bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–01–04
48 papers selected by
Cédric Chaveroux, CNRS
  1. CDC123 is an ATPase that modulates mRNA translation and the Integrated Stress Response by regulating eIF2 complex assembly.
  2. The Janus framework of the integrated stress response: from homeostasis to maladaptation.
  3. Translational control in plants: from basic mechanisms to environmental and developmental responses.
  4. Prime editing links the split integrated stress response to pathogenic eIF2B mutations and white matter degeneration.
  5. The Potential of Noncoding RNAs-siRNAs in Cancer Research and Therapy: Challenges and Solutions.
  6. A novel plasmid-based co-tethered transcription platform for high yield, high purity mRNA synthesis.
  7. The CCR4-NOT complex: a multifaceted sensor of molecular signals instructing eukaryotic mRNA translation and stability.
  8. DEAD-box ATPase-marked condensates coordinate compartmentalized translation and antibiotic persistence.
  9. GLA-3 mediates the heat shock response in Caenorhabditis elegans germ cells: A key role for the tristetraprolin (TTP) family.
  10. Dysregulation of ERAD and Stress Response Proteins by V493F FTO Over-expression: A Proteomic Perspective.
  11. TFEB coordinates autophagosome biogenesis and ribophagy during starvation via SQSTM1.
  12. Synthetic Pentatricopeptide Repeat Proteins: Building a Toolkit for Precise RNA Control.
  13. Application of Synchrotron Radiation Circular Dichroism for mRNA Structural Analysis.
  14. Dual Phosphorylation of Thr175 and Ser176 Is Essential for SnRK1α1 Activation.
  15. Spaceflight alters molecular networks linked to diverse human diseases in a single cellular model.
  16. HER3 enhances ATF4 induction and survival in breast cancer cells during endoplasmic reticulum stress.
  17. Cotranslational assembly directs the biogenesis of the m6A methyltransferase complex.
  18. Noncoding RNAs: The Not So "Junk" DNA Is the Blueprint of the Transcriptional Landscape of the RNA World.
  19. Tip-Enhanced Raman Spectroscopy of RNAs.
  20. The Effect of a Dominant Inhibitory p53 Protein on Stress Responses Induced by Toxic and Non-Toxic Concentrations of Anisomycin in PC12 Cells.
  21. Differential expression of mitomiRs in pancreatic islet cells associated with maternal protein restriction.
  22. NETosis-Like Response Triggered by Extracellular Vesicle (EV)-Delivered Viral Nucleic Acid, a Novel Cellular Immune Mechanism in Crustacean.
  23. Comparison of the Regulatory Effects of Host Factors on Viral Internal Ribosomal Entry Sites.
  24. The roles of the Listeria monocytogenes post-translocation chaperones PrsA1 and PrsA2 in protein secretion and stress resistance.
  25. Translational Downregulation of 5' TOP mRNAs During T Cell Exhaustion.
  26. Crowding Effects in RNA Interactions.
  27. Exploring the Role of Long Noncoding RNAs in Breast Cancer Progression: A Comprehensive Study on Biomarkers and Therapeutic Approaches.
  28. Error-prone translation as a driver of proteostasis collapse and neurodegeneration.
  29. A methodology for calculating the rarity of diverse proteins based on functional specificity and thermodynamic stability.
  30. Autonomous biogenesis of all thirty proteins of the Escherichia coli translation machinery.
  31. Cell type-specific spatiotemporal control of GFP-tagged protein degradation in mice.
  32. Loss of p62 Binding Allows TIF-IA Accumulation in Senescence, Which Promotes Phenotypic Changes to Nucleoli and the Senescence Associated Secretory Phenotype.
  33. Legionella effector Ceg10 acetylates RPS20 to inhibit host translation and induce cell cycle arrest.
  34. Fibrillarin Contributes to the Oncogenic Characteristics of Colorectal Cancer Cells and Reduces Sensitivity to 5-Fluorouracil.
