverse classes of small interfering RNAs (siRNAs), tRNA-derived fragments, epitranscriptomic RNA modifications, and RNA-binding proteins. Collectively, these components influence RNA processing, stability, translation, and genome integrity, thereby shaping plant development and stress adaptation. This review synthesizes current knowledge on these non-miRNA RNA-based regulatory mechanisms, with emphasis on their molecular functions and biological significance. Importantly, we highlight the emerging view that these pathways operate within an interconnected regulatory network rather than as isolated mechanisms. Understanding this integrated framework provides new insights into plant adaptive plasticity and offers potential avenues for crop improvement under changing environmental conditions.
    Keywords:  Gene expression; Genome stability; Molecular mechanisms; epitranscriptomic RNA; micro RNAs (miRNAs); post-transcriptional regulation (PTR)
    DOI:  https://doi.org/10.1016/j.plantsci.2026.113121
  7. NAR Genom Bioinform. 2026 Jun;8(2): lqag033
    G/C-ending and synonymous codon bias define functional translational programs that shape human tissue and cancer proteomes.
    Sherif Rashad, Kuniyasu Niizuma.
      Codon usage bias is a fundamental feature of the genetic code, yet its impact on messenger RNA translation is incompletely defined. Here, we integrate comparative genomics, human tissue proteomes, large cancer cell line, and patient cancer datasets to reveal a conserved codon-bias axis. Across mammals, we show that GC-biased gene conversion drives human-specific GC3 (third codon nucleotide bias score) drifts, yet the functional dichotomy is maintained: A/T-ending codons associate with proliferation and RNA processing, while G/C-ending (Third nucleotide Guanine or Cytosine) codons associate with differentiation and neuronal functions. At the isoacceptors level, synonymous codons segregate into distinct functional categories. To mechanistically connect codon usage to cancer, we introduce the ANN- and m7G-indices, capturing codons decoded by transfer RNA (tRNA) modifications t6A and m7G. Both indices negatively correlate with GC3 and enrich for pro-oncogenic proliferative pathways. Human tissue proteomes reveal strong codon bias discordance between RNA and protein levels, with nervous system tissues enriched for G/C-ending codons while proliferative organs are A/T-biased. Analysis of 2600 cancer cell lines and 21 cancer types revealed heterogeneous codon preferences in cancer cell lines but a global A/T-ending shift in human cancer-upregulated proteins. These findings establish synonymous codon divergence and tRNA modification indices as key determinants of translational reprogramming in health and cancer.
    DOI:  https://doi.org/10.1093/nargab/lqag033
  8. Ann Clin Lab Sci. 2026 Jan;56(1): 76-86
    METTL14 Promotes the Malignancy of Osteosarcoma by Mediating the m6A Methylation of ITGB3.
    Yacun Wan, Zhixiang Zhang, Zhongqiang Li, Juan Du.
       OBJECTIVE: Osteosarcoma (OS) is a malignant tumor originating from osteoblasts. Methyltransferase-like 14 (METTL14) is an N6-methyladenosine (m6A) methyltransferase that has been reported to promote OS progression; however, its underlying mechanism remains unclear.
    METHODS: Gene Expression Omnibus (GEO), RNA modification base version 3.0 (RMbase V3.0), RNA modification variant database (RMvar), RNA modification disease database version 2.0 (RMDisease V2.0), sequence-based RNA adenosine methylation site predictor (SRAMP), the encyclopedia of RNA interactomes (ENCORI), and RNA binding protein map (RBPmap) were used to obtain gene expression and modification information related to OS. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot (WB) were used to detect gene expression at the transcriptional and translational levels. Cell transfection was used to knock down or overexpress target genes. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was used to measure cell viability. Flow cytometry was used to detect cell apoptosis. The Transwell assay was used to evaluate cell migration. Sphere formation assay assessed stemness characteristics. Tube formation assay evaluated angiogenic capability. RNA immunoprecipitation (RIP) was used to detect interactions between proteins and messenger RNA (mRNA).
    RESULTS: METTL14 was highly expressed in OS-related cells. Knockdown of METTL14 reduced cell viability, increased apoptosis, and suppressed cell migration, stemness, and angiogenic capacity. In addition, METTL14 cooperated with insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) to mediate m6A methylation of integrin subunit beta 3 (ITGB3), thereby promoting the malignant behaviors of OS-related cells.
    CONCLUSION: METTL14 and IGF2BP1 mediate the m6A methylation of ITGB3, further promoting the deterioration of OS, providing new insights into the molecular mechanisms and potential therapeutic targets of OS.
    Keywords:  Insulin-like growth factor 2 mRNA-binding protein 1; Integrin subunit beta 3; Methyltransferase-like 14; N6-methyladenosine methylation; Osteosarcoma
  9. Mol Biol Rep. 2026 Apr 03. pii: 582. [Epub ahead of print]53(1):
    Stress granules at the crossroads of retroviral replication and antiviral immunity: mechanisms and therapeutic opportunities.
    Mohammad Mehdi Akbarin, Zahra Farjami, Hugo Ramírez Álvarez.
      Stress granules (SGs) are dynamic cytoplasmic ribonucleoprotein aggregates that form in response to cellular stress and function as key regulators of mRNA translation, stability, and antiviral defense. Increasing evidence demonstrates that retroviruses, including HIV-1, HTLV-1, and other oncogenic retroviruses, interact extensively with stress granule pathways to promote viral replication, persistence, and immune evasion. This review summarizes current knowledge of the molecular mechanisms governing stress granule assembly and highlights how retroviruses manipulate SG components, such as G3BP1, TIA-1, TIAR, and eIF2α signaling, to control host translational arrest and innate immune responses. In HIV-1 infection, viral proteins, including Gag, Tat, and Vpr, interfere with SG formation to support viral RNA translation and replication. Similarly, HTLV-1 modulates stress-response pathways to favor viral persistence and transformation. We also discuss the dual role of stress granules as both antiviral platforms and viral replication facilitators, depending on the stage of infection and cellular context. Importantly, emerging data suggest that dysregulated stress granule dynamics may contribute to chronic inflammation, neurodegeneration, and virus-associated malignancies. Understanding the interplay between retroviruses and stress granule biology provides insight into host-virus coevolution and identifies potential therapeutic targets to restore antiviral stress responses. Targeting SG-associated pathways may represent a novel strategy to limit retroviral replication and virus-induced pathogenesis.
    Keywords:  HIV-1; HTLV-1; Host–virus interaction; Retrovirus infection; Stress granules; Translational control
    DOI:  https://doi.org/10.1007/s11033-026-11747-5
  10. J Exp Bot. 2026 Apr 02. pii: erag162. [Epub ahead of print]
    C/D-box snoRNP assembly and trafficking in plants: organelle-derived insights into 2'-O-methylation.
    Natacha Bies-Etheve, Julio Sáez-Vásquez.
      Two major classes of small nucleolar ribonucleoprotein (snoRNP) complexes have been identified in eukaryotic cells: C/D-box snoRNPs are responsible for 2'-O-methylation (2'-O-Me) of RNA, while H/ACA-box snoRNPs catalyse the conversion of uridine to pseudouridine (Ψ). In this review, we examine the current state of knowledge regarding C/D-box snoRNPs in plants. This knowledge is primarily derived from studies conducted on the model plant Arabidopsis thaliana. We provide a summary of reports concerning the organisation and expression of C/D-box snoRNAs, as well as the proteins that form the C/D-box snoRNP. In addition, we review the factors that are potentially involved in, or have been characterised as being involved in, the process of assembling and translocating C/D-box snoRNPs from the nucleoplasm to the nucleolus via Cajal bodies. Finally, the subject of 2'-O-methylation of ribosomal RNA (rRNA) in chloroplasts and mitochondria is presented, with a focus on the role of site-specific enzymes, as observed in bacterial systems, and in contrast to the involvement of nuclear C/D-box snoRNPs complexes.
    Keywords:   Arabidopsis thaliana ; 2’-O-Me; C/D-box snoRNA; RNA methylation; snoRNP assembly
    DOI:  https://doi.org/10.1093/jxb/erag162
  11. Mol Brain. 2026 Mar 29.
    m6A RNA methylation in neural plasticity, brain aging, and neurodegenerative vulnerability.
    Xuehua Zhou, Peiyang Yu, Xia Shen.
      m6A is a pervasive post-transcriptional RNA modification that regulates RNA splicing, stability, localization, and translation in the brain. In this review, we outline the core m6A regulatory machinery and summarize its spatial organization across neurons and glial cells, highlighting established roles in brain development, synapse formation, and axon growth. We then focus on experience-dependent plasticity, synthesizing evidence that neuronal activity and environmental inputs dynamically reshape m6A to regulate immediate-early transcription and local translation at synapses across sensory, cognitive, emotional, and motor domains. With aging, m6A programs are reconfigured in a cell-type-specific manner, a shift associated with reduced plasticity and increased vulnerability. We further survey disease-associated alterations in m6A across Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke-related cognitive impairment, ALS and FTD, as well as metal or toxin exposure, emphasizing convergent effects on dopaminergic and glutamatergic signaling, synaptic integrity, inflammation, and cellular stress responses. Finally, we discuss emerging opportunities and conceptual challenges in targeting m6A enzymes or reader proteins, and outline priorities for future work, including cell-type- and subcellular-resolved mapping, causal perturbation in defined circuits and life stages, and the development of biomarkers and selective modulators. Together, these observations position m6A as a molecular interface linking experience-dependent plasticity, brain aging, and neurodegenerative vulnerability.