  35. Bridging maternal effects and epitranscriptomics: A novel perspective in developmental biology.
  36. Reconnaissance of the Good, the Bad, and the Ugly Role of tRNAs in Carcinogenesis and Metastasis.
  37. Rhythmicity of TOR (Target of Rapamycin) Activity Supports Circadian Function in Neurospora crassa.
  38. Capturing the Variations in Mutant p53-Driven Regulatory Networks in Breast Cancer Subtypes, Its Clinical Relevance and a Novel Association With Androgen Receptor and EMT.
  39. An Improved Description of the Small RNA Landscape of the Human Fungal Pathogen Aspergillus fumigatus.
  40. LncRNA ZFHX4-AS1 initiates an oncogenic axis involving a ZFHX4/SOX2 positive feedback loop to accelerate glioma progression.
  41. The Role of miRNAs in Parkinson's Disease: A Systematic Review.
  42. [Expression of Concern] MicroRNA-29c inhibits proliferation and promotes apoptosis in non-small cell lung cancer cells by targeting VEGFA.
  43. Functional diversification of the cephalopod proteome by RNA-editing.
  44. Advances in Quantitative Techniques for Mapping RNA Modifications.
  45. RNA G-quadruplexes Mediated Protein Aggregation in Neurodegenerative Diseases.
  46. Cardiac epigenome in heart development and disease.
  47. Activated oligoadenylate synthetase-ribonuclease L pathway promotes endothelial pyroptosis and impairs diabetic wound healing via thioredoxin-interacting protein m6A methylation.
  48. Heat Shock Protein 104 (Hsp104) in the Marine Diatom Ditylum brightwellii: Identification and Transcriptional Responses to Environmental Stress.
  1. J Biol Chem. 2025 Dec 27. pii: S0021-9258(25)02968-0. [Epub ahead of print] 111116
    CDC123 is an ATPase that modulates mRNA translation and the Integrated Stress Response by regulating eIF2 complex assembly.
    Anthony L Erb, Sara K Young-Baird.
      Hyper- and hypo-activation of the Integrated Stress Response (ISR) results in impaired regulation of global and mRNA-specific translation in multiple disease contexts. During the ISR, specific stress-sensing kinases modulate translation by regulating the activity of the heterotrimeric eukaryotic translation initiation factor eIF2. Here, we identify the chaperone CDC123, which promotes eIF2 biogenesis, as a novel regulator of the ISR. We find that impaired CDC123 activity reduces eIF2 complex assembly, promoting the translational and cellular outcomes of the ISR through a noncanonical mechanism. Pharmacological or genetic strategies are sufficient to rescue the translational defects associated with impaired CDC123 activity. Additionally, we report functional insights into eIF2 heterotrimer formation and provide the first evidence that CDC123-mediated eIF2 complex assembly may be regulated by ATP hydrolysis. These data emphasize the essential contribution of eIF2 biogenesis in mRNA translation regulation, and highlight CDC123 as a possible therapeutic target in the treatment of ISR-related diseases.
    DOI:  https://doi.org/10.1016/j.jbc.2025.111116
  2. Life Sci Alliance. 2026 Mar;pii: e202503523. [Epub ahead of print]9(3):
    The Janus framework of the integrated stress response: from homeostasis to maladaptation.
    Dogus M Altintas, Marina Cerqua, Paolo M Comoglio, Cédric Chaveroux.
      Every cell must adapt to environmental changes. When nutrients decrease, oxygen levels fall, or protein synthesis outpaces resources, cells activate stress pathways to restore balance. Among these, the integrated stress response (ISR) stands out for its capability to integrate diverse stress signals into a unified translational output. By temporarily slowing global protein synthesis while maintaining the selective translation of stress-adaptive factors, the ISR saves energy, redirects metabolism, and promotes either recovery or, if challenges surpass repair capacity, cell death. In many chronic diseases-including cancer, metabolic, inflammatory, and fibrotic disorders-ISR activity persists. Is this persistence merely a prolonged defensive phase, or does it represent a rewired, self-sustaining state with its own control mechanisms actively reshaping cell fate and disease? We argue that chronic ISR cannot be defined by time alone, challenging the monolithic view. It signifies a qualitative shift in regulation-from rhythmic homeostasis to entrenched maladaptation. Understanding this Janus framework is essential for elucidating the origins of pathology and for guiding future fundamental and translational research.