    Keywords:  Aging; Experience-dependent plasticity; Neural development; Neurodegenerative diseases; m6A RNA methylation
    DOI:  https://doi.org/10.1186/s13041-026-01297-z
  12. bioRxiv. 2026 Mar 24. pii: 2026.03.21.713407. [Epub ahead of print]
    A Novel Eukaryotic Ribosome Factor Enables Translation Restart Following Cellular Dormancy.
    Maciej Gluc, Higor Rosa, Maria Bozko, Lesley A Turner, Cassidy R Prince, Yelena Peskova, Heather A Feaga, Kathleen L Gould, Simone Mattei, Ahmad Jomaa.
      Dormancy is a survival strategy employed by all domains of life to withstand prolonged nutrient deprivation and environmental stress that is marked by a global shutdown of protein synthesis. However, the molecular mechanisms driving ribosome inactivation and reactivation during and after dormancy in eukaryotes remain poorly understood. Here, we identify SNOR, a novel SBDS-like ribosome-associated factor in Schizosaccharomyces pombe, that is upregulated and associates with ribosomes during induced dormancy triggered by glucose depletion. SNOR contributes to protein synthesis repression by binding the ribosome to probe the peptidyl transferase center (PTC), block tRNA-binding sites, and cap the polypeptide exit tunnel (PET). Importantly, we show that SNOR is essential for the restart of protein synthesis upon glucose reintroduction and exit from dormancy. SNOR is evolutionarily conserved and specifically upregulated in response to glucose stress in fungi. These findings reveal a previously unrecognized ribosome-associated factor that links glucose stress and cellular dormancy to surveillance of protein synthesis and highlight the power of in situ structural biology to uncover stress-responsive regulators of translation.
    DOI:  https://doi.org/10.64898/2026.03.21.713407
  13. bioRxiv. 2026 Mar 24. pii: 2026.03.21.713243. [Epub ahead of print]
    Polycystin-1 C-Terminus Regulates Protein Synthesis-Related Pathways in Cardiomyocytes.
    Matthew Fiedler, Alejandra Vasquez Limeta, Ernesto Reyes-Sanchez, Monserrat Reyes-Lozano, William Perez, Leah Carter, Christopher J Ward, Francisco Altamirano.
      Pathologic cardiac hypertrophy requires increased protein synthesis, but the mechanosensors that link membrane stretch to translational control remain poorly understood. Polycystin-1 (PC1), encoded by PKD1 , has been proposed as a cardiac mechanosensor, with its C-terminal tail (PC1-CT) promoting hypertrophy in rodent cardiomyocytes. However, its subcellular localization and downstream signaling remain incompletely defined, especially in human cardiomyocytes. Here, we examined endogenous PC1 C-terminus localization and the effects of adenoviral PC1-CT overexpression in human iPSC-derived ventricular cardiomyocytes (hiPSC-CMs) and adult mouse ventricular myocytes. Immunofluorescence revealed a striking striated pattern for both endogenous PC1 C-terminus (detected with a PC1-CT antibody) and the overexpressed PC1-CT fragment. In hiPSC-CMs, the PC1 C-terminus localized between the α-actinin bands. In contrast, in adult cardiomyocytes, the overexpressed protein colocalized with α-actinin and desmin, suggesting that PC1-CT sarcomeric distribution depends on cardiomyocyte maturation. We performed RNA-seq to assess transcriptional responses downstream of PC1-CT overexpression in hiPSC-CMs relative to LacZ controls. Gene Set Enrichment Analysis (GSEA) revealed enrichment of gene sets related to ribosome biogenesis, RNA processing, and protein synthesis, while classical hypertrophic markers remained unchanged. Pathway analysis suggested increased PI3K activity. PC1-CT overexpression increased phosphorylation of Akt, ERK, S6K1, and ribosomal protein S6 without altering 4EBP1 phosphorylation, suggesting preferential activation of the mTOR-S6K1-S6 branch. Pharmacological studies showed that pan-PI3K inhibition abolished S6 phosphorylation, whereas MEK blockade did not affect it; pertussis toxin and PI3Kγ-selective inhibitors also did not affect S6, suggesting a G i/o -independent PI3K/Akt signaling driving mTOR-S6K1-S6 activation. Collectively, these data identify a sarcomere-associated pool of PC1-CT that engages PI3K-Akt-mTOR-S6K1-S6 signaling to enhance transcriptional programs related to ribosome biogenesis and protein synthesis, without activating a canonical hypertrophic gene program. These findings reveal a mechanistic link between PC1-CT and cardiomyocyte growth.
    DOI:  https://doi.org/10.64898/2026.03.21.713243
  14. Nucleic Acids Res. 2026 Mar 19. pii: gkag256. [Epub ahead of print]54(6):
    Dissecting host stress responses for predictable heterologous gene expression in E. coli.
    Christoffer Rode, Felix Beulig, Mathias Jönsson, Morten H H Nørholm, Leonie J Jahn, Daniel C Zielinski, Bernhard O Palsson, Emre Özdemir, Lei Yang.
      Predictable expression of heterologous genes remains a key challenge in biotechnology, largely due to cellular stresses imposed on the production host. Here, we systematically dissect stress responses in Escherichia coli MG1655 expressing diverse proteins under varying promoters and translation efficiencies. Using independent component analysis on new and existing large transcriptomic datasets, we identify distinct responses to transcriptional and translational stresses: excessive heterologous messenger RNA (mRNA) triggers a cold shock response that controls mRNA stability (cspA-I, deaD), while protein production activates a heat shock response involving proteolysis and chaperone functions. We further identify a broad adaptation response, consistently co-activated with the heat shock response during protein production, that provides stationary phase regulation (rspAB) and osmoregulation (betABIT). Targeting these latter functions through strain and media modifications significantly increases eGFP production. Other host stress responses depend on the protein being expressed; e.g. we find production of cysteine-rich proteins to uniquely activate functions regulating iron- and redox homeostasis and oxidative stress responses. This work demonstrates a holistic, systems-level view of cellular stresses to heterologous gene expression by considering transcriptional, translational, and product-specific contributions, paving the way toward predictable and optimized expression strategies.
    DOI:  https://doi.org/10.1093/nar/gkag256
  15. Front Pharmacol. 2026 ;17 1780146
    Pharmacological modulation of stress granules via G3BP1/2: A pathway to treat cancer, inflammatory disease, and neurodegeneration.
    Jinhua Yang, Fenfei Gao.
      Stress granules (SGs) are membraneless ribonucleoprotein condensates formed by liquid-liquid phase separation of non-translating mRNAs under stress, acting as dynamic platforms for translational reprogramming and cytoprotection. Ras-GAP SH3 domain-binding proteins 1 and 2 (G3BP1/2) are core nucleators of mammalian SGs-their dual knockout almost abolishes SG assembly, while G3BP1 overexpression alone can drive SG assembly. By sensing cytosolic RNA, G3BP1/2 couple the cyclic GMP-AMP synthase (cGAS)-STING innate immune pathway to stress signaling in cancer and neurodegeneration, positioning these proteins as central hubs linking stress-responsive translation control to disease phenotypes. Recent years have witnessed growing interest in targeting the G3BP-SG axis pharmacologically. Small molecules and peptides that bind G3BP1/2 have revealed that manipulating SG assembly/disassembly is feasible and can modulate downstream stress pathways. However, existing reviews have primarily covered G3BP structure, signaling, and pathology, without a unified focus on direct pharmacological modulators. Here, we present a comprehensive review of G3BP1/2 as druggable stress granule hubs, summarizing all currently reported direct inhibitors and activators, comparing their mechanisms, selectivity and limitations, and discussing translational opportunities and challenges across cancer, viral infection, and neurodegenerative disease contexts. By integrating these findings, we aim to provide an up-to-date framework that not only highlights the novelty of recent G3BP-directed modulators but also addresses prior reviewer concerns regarding overlap with existing literature-emphasizing how our synthesis uniquely compiles both SG inhibitors and "agonists" in one analysis. Ultimately, leveraging the G3BP1/2-SG axis may enable multi-pathway reprogramming of stress responses for therapeutic benefit.
    Keywords:  G3BP1/2; agonists and modulators; cancer; drug development; druggable sites; inflammatory disease; neurodegeneration; stress granules (SGs)
    DOI:  https://doi.org/10.3389/fphar.2026.1780146
  16. Nucleic Acids Res. 2026 Mar 19. pii: gkag271. [Epub ahead of print]54(6):
    RNA binding protein Musashi1 interacts with the viral genomic RNA and restricts SARS-CoV-2 infection by repressing translation.
    Sourav Ganguli, Divya Gupta, Rajashekar Varma Kadumuri, Dixit Tandel, Rajashree Ramaswamy, Aswathy G Krishnan, Deena T David, Soumya Bunk, Sreenivas Chavali, Krishnan Harinivas Harshan, Pavithra L Chavali.
      Musashi RNA-binding proteins are important post-transcriptional regulators of stem cell homeostasis and are known to be involved in viral infections. However, their role in SARS-CoV-2 infection remains largely unknown. Using computational studies, in vivo RNA immunoprecipitation, and biochemical assays, here, we establish that Musashi 1 (Msi1) interacts with viral genomic RNA through direct binding to the SARS-CoV-2 3'UTR. Importantly, binding of Msi1 to the viral 3'UTR results in translational repression that could be mediated by inhibition of poly(A) binding protein. Conversely, Msi1 knockout promotes robust viral replication and increased viral protein expression. Using 2D cell cultures, stem cells, and 3D organoids, we show that depletion of Msi1 in intestinal cells augments infection. This finding explains why the human intestine serves as a reservoir for SARS-CoV-2, in which differentiated enterocytes with negligible Msi1 levels are particularly affected. Contrarily, stem cells, which are enriched for Msi1 expression, are known to be less permissive to SARS-CoV-2 infection despite expressing the entry receptors. Our findings show how translational repression of SARS-CoV-2 by stem cell RNA-binding proteins, such as Msi1, could help evade infection.
    DOI:  https://doi.org/10.1093/nar/gkag271
  17. Plant Methods. 2026 Mar 30.
    Controlling heterologous protein synthesis through a plant RNA ThermoSwitch.
    Filip Lastovka, Hadrien Peyret, George P Lomonossoff, Betty Y-W Chung.
       BACKGROUND: Plants are far from passive in the face of changing temperatures and have evolved transcriptional, post-transcriptional, and post-translational strategies to stay one step ahead of the environment. Among the most exciting recent discoveries are RNA ThermoSwitches, embedded within 5' untranslated regions (UTR) of several mRNAs. These cis-acting RNA elements sense temperature shifts and instantly tune translational output, acting as molecular thermostats inside the cell. First uncovered in Arabidopsis thaliana, ThermoSwitches are now emerging as a powerful new frontier for biotechnology, offering a programmable way to modulate protein production through temperature adjustments.
    RESULTS: Using a dual fluorescence reporter construct introduced by Agrobacterium-mediated transient expression, we have demonstrated that the native ThermoSwitch within the 5' UTR of the Arabidopsis phytochrome-interacting factor 7 (PIF7) mRNA functions as a potent temperature-responsive module in Nicotiana benthamiana leaves. A shift from 17 to 27 °C triggered a pronounced increase in reporter translation, delivering ~ 70% higher output within one day. This magnitude of enhancement mirrors the rise in endogenous PIF7 translation observed in Arabidopsis following the same temperature shift. The response remained even when the native upstream 5' UTR context was replaced with an unrelated sequence, demonstrating that the ThermoSwitch operates autonomously. Crucially, locking the hairpin into a strengthened, rigid conformation abolished the temperature response entirely.
    CONCLUSIONS: This work provides the first in vivo evidence that a native plant RNA ThermoSwitch functions effectively in an Agrobacterium-mediated transient expression system, establishing a homogeneous, temperature-responsive gene regulation system, free from chemical inducers or repressors. Demonstrating that the Arabidopsis PIF7 ThermoSwitch operates autonomously in Nicotiana benthamiana highlights its value as a versatile plug-and-play module that can be readily deployed across plant systems for broad biotechnological applications.
    DOI:  https://doi.org/10.1186/s13007-026-01517-6
  18. Front Immunol. 2026 ;17 1770723
    Decoding m6A: a new frontier in maternal-foetal immunology.
    Ruimin Yuan, Junzhe Hao, Mingyu Huang, Yumeng Lin, Haoran Chen, Chuchu Wang, Lan Yuan, Zhongyu Han.
      m6A is the predominant internal RNA modification in eukaryotic cells and is distinguished by its abundance and evolutionary conservation. This epigenetic mechanism is dynamically controlled by a coordinated system of writer, eraser, and reader proteins. This sophisticated posttranscriptional regulatory mechanism precisely controls gene expression by influencing RNA metabolism, including its stability, translation, and splicing. Recent advances have revealed the functions of m6A in female reproductive cancers, early embryonic development, and stem cell differentiation. However, its functional roles and molecular mechanisms throughout pregnancy and in related disorders remain incompletely understood, which, to some extent, limits its clinical translation. This review systematically outlines the core regulators of m6A, advanced detection technologies, and its regulatory network across the continuum of pregnancy. Given the immunological parallels between the maternal-foetal interface and the tumour microenvironment, we discuss the possible function of m6A modifications in regulating the maternal-foetal immune microenvironment. The aims of this review were to elucidate the m6A regulatory network across gestation and evaluate its potential as a source of diagnostic biomarkers and therapeutic targets for pregnancy-related pathologies.
    Keywords:  diagnostic and therapeutic translation; embryonic development; m6A detection technologies; m6A modification; maternal–foetal immune microenvironment; pregnancy
    DOI:  https://doi.org/10.3389/fimmu.2026.1770723
  19. Biochem J. 2026 Apr 08. 483(4): 565-584
    Protein oxidation in crowded environments.
    Eduardo Fuentes-Lemus.
      Proteins are the most abundant macromolecules in biological systems. This high abundance and the presence of electron-rich side-chains make proteins a major target for biological oxidants. Protein oxidation encompasses a complex set of reactions that, depending on protein structure and the chemical properties of the oxidant, can trigger specific and reversible modifications, or can irreversibly damage multiple side-chains. Therefore, understanding protein oxidation from a mechanistic and kinetic perspective is important to illuminate the molecular basis of physiological (e.g. redox signaling) and pathological processes (e.g. cardiovascular disease and neurodegenerative diseases). However, an existing conundrum in the redox biochemistry field is whether (and how) intrinsic properties of biological environments, such as the crowded intracellular conditions resulting from the high abundance of macromolecules and protein confinement, modulate oxidation rates and pathways. These obvious, but often neglected, aspects of biological environments have begun to be systematically addressed, suggesting that the crowded intracellular conditions would be an important player in the oxidative biology of proteins. This review outlines the importance of protein oxidation in physiology and pathology. Then, thoroughly discusses the modulatory effect that crowding exerts on biochemical processes that involve proteins, particularly on the oxidative modification of proteins. Finally, evidence that illustrates the interplay that would exist between crowding, protein oxidation, and protein confinement by phase separation is discussed. The author proposes that the transition from using dilute in vitro studies to an experimental workflow that takes into account the crowded and heterogeneous conditions encountered is the cell is mandatory to rigorously investigate protein oxidation.
    Keywords:  Protein oxidation; macromolecular crowding; oxidative stress; post translational modification; protein confinement; redox signalling
    DOI:  https://doi.org/10.1042/BCJ20250150
  20. bioRxiv. 2026 Mar 26. pii: 2026.03.26.714479. [Epub ahead of print]
    Centriolar satellites regulate CEP350 mRNA localization and centrosome amplification.
    Abraham Martinez, Chad G Pearson.
      Messenger RNAs (mRNAs) accumulate at centrosomes in mitosis and interphase, yet the mechanisms governing their localization and the functional significance of centrosomal localization remain poorly understood. Here, we investigate the regulation and function of the centrosome-localized mRNA, CEP350 . We find that CEP350 mRNA localizes to centrosomes during S phase via the centriolar satellite protein CEP131 and the RNA binding protein (RBP) Unkempt (UNK), in a microtubule (MT)-dependent manner. CEP131 and UNK stabilize CEP350 mRNA to maintain CEP350 mRNA steady-state levels. Furthermore, CEP131 and UNK promote normal CEP350 protein levels at centrosomes. CEP350 is required for PLK4-induced centriole overduplication but is less important for canonical centriole duplication. Moreover, CEP131, UNK, and CEP350 are important for centrosome amplification in triple-negative breast cancer cells. Together, these findings reveal a centriolar satellite-RBP pathway regulating CEP350 mRNA localization to centrosomes.
    Significance Statement: mRNAs encoding centrosomal proteins localize to centrosomes during interphase, though the mechanism and functional significance of this localization remains unclear. This study finds that the centriolar satellite proteins CEP131 and UNK regulate centrosomal localization of CEP350 mRNA and protein during S phase. CEP131, UNK, and CEP350 are required for centrosome amplification in triple negative breast cancer cells - a dependency that identifies them as potential therapeutic targets.
    DOI:  https://doi.org/10.64898/2026.03.26.714479
  21. Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2603593123
    How do RNA molecules distinguish self from non-self?
    Ofer Kimchi, Kira Mitchel, Andrew G T Pyo, Ned S Wingreen, Elizabeth R Gavis.
      RNA molecules form homotypic clusters in a variety of contexts. mRNAs enriched in germ granules in Drosophila embryos are a canonical example, with polar granule component (pgc) mRNAs colocalized with other pgc mRNAs, and nanos mRNAs with other nanos mRNAs. The observation of homotypic clustering poses a conundrum: how can RNAs of a given sequence distinguish other RNAs of the same sequence from those with different sequences? Here we show in silico that RNAs can distinguish self from non-self through the presence of palindromic regions within RNA sequences, and that palindromes can mediate homotypic clustering. We further show that RNA-RNA interactions are unlikely to lead to homotypic clusters in the absence of palindromes due to a competition between intra- and intermolecular RNA structures. We explore the implications of the palindrome-based clustering hypothesis for nanos and pgc mRNAs, and suggest how it may clear up a surprising feature of nanos clusters. More broadly, our results indicate that the palindrome content of RNAs may be under evolutionary selection pressure across a range of contexts.
    Keywords:  RNA; condensate; germ granule; phase separation; self-assembly
    DOI:  https://doi.org/10.1073/pnas.2603593123
  22. bioRxiv. 2026 Mar 29. pii: 2026.03.28.715045. [Epub ahead of print]
    Synthetic circRNAs employ IRES activity for translation in cells and in cell-free translation systems.
    Philipp Koch, Frederic S W Arendrup, Chaehee Lim, Samyukta Narayanan, Amina Adam, Massimiliano Clamer, Anders H Lund, Chun-Kan Chen, Kathrin Leppek.