    DOI:  https://doi.org/10.26508/lsa.202503523
  3. Plant J. 2026 Jan;125(1): e70647
    Translational control in plants: from basic mechanisms to environmental and developmental responses.
    Jade Lyons, Catharina Merchante, Anna N Stepanova, Jose M Alonso.
      Protein synthesis is an essential process for all living organisms and is tightly regulated to ensure the proper production of proteins needed for growth, development, and stress responses. As sessile organisms, plants have evolved distinct mechanisms to regulate translation, allowing them to adapt to their environment. In this review, we highlight the general translation process, discuss the translational machinery in plants, and examine cis-regulatory elements that influence translation. Additionally, we explore recent studies on how plants regulate translation in response to environmental and developmental cues.
    Keywords:  Translation regulation; cis‐regulatory RNA elements; plant adaptation; plant development
    DOI:  https://doi.org/10.1111/tpj.70647
  4. Cell Death Dis. 2025 Dec 27.
    Prime editing links the split integrated stress response to pathogenic eIF2B mutations and white matter degeneration.
    Alessandra Scagliola, Annarita Miluzio, Martina Pauselli, Marcello Ceci, Stefano Biffo, Sara Ricciardi.
      Vanishing White Matter Disease (VWMD) is a devastating, currently incurable neurodevelopmental disorder primarily affecting white matter. The prevailing view attributes VWMD to the activation of the canonical integrated stress response (c-ISR). However, recent studies have identified a novel, distinct pathway called the split ISR (s-ISR), though its activation has so far only been documented in mouse stem cells harboring a single eIF2B mutation, leaving uncertainty about whether it occurs in human cells, whether other mutations can trigger it, and what role it plays in the disease. Here, we used prime editing (PE) to engineer multiple eIF2B pathogenic mutations into HEK293T and induced pluripotent stem cells (iPSCs), generating human models. We demonstrated PE's effectiveness and safety, marking the first successful application of PE for modeling VWMD. We found that all modeled mutations activate the s-ISR, indicating that this response is a common feature across VWMD mutations, and that it can be further amplified by stress-induced c-ISR and effectively suppressed by ISRIB. Mechanistically, we show that s-ISR hinders mutant iPSCs from achieving the high protein synthesis levels necessary for proper differentiation, expecially into astrocytes. This impairment disrupts their maturation process, directly linking s-ISR activation to the white matter abnormalities of VWMD.
    DOI:  https://doi.org/10.1038/s41419-025-08399-x
  5. Exp Suppl. 2026 ;115 123-168
    The Potential of Noncoding RNAs-siRNAs in Cancer Research and Therapy: Challenges and Solutions.
    Himanshu, Mudasir Bashir, Moien Lone, Mohsin Maqbool.