      Gene regulation through translation is critical for spatiotemporal protein expression. Internal ribosomal entry sites (IRESes) mediate mRNA-specific translation by recruiting ribosomes to 5' untranslated regions. Circular RNAs (circRNAs), naturally occurring and stable RNA species, are increasingly used as synthetic tools for sustained therapeutic protein translation by IRES-driven initiation. However, the functionality of different IRESes in synthetic circRNAs remains sparsely characterized. We systematically examine circRNA reporter translation by viral and cellular IRESes in human cells and in diverse in vitro translation systems. Improved circRNA purification by urea-PAGE and RNase R-treatment removes contaminants that induce RNA sensing. Viral CVB3 and HCV, as well as cellular Hoxa9 , Chrdl1 , Cofilin and c-Myc IRESes, effectively drive circRNA translation. We also establish circRNA translation in an improved human cell-free extract that recapitulates IRES-dependent regulation, and allows for precise engineering of HCV IRES-mediated translation. These findings inform IRES selection for synthetic circRNA translation relevant for circRNA-based medicines.
    DOI:  https://doi.org/10.64898/2026.03.28.715045
  23. bioRxiv. 2026 Mar 28. pii: 2026.03.28.715003. [Epub ahead of print]
    The Helicobacter pylori ribosomal silencing factor RsfS is required for low-growth states and chronic infection.
    Yasmine O Elshenawi, Skander Hathroubi, Angela E Lane, Megan Hetzel, Karen M Ottemann.
      Helicobacter pylori is a prevalent bacterial pathogen that chronically colonizes the human gastric epithelium, but the bacterium's physiological mechanisms that promote this are understudied. Dormancy and low growth are known to facilitate other microbial chronic infections. A critical feature of low growth states is the down regulation of ribosome translational activity via regulation factors. The H. pylori genome is predicted to encode only one ribosome regulation factor, called RsfS (Ribosomal Silencing Factor S). In other bacterial species, RsfS prevents ribosome assembly by binding to a protein called L14 on the 50S large ribosomal subunit. Although H. pylori RsfS has not been experimentally investigated prior to this work, it conserves key residues, suggesting it is a bona fide RsfS homolog. To investigate phenotypes associated with rsfS , the gene was deleted and mutant phenotypes characterized. H. pylori rsfS null mutants had no defects during exponential phase but had viability defects in stationary phase and low growth factor conditions. Additionally, rsfS null mutants could not form biofilms, and instead were only able to form monolayers of multicellular aggregates. These defects were corrected by the re-introduction of rsfS in a second site on the chromosome. To explore whether rsfS is required in vivo , a mouse model was employed. rsfS mutants initially colonized in low numbers in both the glands and total stomach but were unable to develop robust long-term colonization. This work supports that H. pylori requires RsfS for survival in low growth states and to maintain chronic infections in the host.
    Importance: H. pylori chronic infections are difficult to cure in part because H. pylori is proposed to adopt low-growth states known to render bacteria tolerant to antibiotics. One key signature of a low growth state includes low translation via ribosome regulation factors. Unlike other bacterial species, H. pylori contain only one known ribosome regulation factor called Ribosomal Silencing Factor S (RsfS). This gene was previously found to be transcriptionally upregulated in at least one low growth state, biofilms. In this work, we found that H. pylori rsfS is required for this microbe to thrive in low growth states and during infection. This study is one of only two studies that investigates the phenotypes of rsfS knockout mutants in any bacterial species and the first to address knowledge gaps in ribosomal regulation by H. pylori in vivo .
    DOI:  https://doi.org/10.64898/2026.03.28.715003
  24. Bioorg Med Chem Lett. 2026 Mar 28. pii: S0960-894X(26)00109-5. [Epub ahead of print]137 130642
    Nitroxoline-O-protected derivatives inhibit MetAP2 and activate ATF4 through mTORC1 to inhibit cancer cell growth.
    Michael J Williams, Conor T Ronayne, Tanner J Schumacher, Kayla M Johnson, Matthew D Wittmer, Joseph L Johnson, Grant W Anderson, Venkatram R Mereddy.
      Reprogrammed cancer cell proliferation requires high levels of protein synthesis and concomitant folding and processing. N-terminal methionine amino peptidases (MetAP) are a class of enzymes that cleave the initiator methionine amino acids to allow for peptide maturation and co-translational processing. The protein MetAP2 is upregulated in cancer cells and has been explored as a potential anticancer target. Cellular perturbations that impinge on protein synthesis activate cellular stress pathways, including the integrated stress response and mTORC1. Nitroxoline, a MetAP2 inhibitor has been explored as an anticancer agent but is hampered by poor pharmacokinetic properties. Here, we synthesized O-substituted silyl and nonsilyl nitroxoline analogs to diversify the nitroxoline template. In vitro MetAP2 and cancer cell proliferation inhibition assays demonstrated that synthesized analogs retain potency when compared to the parent nitroxoline. Mechanistically, we showed that the lead compound 3 and nitroxoline activate ATF4 mediated stress responses through non-canonical mTORC1. These results further implicate MetAP2 protein processing in mTORC1 nutrient sensing pathways and provide novel synthetic analogs of nitroxoline.
    Keywords:  ATF4; Integrated stress response; MetAP2; Nitroxoline; mTORC1
    DOI:  https://doi.org/10.1016/j.bmcl.2026.130642
  25. Redox Biol. 2026 Mar 26. pii: S2213-2317(26)00141-2. [Epub ahead of print]92 104143
    Mitochondrial translational control in cardiovascular diseases: from mechanisms to therapies.
    Yunong Deng, Ningning Guo, Die Li, Zhihua Wang.
      Mitochondria orchestrate cardiac metabolic homeostasis, and their dysfunction constitutes a fundamental mechanism driving cardiovascular diseases (CVDs). During eukaryotic evolution, most of the mitochondrial genes required for oxidative phosphorylation (OXPHOS) function have been transferred to the nuclear genome, except for 13 genes coding for core subunits of the OXPHOS machinery. The translational regulation of these 13 genes inside mitochondria is precisely and dynamically regulated according to the external environment under diverse metabolic conditions. However, our understanding of these biological processes in CVDs remains limited. This review summarizes recent advances in the regulatory processes of mitochondrial translation, highlighting mitoribosome biogenesis, dynamic tRNA epitranscriptomic modifications, and coupling between translation and inner-membrane assembly. We additionally integrate emerging upstream regulatory mechanisms, including redox and metabolite-sensitive signaling, mitoepigenetic remodeling, and mitochondria-localized microRNA (mitomiR)-mediated control of mitochondrial RNA fate, which collectively tune translational output under stress. Moreover, this review delineates how these processes are dysregulated in major cardiovascular pathologies, including ischemia-reperfusion (I/R) injury, cardiac hypertrophy, heart failure (HF), and inherited cardiomyopathies. Emerging therapeutic strategies designed to restore translational fidelity and throughput, ranging from pharmacological interventions and metabolic tuning to precise mitochondrial gene editing, are also discussed. By repositioning mitochondrial translation from a passive marker of injury to a druggable control node, this review offers a new paradigm for targeting mitochondrial translation to preserve myocardial resilience and treat CVDs.
    Keywords:  Cardiovascular diseases; Mitochondrial translation; Mitoribosome; OXPHOS; tRNA modification
    DOI:  https://doi.org/10.1016/j.redox.2026.104143
  26. bioRxiv. 2026 Mar 24. pii: 2026.03.22.713398. [Epub ahead of print]
    Multiple mTOR RNA localization signals regulate subcellular protein synthesis and axonal growth.
    Nitzan Samra, Pabitra K Sahoo, Agostina Di-Pizio, Courtney N Buchanan, Nataliya Okladnikov, Ofri Abraham, Shifra Ben-Dor, Rebecca Haffner-Krausz, Ida Rishal, Jeffery L Twiss, Mike Fainzilber.
      Subcellular localization of mTOR is thought to be key for regulating cell size and growth, but the relative contributions of mRNA versus protein localization are unclear. We used reporter mRNA localization assays to identify two distinct mTOR Localizing Sequences (MLS) in its 5'UTR, in addition to the localization activity already reported for the 3'UTR. Gene-edited mice with deletion of both 5'UTR MLS are mTOR hypomorphs with reduced body weight and brain size. In contrast, a mouse line lacking the second 5'UTR MLS and the 3'UTR retains near normal overall mTOR expression levels with specific subcellular perturbation of mTOR localization to neuronal axons. This subcellular mTOR deficit affects axonal local protein synthesis and neuronal growth. Thus, mTOR transcripts are localized by multiple UTR sequences, and subcellular localization of mTOR mRNA regulates local protein synthesis and neuronal growth.
    DOI:  https://doi.org/10.64898/2026.03.22.713398
  27. RNA. 2026 Mar 31. pii: rna.080869.125. [Epub ahead of print]
    Chronology of tRNA structural dynamics prior to and during interaction with a pseudouridine synthase.
    Emily M Dennis, Nico E Conoan Nieves, Madison G Kadrmas, Abigail L Vaaler, Margaret L Barry, David M Garcia, Julia R Widom.