      Noncoding RNAs (ncRNAs) are RNA molecules, which play critical roles in regulating gene expression and cellular activities, influencing processes like differentiation, proliferation, and cell survival, unlike messenger RNAs (mRNAs) that act as templates for protein production. Examples of ncRNAs include small interfering RNAs (siRNAs), microRNAs (miRNAs), ribosomal RNAs, transfer RNAs, small nucleolar RNAs (sno RNAs), and small nuclear RNAs (snRNAs). Small interfering RNAs (siRNAs) are a type of noncoding RNA that function primarily by silencing specific genes through a process called RNA interference (RNAi), in which they bind to complementary messenger RNA (mRNA) molecules, causing their degradation and preventing the translation of that mRNA into protein; essentially, they act as a "gene silencing" mechanism by targeting and destroying specific transcripts. In this chapter, we review the biogenesis, functions, and role of RNAs (siRNAs), in cancer research and role in therapy. siRNA (small interfering RNA) denotes small interfering RNA, consisting of 21-25 nucleotides. Discovery of siRNA (small interfering RNA) has been a significant breakthrough in biology. Small interfering RNAs (siRNAs) are single-stranded RNAs that are formed by the cleavage of longer double-stranded RNAs by the enzyme DICER1 within the RISC loading complex, which includes DICER1, an Argonaute protein, and either TARBP2 or PRKRA (PACT). Small interfering RNA (siRNA) is essential for health as it serves as a natural gene silencing tool, controlling gene expression posttranscriptionally, and is involved in several cellular processes such as development, immune response, and stress response; however, when not regulated properly, siRNAs may lead to diseases like cancer and viral infections, positioning them as a promising therapeutic target for targeted gene silencing therapies. siRNAs play a pivotal role in RNA interference (RNAi), a natural cellular process where they degrade complementary mRNA targets, preventing protein synthesis. This gene silencing mechanism has proven to be a valuable tool for controlling gene expression in research and therapeutic contexts. In cancer, siRNAs offer a promising approach to selectively silence oncogenes or other genes involved in tumor progression, thus hindering the development and spread of malignancies. However, the therapeutic potential of siRNAs faces several challenges, including efficient delivery to target cells, off-target effects, and stability issues. This chapter focuses on the biogenesis and functional significance of siRNAs, exploring their roles in cancer research and their promising therapeutic potential. With the continued advancement of RNA-based technologies, siRNAs hold considerable promise as a powerful tool for cancer treatment, offering new avenues for targeted therapies and personalized medicine.
    Keywords:  Cancer research; Gene expression; Gene silencing; Molecular therapy; Noncoding RNAs; Oncogenes; RNA interference; RNAi; Small interfering RNAs; siRNAs
    DOI:  https://doi.org/10.1007/978-3-032-06948-1_5
  6. Nucleic Acids Res. 2025 Nov 26. pii: gkaf1355. [Epub ahead of print]53(22):
    A novel plasmid-based co-tethered transcription platform for high yield, high purity mRNA synthesis.
    Purnima Mala, Ruptanu Banerjee, Amin Abek, James Forster Iii, Aniruddha Pinjari, Ashish A Kulkarni, Craig T Martin.
      This work aims to improve RNA synthesis and manufacturing, exemplified by T7 RNA polymerase-driven in vitro transcription. We developed a novel, plasmid-compatible co-tethering strategy that functionally couples RNA polymerase to its promoter DNA immobilized on a solid matrix. As demonstrated recently, co-tethering enhances promoter binding, increases RNA yield, and suppresses RNA re-binding, especially under high-salt conditions, thereby reducing double-stranded RNA by-products. The system leverages asymmetric end-labeling of linearized plasmid DNA using a simple "Klenow fill-in" reaction with modified nucleotides, enabling stable attachment of DNA to both RNA polymerase and solid support (magnetic beads). The immobilized co-tethered polymerase-DNA complex supports efficient transcription initiation in high-salt environments (which further reduces RNA re-binding), yielding RNA of high purity. Co-tethered complex remains functionally stable over extended storage and multiple transcription cycles (10-20 rounds), re-using the enzyme-DNA catalyst. Transcripts of lengths (0.8, 5.6, and 8.6 kb) are efficiently produced. Highly sensitive in vitro assays with immune cells confirm low immunogenicity and strong translational output, while in vivo validation using a novel Matrigel-plugged mouse model demonstrates robust expression and safety. With a simple modification to the DNA template, the reusable, co-tethered enzyme-DNA catalytic complex streamlines mRNA manufacturing by producing RNA of higher purity from the outset.
    DOI:  https://doi.org/10.1093/nar/gkaf1355
  7. Nucleic Acids Res. 2025 Nov 26. pii: gkaf1401. [Epub ahead of print]53(22):
    The CCR4-NOT complex: a multifaceted sensor of molecular signals instructing eukaryotic mRNA translation and stability.
    Guillaume Caulier, Joseph Siblini, Lina Sène, Fabienne Mauxion, Bertrand Séraphin.