      Transfer RNA has long served as an exemplar of a thermodynamically stable, structured RNA. Yet it undergoes significant structural changes upon binding and catalysis by diverse modification enzymes. We leveraged optical binding assays and single-molecule FRET to observe the structural dynamics of two yeast tRNAs, in isolation, and upon interaction with the conserved pseudouridine synthase Pus4/TruB. We show that unmodified and pseudouridylated tRNAeMet(CAU) and tRNAThr(AGU) all sample open, compact and intermediate conformations, though tRNAThr(AGU) exhibits faster dynamics. Consistent with its role in modifying RNAs with different structural properties, Pus4 binds robustly to unmodified tRNA, tRNA that was pseudouridylated prior to engaging Pus4 ("pre-modified"), and even an unrelated riboswitch RNA. Pus4 binding to tRNAeMet(CAU) leads to additional tRNA conformational states. The ensemble of conformations explored by Pus4-bound pre-modified tRNA resolved within minutes back into open, compact and intermediate states. tRNAeMet(CAU) that is initially unmodified more gradually approached the ensemble of structures that were attained rapidly by pre-modified tRNA. Thus, Pus4 both catalyzes a lasting chemical change on tRNA and remodels it over time after catalysis, perhaps to promote subsequent steps of tRNA maturation.
    Keywords:  Dynamics; Pseudouridine; smFRET; tRNA; tRNA modification
    DOI:  https://doi.org/10.1261/rna.080869.125
  28. bioRxiv. 2026 Mar 25. pii: 2026.03.20.711686. [Epub ahead of print]
    Activation of the protective arm of renin-angiotensin system enhances mitochondrial turnover improving respiration and decreasing integrated stress response in a human Complex III deficiency model.
    Lucía Fernández-Del-Río, Andrea Eastes, David Rincón Fernández Pacheco, Nikole Scillitani, Jasmine Garza, Matthew Dugan, Matheus Pinto de Oliveira, Pradnya Kadam, Iman Gauhar, Karel Erion, Kathleen Rodgers, Kevin Gaffney, Amy Wang, Marc Liesa, Cristiane Benincá, Orian Shaul Shirihai.
      Primary mitochondrial diseases are clinically and genetically heterogeneous disorders, commonly caused by defects in the oxidative phosphorylation system. This heterogeneity presents major challenges for therapeutic development; however, a shared hallmark across these diseases is the accumulation of dysfunctional mitochondria. Enhancing mitochondrial turnover, by activating the selective degradation of dysfunctional mitochondria via mitophagy, concurrently with the activation of mitochondrial biogenesis, could represent a shared therapeutic strategy for mitochondrial diseases. Here, we describe a novel mitophagy inducer, CAP-1902. CAP-1902 is a new agonist of the MAS G-Protein Coupled Receptor (MasR). In fibroblasts from patients carrying a BCS1L mutation that impairs complex III (CIII) assembly, CAP-1902 increased mitochondrial turnover by promoting both mitophagy and biogenesis. Specifically, MasR activation triggered the AMPK/ULK1/FUNDC1 mitophagy pathway. Knockdown of FUNDC1 blocked mitophagy but not AMPK activation, confirming pathway specificity. Additionally, a decrease in the occurrence of depolarized mitochondria with treatment indicated the selective targeting of accumulated damaged mitochondria in the disease context. MasR activation by CAP-1902 also stimulated the nuclear translocation of PGC-1α, promoting increased expression of transcripts associated with mitochondrial biogenesis, respiratory chain components, and mitochondrial translation. Remarkably, CAP-1902 was ultimately able to restore key defects in CIII-deficient fibroblasts by rescuing bioenergetics and correcting both the aberrant lysosomal distribution and the elevated integrated stress response markers, which is consistent with a shift toward a healthier mitochondrial population. In summary, we describe the first potential GPCR-mediated treatment of mitochondrial diseases and demonstrate that MasR activation by CAP-1902 induces mitochondrial turnover and improves mitochondrial function.
    DOI:  https://doi.org/10.64898/2026.03.20.711686
  29. Histol Histopathol. 2026 Mar 31. 25070
    Methyltransferase 3 promotes v-set and transmembrane domain-containing 2-like protein expression to intensify ferroptosis-mediated prostate adenocarcinoma progression through the m6A methylation modification.
    Jinming Li, Jun Jiang, Shaoxing Wang, Jiahao Liu, Shusen Zuo.
       BACKGROUND: Prostate adenocarcinoma (PRAD) is a common malignancy with high incidence in men. The role of v-set and transmembrane domain-containing 2-like protein (VSTM2L) in PRAD remains largely unreported.
    METHODS: Gene expression was analyzed using The Cancer Genome Atlas (TCGA), the Tumor Immune Estimation Resource (TIMER) 2.0, and the University of Alabama at Birmingham CANcer data analysis Portal (UALCAN) databases, and validated by quantitative real-time PCR (qRT-PCR) and western blot. Cell proliferation was assessed by 5-ethynyl-2'-deoxyuridine (EdU) staining. Apoptosis and mitochondrial membrane potential were examined by flow cytometry. Intracellular iron, Fe2+, and reactive oxygen species (ROS) levels were measured using commercial kits and flow cytometry. The role of VSTM2L in tumor growth was evaluated using xenograft mouse models, with protein expression in tumors evaluated by immunohistochemistry (IHC). The N6-methyladenosine (m6A) modification sites on VSTM2L mRNA were predicted using the sequence-based RNA adenosine methylation site predictor (SRAMP) website. The interaction between methyltransferase 3 (METTL3) and VSTM2L was confirmed by methylated RNA immunoprecipitation (MeRIP) and dual-luciferase reporter assay. Correlation analysis was performed using the TCGA database.
    RESULTS: VSTM2L was overexpressed in PRAD tissues and cell lines. Silencing VSTM2L inhibited PRAD cell proliferation, promoted apoptosis, and enhanced ferroptosis and oxidative stress in vitro. Consistently, VSTM2L knockdown suppressed tumor growth in vivo. Mechanically, METTL3 mediated m6A methylation to stabilize VSTM2L mRNA. Furthermore, METTL3 promoted proliferation and inhibited apoptosis, ferroptosis, and oxidative stress in PRAD cells via a VSTM2L-dependent manner.
    CONCLUSION: METTL3 promotes PRAD progression by stabilizing VSTM2L expression through m6A methylation, thereby inhibiting ferroptosis. This study establishes a direct link between RNA methylation and ferroptosis in PRAD, revealing the METTL3/VSTM2L axis as a novel regulatory pathway and a potential therapeutic target.
    DOI:  https://doi.org/10.14670/HH-25-070
  30. QJM. 2026 Apr 03. pii: hcag101. [Epub ahead of print]
    RNA-Centric Tumour Evolution: Transcriptional Reinforcement, Reversibility, and Clinical Plasticity Beyond Genetics.
    Neetu Singh.
      Cancer progression is traditionally interpreted through genetic mutation and clonal selection. While this framework explains tumour initiation, it does not fully account for prolonged dormancy, late relapse, spatial heterogeneity, or metastasis occurring without new driver mutations. Increasing evidence instead implicates reversible regulatory layers operating downstream of DNA sequence. We propose an RNA-centric framework in which transcriptional reinforcement and RNA fate control jointly shape tumour evolution across time and space. Weak or context-dependent promoters-common in cancer-can generate sustained transcriptional output through exon-dependent reinforcement without promoter mutation, enhancer hijacking, or immediate protein production. The resulting RNA output is then filtered through RNA fate checkpoints that govern decay, nuclear retention, export, or persistence, functionally uncoupling transcription from translation. Within this model, non-coding and non-canonical RNAs act as spatiotemporal reporters of tumour state, reflecting when and where transcriptional programmes are engaged rather than which proteins are produced. RNA persistence enables tumours to remain transcriptionally primed under hypoxia, therapy, or immune pressure, supporting dormancy and rapid reactivation without irreversible genetic change. Reframing tumour evolution around RNA state regulation provides a coherent explanation for relapse and resistance and highlights RNA states as clinically tractable biomarkers and therapeutic targets that complement DNA-based oncology.
    Keywords:  RNA surveillance; metastasis; non-coding RNAs; phenotypic plasticity; transcriptional reinforcement; tumour dormancy and relapse
    DOI:  https://doi.org/10.1093/qjmed/hcag101
  31. Methods Mol Biol. 2026 ;3026 209-219
    Detection of tRNA-Derived Small RNAs in Arabidopsis thaliana via Northern Blotting: Exploring Potential Biomarkers for Phytohormone Analysis.
    Dinesh Singh Pujara, Tanzila Kamal Choity, Yogendra Bordiya, Susan M Magdaleno, Hong-Gu Kang.
      Noncoding small RNAs (sRNAs) are well-known regulatory molecules that influence a wide range of cellular processes in eukaryotes and often function in concert with phytohormones. Advances in next-generation sequencing (NGS) have further expanded the identification and characterization of sRNAs from diverse sources, highlighting their potential as early biomarkers for hormone and stress signaling. In recent work, we identified transfer RNA-derived fragments (tRFs) as a prominent class of sRNAs, induced as early as 1 h post-infection with Pseudomonas syringae, that positively regulates defense gene expression in Arabidopsis. However, verifying these sRNA findings from NGS data presents a technical challenge, as the small size and often low abundance of these sRNAs complicate accurate detection and quantification. Here, we present a procedure to enrich sRNAs and facilitate the detection of sRNAs in Arabidopsis using a sensitive northern blot protocol. We evaluated sRNA enrichment using the conventional Trizol method with and without nucleic acid precipitants, as well as commercial column-based extraction kits. Our northern blot results show that total RNA purified by both methods is enriched with sRNAs. Additionally, the precipitants, such as linear acrylamide and glycogen, improved the detection of tRFs. Column-based kits also yielded comparable enrichment of tRFs and provided a rapid and straightforward protocol essential for preserving RNA integrity. This study thus presents a robust, nonradioactive and PCR-free detection method for characterizing the regulatory functions of sRNAs.
    Keywords:  Arabidopsis thaliana; Noncoding small RNAs; Northern blot; Total RNA isolation method; Transfer RNA-derived fragments
    DOI:  https://doi.org/10.1007/978-1-0716-5214-5_15
  32. Aging (Albany NY). 2026 Mar 27. 18(1): 213-233
    ATF5 is required for the maintenance of mitochondrial homeostasis and skeletal muscle health during aging.
    Victoria C Sanfrancesco, David A Hood.
      In skeletal muscle, the mitochondrial network is highly regulated by quality control (MQC) processes including the Integrated Stress Response (ISR) and the mitochondrial Unfolded Protein Response (UPRmt), controlled in part by the transcription factor, Activating Transcription Factor 5 (ATF5). With age, mitochondrial health and function become altered in muscle, but the role of ATF5 in regulating these processes has not yet been evaluated. This study therefore aimed to evaluate the role of ATF5 in mediating mitochondrial quality control and function during aging. To investigate this, we utilized young (4-6 months) and middle-aged (14-16 months; denoted as aged) ATF5 whole-body KO and WT male mice. The normal age-related decline in muscle mass was prevented in the absence of ATF5. This was accompanied by an attenuated rise in important protein degradation regulators, indicating that ATF5 regulates muscle protein turnover with age. Aged ATF5 KO muscle exhibited greater muscle fatiguability than WT counterparts, accompanied by accelerated mitochondrial ROS production. The expression of the co-regulatory ISR/UPRmt transcription factors, CHOP and ATF4, was attenuated in response to acute contractile activity in the absence of ATF5. The lack of ATF5 led to a reduction in the levels of LonP and was accompanied by an increase in mitochondrial:nuclear derived protein imbalance. Collectively, these results suggest that ATF5 functions to maintain mitochondrial quality control and muscle endurance at the expense of muscle mass, and its absence attenuates the normal compensatory stress response to contractile activity with age.
    Keywords:  ATF5; aging; mitochondria; skeletal muscle; stress response
    DOI:  https://doi.org/10.18632/aging.206365
  33. Cell Biol Toxicol. 2026 Apr 02.
    The PRKN/METTL3/CLDN2 axis promotes colorectal cancer development through epigenetic mechanisms.
    Hongtao Ren, Mincong Wang, Xiulong Ma, Lei An, Yuyan Guo, Hongbing Ma.
       BACKGROUND: Dysregulation of N6-methyladenosine (m6A) RNA methylation plays a crucial role in colorectal cancer (CRC) development. Despite the established oncogenic role of methyltransferase-like 3 (METTL3) in CRC, the mechanisms behind its tumor-promoting functions are not fully understood.
    METHODS: Functional impacts were assessed by measuring cell viability, invasion, colony formation, migration, apoptosis, and M2 macrophage polarization in vitro, as well as in vivo tumorigenicity. The interaction between METTL3 and claudin 2 (CLDN2) was validated via RNA immunoprecipitation and luciferase assays. The PRKN/METTL3 interaction was analyzed using immunoprecipitation (IP) and Co-IP experiments. The stability of mRNA and protein levels was examined by treating cells with actinomycin D or cycloheximide.
    RESULTS: METTL3 and CLDN2 levels were upregulated in CRC samples and cells. Depletion of METTL3 or CLDN2 suppressed CRC cell proliferation, invasion, and migration, and inhibited M2 polarization of THP-1-derived macrophages. Mechanistically, METTL3 promoted m6A methylation and stability of CLDN2 mRNA in an insulin-like growth factor 2 binding protein 2 (IGF2BP2)-dependent manner. METTL3 silencing diminished CRC cell malignant phenotypes and M2 macrophage polarization via CLDN2 reduction. Moreover, PRKN enhanced METTL3 protein degradation through K63-linked polyubiquitination. The PRKN/METTL3 axis regulated malignant phenotypes of CRC cells. Additionally, METTL3 depletion repressed tumor growth and lung metastasis of xenografts in vivo via CLDN2.
    CONCLUSION: Our work uncovers a previously unrecognized PRKN-METTL3-CLDN2 signaling network that orchestrates colorectal tumorigenesis, providing a compelling rationale for developing METTL3-targeted therapies against CRC.
    Keywords:  Colorectal cancer; Epigenetic modifications; M6A methylation; METTL3; Ubiquitination
    DOI:  https://doi.org/10.1007/s10565-026-10180-5
  34. G3 (Bethesda). 2026 Mar 30. pii: jkag083. [Epub ahead of print]
    Autoregulation of three yeast ribosomal protein genes by splicing inhibition.
    David Granas, Anirudh Kesanapally, Michael A White, Gary D Stormo.
      Yeast ribosomal protein genes RPL18B, RPL28 and RPS22B are autoregulated by inhibition of splicing. This is demonstrated by inserting their introns into a chromosomal copy of GFP and observing repression upon induction of the cognate protein. In RPL18B and RPS22B, a predicted conserved secondary structure within the intron is required for regulation, while in RPL28 it is not.
    Keywords:  autoregulation; mRNA structure; splicing
    DOI:  https://doi.org/10.1093/g3journal/jkag083
  35. Trends Cancer. 2026 Apr 01. pii: S2405-8033(26)00056-7. [Epub ahead of print]
    Unexpected role of the integrated stress response in cancer immune evasion.
    Lucia Borriello, Lorenzo Galluzzi.
      Viral mimicry, i.e., the ability of uninfected cancer cells to emit molecular signals normally associated with infection, is paramount for anticancer immunity. Recent findings from Bossowski et al. indicate that the integrated stress response (a crucial component of cellular responses against infection) can unexpectedly promote immune evasion via an LCN2-driven, macrophage-dependent mechanism.
    Keywords:  ATF4; ER stress response; SLC22A17; T cell exclusion; immunogenic cell death; three Cs
    DOI:  https://doi.org/10.1016/j.trecan.2026.03.001
  36. RNA. 2026 Apr 02. pii: rna.080861.125. [Epub ahead of print]
    A method of comprehensive sequencing analysis of the small RNA fragmentome (RiboMarker).
    Rachel C Clark, Aidan C Manning, Jonathan M Howard, Sergio Barberan-Soler, Sergei A Kazakov.
      Circulating cell-free nucleic acids (cfDNA and cfRNA) found in blood and other biofluids are promising biomarkers for cancer. However, current methods exploiting tumor-derived cfDNA (ctDNA) are not sensitive enough in detecting minimal residual disease and early stages of cancer when it is more treatable. Small RNAs and RNA fragments (sRNA) can potentially provide higher detection sensitivity and specificity than ctDNA. Sequencing analysis of the variety of sRNAs representing the entire RNA fragmentome would improve our understanding of their roles in cancer development and help to discover novel sRNA biomarkers for cancer diagnostics and personalized treatments. However, conventional methods of sRNA-Seq library preparation are limited to detection of sRNA with 5'-P and 3'-OH ends that represent only less than 10% of the whole RNA fragmentome, whereas sRNAs having different phosphorylation statuses (P or OH) of their termini are hidden. Although recently developed sRNA-Seq methods allow detection of most sRNA (including the hidden ones) simultaneously, these methods cannot both detect and distinguish among the individual RNAs with differing termini combinations (RNA Types). Here we describe the RiboMarker® platform for preparation of sRNA sequencing libraries that addresses these shortcomings. It uses distinctive enzymatic pretreatment(s) of RNA samples that can both detect all and enrich for individual sRNA Types upfront of sequencing library preparation. The RiboMarker® platform has the potential capability to both identify and detect with enhanced sensitivity low abundance sRNA biomarkers of specific RNA classes and their termini.
    Keywords:  RNA circularization; RNA ends conversion; RNA fragments; cell-free small RNA; sequencing library preparation
    DOI:  https://doi.org/10.1261/rna.080861.125
  37. J Dermatol Sci. 2026 Mar 20. pii: S0923-1811(26)00071-X. [Epub ahead of print]
    Inhibition of eukaryotic translation initiation factor 1 A (eIF1A) and 3B (eIF3B) diminishes the psoriatic phenotype in two mouse models and human 3D model samples.
    Nicole Golob-Schwarzl, Natalie Bordag, Nitesh Shirsath, Christin-Therese Müller, Amin El-Heliebi, Peter Wolf.
       BACKGROUND: Psoriasis is a systemic inflammatory skin disease for which new topical treatments are needed. Psoriatic inflammation is associated with overexpression of eukaryotic translation initiation factors (eIFs), which regulate gene expression in processes such as proliferation, apoptosis, and differentiation. However, their role in psoriasis remains unclear.
    OBJECTIVE: To investigate the contribution of eIF1A and eIF3B to psoriasis pathogenesis and evaluate the therapeutic potential of their inhibition via small interfering RNA (siRNA).
    METHODS: We used two mouse models reflecting different mechanisms of psoriasis: (i) topical application of imiquimod (IMQ) and (ii) K5.TGFβ transgenic mice promoting keratinocyte proliferation. eIF1A and eIF3B were inhibited by either topical or systemic siRNA administration. A 3D human psoriasis model was also used for validation.
    RESULTS: Inhibition of eIF1A and eIF3B reduced inflammation in both mouse models and the 3D human model. Downregulation of these factors normalized keratinocyte proliferation, epidermal thickness, and cytokine expression (e.g., TNFα, IL-1β, IL-17, IL-22). Differentiation markers such as KRT16 and FLG were restored. These findings suggest that eIF1A and eIF3B play a key role in maintaining the psoriatic inflammatory phenotype.