      The CCR4-NOT complex is a multi-subunit assembly found in all eukaryotic cells. Yet, its composition varies across organisms, with a universally conserved core enriched by lineage-specific subunits. Further, heterogeneity results from the occurrence of paralogous proteins, substoichiometric subunits, transient partners, and protein isoforms. Altogether, multiple CCR4-NOT complexes exist, and some even coexist within a single cell. The CCR4-NOT complex is an essential actor of gene expression through its roles in messenger RNA (mRNA) deadenylation, decay, and translation. Over time, support for the originally proposed role of the CCR4-NOT complex in transcription has been waning. Consistent with a role in post-transcriptional regulation, ribosomes appear to be major partners of the CCR4-NOT complex to coordinate translation and mRNA decay. Further, the CCR4-NOT complex is at the center of a network involving RNA-binding proteins and ubiquitin ligases, as well as factors of currently unknown function. Structural and functional analyses indicate that the CCR4-NOT complex integrates different levels of information present in mRNAs to control their stability and translation, thereby contributing to diverse functions including intricate processes such as human brain or pancreas development. It is thus not surprising that genetic alteration of this essential cellular machine, or impairment of its activity by pathogens, contributes to human diseases.
    DOI:  https://doi.org/10.1093/nar/gkaf1401
  8. Sci Adv. 2026 Jan 02. 12(1): eady1930
    DEAD-box ATPase-marked condensates coordinate compartmentalized translation and antibiotic persistence.
    Ziyin Zhang, Daqian Li, Bo Zheng, Jia-Feng Liu.
      Antibiotic-tolerant persisters use dormancy as a bet-hedging strategy to evade lethal antibiotics, undermining therapeutic efficacy. Protein condensates have been implicated in bacterial dormancy, yet how these assemblies orchestrate dormancy entry remains unclear. We evolved persisters that enter dormancy before the stationary phase, most harboring mutations in serS, encoding seryl-transfer RNA synthetase (SerRS). These variants recapitulated persistence induced by serine hydroxamate (SHX), a serine analog and SerRS inhibitor. Both the serS mutation and SHX treatment trigger SerRS sequestration into conserved DEAD-box adenosine triphosphatase-associated condensates, coinciding with growth arrest and dormancy. In vitro, the SerRS variant preferentially partitions into DeaD granules, consistent with its distinct in vivo localization. Microscopy revealed spatially restricted translation silencing within condensates upon SerRS partitioning. Together, these phase-separated condensates act as hubs that coordinate the transition from proliferation to dormancy, paralleling eukaryotic cell fate control via localized translation. Our findings provide mechanistic insight into bacterial persistence and suggest that targeting condensates could help combat antibiotic tolerance and delay resistance.
    DOI:  https://doi.org/10.1126/sciadv.ady1930
  9. PLoS One. 2026 ;21(1): e0312069
    GLA-3 mediates the heat shock response in Caenorhabditis elegans germ cells: A key role for the tristetraprolin (TTP) family.
    Laura Silvia Salinas, Ángel Armando Dámazo-Hernández, Arianne Melisa Cristino-Miranda, Mariana Zurita-León, Enrique Morales-Oliva, Laura Ivón Láscarez-Lagunas, Rosa Estela Navarro.
      Tristetraprolin or TTP is an RNA-binding protein that possesses two CCCH-like zinc-finger domains that bind AU-rich elements to promote their degradation. One of its targets is the mRNA of tumor necrosis factor alpha (TNF-α). When TTP is absent, the TNF-α factor accumulates causing severe, generalized inflammation in knockout mice. TTP is also considered a tumor suppressor protein because it regulates the expression of several mRNAs that encode for proteins involved in cell cycle regulation and it is downregulated in various types of human cancers. Under stress, TTP associates with stress granules (SGs), dynamic cytoplasmic condensates formed by liquid-liquid phase separation (LLPS) that protect mRNAs from harmful conditions. Despite TTP's important role in mRNA turnover, much remains to be explored about its participation in stress resistance in living animals. For this reason, we investigated the role of GLA-3, one of TTP's homologs, in the nematode Caenorhabditis elegans during the heat shock response. Previously, it has been shown that nematodes lacking gla-3/TTP exhibit phenotypes such as progressive loss of motility, reduced brood size, and increased embryonic lethality. As well as defects in meiotic progression, and increased germ-cell apoptosis. Here, we show that a GFP::GLA-3 reporter is primarily expressed in the C. elegans germline. During heat shock, GLA-3 localizes to condensates that contain both processing bodies, sites of mRNA storage and decay, and stress granules. We demonstrate that, in the C. elegans gonad under heat shock conditions, the canonical P body marker CGH, the DDX6 homolog, associates with GLA-3, as well as with the canonic stress markers TIAR-1/TIA1 and GTBP-1/G3BP. These data show that in C. elegans, P bodies and stress granules colocalize during heat shock. Similarly, in yeast, P bodies and stress granules fuse during stress, suggesting that C. elegans induces condensates that resemble those observe in yeast. Additionally, we demonstrate that GLA-3 is important for the formation of both P bodies and stress granules. Finally, we show that oogenic germ cells of GLA-3 mutant animals that were exposed to heat shock resulted in embryos that did not survive, showing that GLA-3 plays an important role in protecting germ cells from this condition. Our results demonstrate that the role of GLA-3 is conserved in C. elegans, and this model can be very useful for further investigating the role of this protein in the future.
    DOI:  https://doi.org/10.1371/journal.pone.0312069
  10. In Vivo. 2026 Jan-Feb;40(1):40(1): 249-263
    Dysregulation of ERAD and Stress Response Proteins by V493F FTO Over-expression: A Proteomic Perspective.
    Aylin Kanli.
       BACKGROUND/AIM: Demethylase fat mass and obesity-related protein (FTO), which belongs to the AlkB homologous (ABH) family, is associated with various neurological diseases, cancer, and obesity. This protein, which contains many structurally and functionally different regions, contains a COOH-terminal domain whose function, unlike other ABH members, is not fully understood. This study aimed to investigate the effects of the exonic V493F mutation in this region of FTO on the soluble proteome.
    MATERIALS AND METHODS: SH-SY5Y cells stably over-expressing wild-type (WT-FTO) or mutant FTO (V493F-FTO) proteins under the control of the Tet promoter were created and used. Comparative proteomic analysis using two-dimensional gel electrophoresis (2DE) identified over 500 protein spots, with 10 showing significant (≥2-fold) differential expression. These proteins were identified by MALDI-TOF/TOF mass spectrometry and validated by western blotting.
    RESULTS: WT-FTO over-expression primarily affected proteins related to DNA replication and repair, including PCNA, whereas V493F-FTO over-expression altered the expression of stress response and endoplasmic reticulum-associated degradation (ERAD) pathway proteins, such as HSPA4, ARHGDIA, and VCP. Although the mutation did not alter the nuclear localization or predicted 3D structure of FTO, it distinctly modulated pathways associated with protein homeostasis and cellular stress.
    CONCLUSION: FTO participates in the regulation of the cellular stress response and the ubiquitin-dependent ERAD pathway, functions potentially independent of its demethylase activity. Importantly, dysregulation of these pathways has been implicated in cancer initiation, progression, and therapeutic resistance. Therefore, our findings provide new insights into how FTO mutations might influence oncogenic processes, highlighting FTO as a potential biomarker and therapeutic target in cancer biology.
    Keywords:  ERAD pathway; FTO protein; V493F mutation; VCP; cancer biology; neuroblastoma cells; proteomics
    DOI:  https://doi.org/10.21873/invivo.14188
  11. Sci Adv. 2026 Jan 02. 12(1): eaea9302
    TFEB coordinates autophagosome biogenesis and ribophagy during starvation via SQSTM1.
    Maria Iavazzo, Laura Cinque, Sophie Levantovsky, Castrese Morrone, Jlenia Monfregola, Andrea Raimondi, Elena Polishchuk, Rossella De Cegli, Diego Carrella, Edoardo Nusco, Luigi Ferrante, Francesca Sacco, Lisa B Frankel, Christian Behrends, Carmine Settembre.