    CONCLUSION: Our findings reveal a translational imbalance in psoriasis and identify eIF1A and eIF3B as crucial regulators of disease pathophysiology. Targeting these factors represents a promising new therapeutic strategy for psoriasis treatment.
    Keywords:  Eukaryotic translation initiation factors; New therapeutic targets; Psoriasis
    DOI:  https://doi.org/10.1016/j.jdermsci.2026.03.008
  38. bioRxiv. 2026 Mar 27. pii: 2026.03.25.714317. [Epub ahead of print]
    Pathogenic human mitochondrial tRNA variants impair RNA processing by compromising 5' leader removal.
    Jubilee H Muñozvilla, Avery Ontiveros, Tatiana V Mishanina.
      Human mitochondrial genome (mtDNA) encodes multiple proteins in the oxidative phosphorylation complexes as well as the ribosomal and transfer RNAs (tRNAs) needed for in situ translation. These genes are transcribed from only three promoters, producing polycistronic transcripts that are co-transcriptionally cleaved by mitochondrial RNase enzymes to release majority of individual gene products. tRNAs separate many of these genes and are thought to serve as "punctuation" marks that enable RNase recognition, binding, and hydrolysis of the 5' "leader" and 3' "trailer" sequences flanking the tRNA. Mutations in the tRNA genes dominate the mtDNA-linked mitochondrial pathologies; yet a systematic study of the impact of tRNA sequence variation on the RNase-catalyzed processing is lacking. Here, we employed human mitochondrial tRNA Tyr as a model system to dissect the effect of tRNA variants on the in vitro 5' leader and 3' trailer hydrolysis. We found that nucleotide variations located near the catalytic interfaces - particularly within or near the tRNA acceptor stem - showed the strongest defects in 5' processing and prevented release of the downstream tRNA in a tRNA cluster where multiple tRNAs are transcribed in tandem. This work provides mechanistic insight into how mutations disrupt coordinated mitochondrial tRNA processing and establish a framework for predicting variant effects based on their structural position relative to the processing enzymes.
    DOI:  https://doi.org/10.64898/2026.03.25.714317
  39. Mol Cell. 2026 Apr 02. pii: S1097-2765(26)00162-0. [Epub ahead of print]86(7): 1293-1310.e14
    U2AF regulates the translation and localization of nuclear-encoded mitochondrial mRNAs.
    Gloria R Garcia, Murali Palangat, Josquin Moraly, Benjamin T Donovan, Bixuan Wang, Ira Phadke, David Sturgill, Jiji Chen, Guofeng Zhang, Ronald J Holewinski, Brittney Short, Gustavo A Rivero, David M Swoboda, Naomi Taylor, Kathy McGraw, Daniel R Larson.
      The mechanisms underlying molecular targeting to mitochondria remain enigmatic, yet this process is crucial for normal cellular function. The RNA-binding proteins U2AF1 and U2AF2 form a heterodimer (U2AF) that shuttles between the nucleus and cytoplasm, regulating splicing in the nucleus and translation in the cytoplasm. Our study in human bronchial epithelial cells (HBECs) identifies an unexpected role for U2AF in mitochondrial function. We demonstrate that U2AF interacts with nuclear-encoded mitochondrial (NE-mt) mRNAs and proteins, inhibits translation, localizes to the mitochondria, and regulates mRNA localization to mitochondria. Moreover, an oncogenic point mutation in U2AF1(S34F) disrupts this regulation, leading to altered mitochondrial structure, increased translation, large changes in the mitochondria proteome, and oxidative phosphorylation (OXPHOS)-dependent metabolic rewiring, recapitulating changes observed in bone marrow progenitors from patients with myelodysplastic syndromes. These findings reveal a non-canonical role for U2AF, where it modulates multiple aspects of mitochondrial function by regulating the translation and mitochondrial localization of nuclear-encoded mRNAs.
    Keywords:  U2AF1; cancer; mRNA localization; metabolism; mitochondria; myeloid leukemia; translation
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.006
  40. Endocr Regul. 2026 Jan 01. 60(1): 37-47
    ERN1-dependent regulation of BAG cochaperone 1 expression and the sensitivity to glutamine deprivation in U87MG glioblastoma cells.
    Yuliia M Viletska, Oleksandr H Minchenko, Olena O Khita, Daria O Tsymbal, Myroslava Y Sliusar, Oleh V Halkin, Halyna E Kozynkevych, Dmytro O Minchenko.
      Objective. The BAG cochaperone 1 (BAG1) binds to oncogene BCL2 and markedly enhances its anti-apoptotic effects. This cochaperone represents a link between growth factor receptors and anti-apoptotic mechanisms mediated by endoplasmic reticulum stress. BAG1 interacts with the glucocorticoid receptor and modulates its transcription activity. As a cochaperone for several HSP70 proteins, it participates in control of protein folding. The present study aims to investigate the regulation of the BAG1 mRNA expression in U87MG glioblastoma cells by hypoxia and glucose or glutamine deprivation, depending on the inhibition of ERN1 (endoplasmic reticulum to nucleus signaling 1) with the intent to reveal the role of ERN1 signaling in the regulation of this gene expression and function in oncogenesis. Methods. The U87MG glioblastoma cells (transfected by an empty vector; control) and cells with inhibited ERN1 endoribonuclease and protein kinase (dnERN1) or only ERN1 endoribonuclease (dnrERN1) were used. Silencing of ERN1 and XBP1 mRNAs for suppression of ERN1 function was also used. A hypoxic condition was created by dimethyloxalylglycine (4 h). DMEM medium without glucose or glutamine was used for glucose and glutamine deprivation (16 h). The expression level of the BAG1 mRNA was studied by real-time qPCR and normalized to the beta-actin mRNA. Results. Inhibition of the endoribonuclease activity of ERN1 significantly decreased BAG1 mRNA expression. However, a lesser suppression of this mRNA expression was observed in dnERN1 cells (with inhibited ERN1 endoribonuclease and protein kinase) indicating the involvement of protein kinase in controlling BAG1 expression. The silencing of ERN1 and XBP1 mRNAs also reduced the expression of BAG1 mRNA demonstrating the involvement of XBP1s in this regulation. The expression of the BAG1 gene was resistant to glutamine deprivation and upregulated in response to glucose deprivation in control glioblastoma cells. However, the inhibition of ERN1 increased the sensitivity of BAG1 gene expression to both glucose and glutamine deprivation. Furthermore, the expression of the BAG1 gene was increased under hypoxia in control U87MG cells; however, a greater induction was observed in dnERN1 cells. Conclusion. The results of this study demonstrated that ERN1 inhibition reduces BAG1 mRNA expression through the endoribonuclease activity of ERN1 and that protein kinase activity counteracts endoribonuclease in regulating the expression of BAG1 mRNA. Moreover, ERN1 inhibition also enhances the sensitivity of BAG1 mRNA expression to nutrient supply and hypoxia resulting in reduced resistance of glioblastoma cells.
    Keywords:  BAG1; ERN1 and XBP1 silencing; ERN1 endoribonuclease; ERN1 inhibition; ERN1 protein kinase; gene expression; glioblastoma cells; glutamine and glucose deprivation; hypoxia
    DOI:  https://doi.org/10.2478/enr-2026-0005
  41. Science. 2026 Apr 02. 392(6793): eaea8782
    Harnessing viral strategies to reverse cognitive dysfunction through the integrated stress response.
    Lucas C Reineke, Ping Jun Zhu, Udit Dalwadi, Sean W Dooling, Yuwei Liu, I-Ching Wang, Sara Young-Baird, James Okoh, Santosh Kumar Kuncha, Hongyi Zhou, Akshara Kannan, Hyekyung Park, Nicolas A Debeaubien, Tristan Croll, D John Lee, Christopher Arthur, Thomas E Dever, Peter Walter, Jin Chen, Adam Frost, Mauro Costa-Mattioli.
      The integrated stress response (ISR) is essential for cellular homeostasis and cognitive function. We investigated how persistent ISR activation affects cognitive performance by studying the PPP1R15BR658C genetic variant associated with intellectual disability. To model this condition, we generated a mouse line with the pathogenic allele inserted. This variant destabilized the PPP1R15B•PP1 phosphatase complex, causing persistent ISR activation, impaired protein synthesis, and long-term memory deficits. We demonstrated that the cognitive and synaptic impairments in Ppp1r15bR658C mice arise directly from ISR activation. Furthermore, we characterized DP71L, a viral ortholog of PPP1R15B, which acted as a potent pan-ISR inhibitor. DP71L reversed the cognitive and synaptic deficits across mouse models of Down syndrome, Alzheimer's disease, and aging, and enhanced synaptic plasticity and memory in healthy mice.
    DOI:  https://doi.org/10.1126/science.aea8782
  42. Chimia (Aarau). 2026 Mar 25. 80(3): 130-137
    Expanding Biological Roles of Post-translational Arginylation.
    Dominic Scopelliti, Changfeng Deng, Benjamin A Garcia, Zongtao Lin.