      (Macro)autophagy is a conserved cellular degradation pathway that delivers substrates to lysosomes via autophagosomes. Among various physiological stimuli, nutrient starvation is the most potent inducer of autophagy. In response to starvation, transcription factor EB (TFEB) is activated and up-regulates a broad set of autophagy-related genes. However, the mechanisms by which TFEB promotes autophagosome biogenesis remain incompletely understood. Here, we demonstrate that TFEB-mediated transcriptional induction of sequestosome 1 (SQSTM1; p62) triggers the formation of SQSTM1-positive bodies that recruit essential autophagy factors, thereby initiating autophagosome biogenesis. Genetic disruption of TFEB-dependent SQSTM1 regulation markedly impairs starvation-induced autophagy, underscoring the critical role of the TFEB-SQSTM1 axis in the autophagic response to nutrient stress. Furthermore, we show that these SQSTM1 bodies contain ubiquitinated ribosomal proteins and that TFEB promotes ribosomal protein ubiquitination by inducing the E3 ubiquitin ligase ZNF598. Collectively, our findings uncover a transcriptionally coordinated mechanism that regulates both autophagosome biogenesis and substrate ubiquitination, facilitating efficient cargo clearance during starvation-induced autophagy.
    DOI:  https://doi.org/10.1126/sciadv.aea9302
  12. Int J Mol Sci. 2025 Dec 14. pii: 12033. [Epub ahead of print]26(24):
    Synthetic Pentatricopeptide Repeat Proteins: Building a Toolkit for Precise RNA Control.
    Jose M Lombana, Maureen R Hanson, Stephane Bentolila.
      In plants, cytidine-to-uridine (C-to-U) and uridine-to-cytidine (U-to-C) editing events are directed by pentatricopeptide repeat (PPR) proteins, modular RNA-binding factors that recognize their RNA targets through a predictable amino acid-nucleotide recognition code. Deciphering this code has enabled the rational design of synthetic PPR (synPPR) proteins with programmable RNA-binding specificity and robust stability in heterologous systems. Recent advances have extended these synthetic scaffolds to active RNA editors by fusing them to catalytically competent DYW deaminase domains, generating customizable enzymes capable of precise base conversion in bacteria, plants, and even human cells. This review summarizes current understanding of the structural and mechanistic principles underlying PPR-mediated RNA editing and highlights recent progress in the design and application of synPPR proteins. We discuss how synthetic PPR proteins have been used as programmable RNA stabilizers, translational regulators, and targeted C-to-U or U-to-C editors, as well as their emerging therapeutic potential in RNA-mediated diseases. The development of compact, cofactor-independent editors derived from early-diverging plant lineages further expands the versatility of this platform. Together, these efforts establish synthetic PPR proteins as a powerful and flexible class of RNA engineering tools with applications spanning basic research, biotechnology, and biomedicine. Continued refinement of targeting specificity, catalytic efficiency, and effector modularity will propel PPR-based editors toward broader use in synthetic biology and therapeutic RNA modulation.
    Keywords:  RNA editing; RNA engineering; pentatricopeptide repeat (PPR) proteins; programmable RNA recognition; synthetic biology
    DOI:  https://doi.org/10.3390/ijms262412033
  13. Methods Mol Biol. 2026 ;3004 153-161
    Application of Synchrotron Radiation Circular Dichroism for mRNA Structural Analysis.
    Ayoub Medjmedj, Josef Hamacek, Frank Wien, Federico Perche.
      Circular dichroism is a useful tool to study the impact of mRNA sequence optimization on mRNA structure. mRNA can fold into several conformations according to the sequence of nucleotides. Structural characteristics of mRNA (melting temperature, unfolding trajectories) are important for their biological function. Circular dichroism is a powerful technique to characterize mRNA structure. In this chapter we describe how to analyze protein coding mRNA by Synchrotron Radiation Circular Dichroism (SRCD). The emphasis is put on mRNA synthesis and sample preparation, which are critical for mRNA analysis. We also provide a protocol for the in vivo evaluation of vaccine activity.