      Protein arginylation is a conserved post-translational modification in eukaryotes, involving the conjugation of arginine residues to proteins by the enzyme arginyl-tRNA transferase. Historically associated with targeted degradation, recent studies have expanded this view by uncovering its broader regulatory influence across diverse cellular functions. This review first examines the established roles of arginylation in protein degradation through the Ubiquitin-Proteasome System and Autophagy-Lysosome System. It then highlights its non-degradative functions, including the modulation of protein-protein interactions, complex assembly, protein stability, and crosstalk with other post-translational modifications. Emerging evidence supports the notion that arginylation functions in a context dependent manner, simultaneously affecting both the stability and functional behaviour of proteins. Together, these works reveal arginylation as a dynamic and versatile mechanism that extends well beyond proteolysis, positioning it as a key global regulator of cellular functioning.
    Keywords:  Arginylation; Biology; Degradation; Non-degradative functions; Post-translational modification
    DOI:  https://doi.org/10.2533/chimia.2026.130
  43. Chimia (Aarau). 2026 Mar 25. 80(3): 150-156
    Recent Advances in Small-Molecule Modulators Targeting IRE1α.
    Yang Liu, Peng Wu.
      IRE1α is an important ER stress sensor located on the ER membrane with dual kinase and ribonuclease activity. It plays a crucial role in restoring ER proteostasis and is associated with various human diseases. Targeting IRE1α has become a promising therapeutic approach. Many IRE1α modulators have been identified in recent years, and some of these have demonstrated excellent pre-clinical efficacy. The modulation of IRE1α RNase activity by small molecules can be achieved through two main mechanisms: directly binding to the RNase domain to block RNA splicing, or allosteric modulation of its activity through binding to the kinase domain. Apart from monovalent inhibitors and activators, proteolysis targeting chimeras have been reported to degrade IRE1α and block its downstream signalling by recruiting the E3 ligase-ubiquitin system. In this review we summarize the recent advances of targeting IRE1α with small molecules, including inhibitors, activators, and bifunctional molecules, providing an insight into future development of chemical modalities targeting IRE1α.
    Keywords:  Allosteric inhibitors; PROTAC; RNA splicing; Ribonuclease and IRE1α; Small-molecule modulators
    DOI:  https://doi.org/10.2533/chimia.2026.150
  44. Nucleic Acids Res. 2026 Mar 19. pii: gkag278. [Epub ahead of print]54(6):
    KREPA6 functions in RNA editing catalytic complex structural organization and gRNA utilization in Trypanosoma brucei.
    Brittney Davidge, Jason Carnes, Isaac Lewis, Tyler Rodshagen, Maxwell Tracy, Suzanne M McDermott, Kenneth D Stuart.
      Functional mitochondrial mRNAs in Trypanosoma brucei are generated by the post-transcriptional guide RNA (gRNA) directed insertion and deletion of uridine residues, called RNA editing, that is catalyzed by three closely related multiprotein RNA Editing Catalytic Complexes (RECCs). These RECCs contain a common set of 12 proteins including KREPA6 which is largely comprised of an oligonucleotide binding (OB)-fold domain with a predicted intrinsically disordered region (IDR) at its C-terminus. Here we show that certain single amino acid substitutions throughout KREPA6 or deletion of the IDR inhibit the growth and viability of bloodstream form (BF) parasites. These mutations variously impact RECC structure, many alter but do not eliminate RNA editing, and some result in differential utilization of gRNAs. The results indicate that KREPA6 protein has multiple functions some of which stem from its interactions with multiple RECC proteins and perhaps with substrate RNA in each of the three different RECCs. These functions likely involve dynamic interactions of KREPA6 with key domains of other RECC proteins, other editing proteins, and with messenger RNA/gRNA substrates during the multiple catalytic and noncatalytic steps that occur during the complicated editing process.
    DOI:  https://doi.org/10.1093/nar/gkag278
  45. bioRxiv. 2026 Mar 28. pii: 2026.03.27.711928. [Epub ahead of print]
    ATF4 Coordinates Transcriptomic and Structural Adaptations in Aging Muscle.
    Amber Crabtree, Mohd Mabood Khan, Estevao Scudese, Calixto Pablo Hernandez Perez, Prasanna Venkhatesh, Andrea G Marshall, Benjamin Rodriguez, Edgar Garza Lopez, Okwute M Ochayi, Estélio Henrique Martin Dantas, Pamela Martin, Matheus Baffi, Fabiana Scartoni, Margaret Mungai, Kit Neikirk, Jennifer Streeter, Renata Oliveira Pereira, Dao Fu Dai, Han Le, Harrison Mobley, Jeremiah Afolabi, Bret C Mobley, Celestine N Wanjalla, Duane Hall, Julia Berry, Oleg Kovtun, Jenny C Schafer, Sean Schaffer, Prasanna Katti, Chantell Evans, Andre Kinder, Joyonna Gamble George, Melanie McReynolds, Annet Kirabo, Sepiso Kenias Masenga, Antentor Hinton.
      Aging is associated with a progressive loss of skeletal muscle function, known as sarcopenia; however, the molecular mechanisms coordinating cellular stress responses and structural adaptations remain incompletely understood. The aim of this study was to investigate the role of activating transcription factor 4 (ATF4), a master regulator of the integrated stress response (ISR), in aging muscle using complementary human population and mouse model approaches. Older adults exhibited a marked decrease in aerobic capacity, muscle strength, and endurance when compared with young participants. These results paralleled findings in aged mice, with significant loss of muscle mass across multiple hindlimb muscles. Ultrastructural analysis revealed substantial age-related changes in mitochondrial morphology, including decreased volume, surface area, and branching index, as well as a shift toward smaller, more fragmented, and spherical mitochondria. These structural changes likely impair oxidative capacity and drive a feed-forward cycle of mitochondrial dysfunction and ISR activation. Our findings indicate that ATF4 coordinates transcriptomic and structural adaptations in aging muscle, identifying the ISR pathway as a potential therapeutic target for preserving muscle function in older adults.
    DOI:  https://doi.org/10.64898/2026.03.27.711928
  46. bioRxiv. 2026 Mar 26. pii: 2026.03.24.714019. [Epub ahead of print]
    Muscleblind-like proteins dimerize by forming disulfide bonds to regulate alternative splicing and pathogenic RNA foci formation.
    Luke A Knudson, Adam Kosti, Kathryn R Moss, Liang Shi, GiaLinh N Nguyen, Aleksandra Janusz-Kaminska, Eric X Zhou, Ryan P Hildebrandt, Eric T Wang, Gary J Bassell.
      Muscleblind-like (MBNL) RNA-binding proteins (RBPs) possess modular domains that mediate regulation of alternative splicing and RNA localization. Myotonic Dystrophy Type 1 is a CTG repeat expansion disorder where MBNL is sequestered into intranuclear RNA foci, impairing its function. Previous studies found that MBNL self-associates through its exon 7, but the nature of this interaction is not well understood. We identified a cysteine in MBNL1 exon 7 that enables dimerization through formation of an intermolecular disulfide bond. We likewise demonstrate that MBNL2 dimerizes by forming disulfide bonds between multiple cysteines in its carboxy-terminus. Nucleocytoplasmic fractionation revealed a greater proportion of MBNL1 dimer in the nucleus, suggesting a nuclear function for the MBNL1 dimer. We investigated a connection between MBNL1 dimerization and MBNL1-mediated regulation of alternative splicing. To accomplish this, we mutated the MBNL1 cysteine in question to alanine (C325A) and performed RNAseq. We uncovered novel splicing events sensitive to MBNL1 dimerization. We also found that MBNL1 C325A, when co-expressed with expanded CTG repeats, produces smaller, more numerous foci, suggesting a role for the MBNL1 dimer in maintaining foci integrity. These results provide insight into biological and pathological mechanisms of MBNL1 dimerization and suggest other RBPs might similarly dimerize to regulate function.
    GRAPHICAL ABSTRACT:
    DOI:  https://doi.org/10.64898/2026.03.24.714019
  47. bioRxiv. 2026 Mar 25. pii: 2026.03.23.713686. [Epub ahead of print]
    The glp-1 3' untranslated region regulates germline proliferation and promotes reproductive fecundity through multiple mechanisms.
    Peren Coskun, Sean P Ryder.
      Germline development and successful embryogenesis depend upon the post-transcriptional regulation of maternal mRNAs. In Caenorhabditis elegans , the Notch-like receptor glp-1 is necessary for germline progenitor cell proliferation in adults and anterior cell fate determination in embryos. The spatiotemporal patterning of GLP-1 protein has long served as a paradigm of maternal mRNA regulation in metazoans. The glp-1 3'UTR has been shown to be sufficient to pattern the expression of reporter genes, and multiple regulatory regions and RNA-binding protein interaction sites have been mapped. The RNA-binding proteins POS-1 and GLD-1 directly regulate glp-1 mRNA via sequence specific interactions with motifs found in the glp-1 3'UTR. The impact of mutating the endogenous glp-1 3'UTR has not been studied, and the mechanism by which POS-1 and GLD-1 mediate repression is not understood. Here, we investigate the post-transcriptional mechanisms that govern glp-1 expression, revealing that GLD-1 and POS-1 regulate this pattern through different pathways requiring different co-factors. Remarkably, mutations in the endogenous locus that disrupt either POS-1 or GLD-1 binding to the glp-1 3'UTR have minimal impact on reproductive fecundity. By contrast, a larger deletion that eliminates the binding of both has a strong effect on brood size, hatch rate, and displays an increase in the length of the germline mitotic region that corresponds with enhanced mitotic activity. Together, our results show that multiple post-transcriptional mechanisms work in concert to ensure robust GLP-1 patterning and thus maximize reproductive outcomes.
    DOI:  https://doi.org/10.64898/2026.03.23.713686
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