    Keywords:  mRNA spectroscopy; mRNA structure
    DOI:  https://doi.org/10.1007/978-1-0716-5084-4_10
  14. Physiol Plant. 2026 Jan-Feb;178(1):178(1): e70726
    Dual Phosphorylation of Thr175 and Ser176 Is Essential for SnRK1α1 Activation.
    Alejandra Ávila, Aitana López, Jacquelynne Cervantes, Rogelio Rodríguez-Sotres, Eleazar Martínez-Barajas, Patricia Coello.
      SnRK1 protein kinases play a pivotal role in regulating plant development, growth signaling, and stress responses by managing cellular responses to energy fluctuations. SnRK1 activation was thought to depend mainly on the phosphorylation of threonine at position 175 (Thr175) within the activation loop. However, recent phosphoproteomic studies have identified additional phosphorylation sites. We explored the functional significance of these modifications, focusing on serine at position 176 (Ser176), adjacent to Thr175 in SnRK1α1. Our results reveal that dual phosphorylation of Ser176 and Thr175 is vital for optimal SnRK1 activity. Structural modeling and thermodynamic analyses highlight the critical role of these modifications in optimising substrate positioning and enzymatic efficiency. Furthermore, only the wild-type SnRK1α1, which can be phosphorylated at both sites, retains full functionality in in vivo experiments with yeast and Arabidopsis. Interestingly, pSer176 exhibits greater stability than pThr175 at various times throughout the day. Mutant proteins with substitutions at these sites (T175A/S176A mutants) accumulate in cytoplasmic aggregates after heat shock, suggesting a strong link between phosphorylation status, protein stability, and SnRK1 degradation pathways.
    Keywords:  SnAKs; SnRK1 activation; phosphorylation; stress
    DOI:  https://doi.org/10.1111/ppl.70726
  15. Sci Adv. 2026 Jan 02. 12(1): eadw7832
    Spaceflight alters molecular networks linked to diverse human diseases in a single cellular model.
    Wijdan Al-Ahmadi, Rayyanah Barnawi, Edward G Hitti, Khalid S A Khabar.
      The International Space Station provides an opportunity to study the impact of spaceflight on gene expression and possible links to human health. Our study investigates global changes in messenger RNA (mRNA) abundance in the THP-1 cell line, a monocyte-macrophage lineage known for plasticity and immune reprogramming features. We identified pathways positively enriched with genes affecting muscle and cardiac contraction, neuronal system, and sensory perception. Available computational models identified links with health issues, including cardiac, neurological, muscular, and renal disorders and alterations in senses. Specific mechanistic networks were identified: retinoid metabolism, cAMP (adenosine 3',5'-monophosphate)/CREB (cAMP response element-binding protein) signaling, and glutamatergic receptor signaling, which were associated with changes in vision, sleep, and movement, respectively. A considerable reduction is observed in E2F-regulated transcription of G2-M and DNA repair genes. A c-myc-regulated mRNA splicing pathway was identified and found commonly down-regulated in other mission datasets. Our results offer a stimulating framework for several health states encountered during spaceflight and can be further used as an accelerated disease and drug discovery model.
    DOI:  https://doi.org/10.1126/sciadv.adw7832
  16. Biochem Biophys Res Commun. 2025 Dec 26. pii: S0006-291X(25)01931-X. [Epub ahead of print]797 153215
    HER3 enhances ATF4 induction and survival in breast cancer cells during endoplasmic reticulum stress.
    Miku Otsuka, Yuka Okamoto, Akiko Hasebe, Hitomi Shirahama, Akihiro Tomida.
      Oncogenic signaling and stress response pathways interact to drive tumorigenesis and therapy resistance. However, little is known about such interactions for HER3, a member of the HER/ErbB receptor family that is aberrantly expressed in many tumors, including breast cancer. Here, we show that HER3 cooperates with HER2 to enhance induction of ATF4, a central transcription factor of the integrated stress response and the unfolded protein response, during endoplasmic reticulum (ER) stress. ATF4 induction was enhanced by ligand-activated HER3 and conversely reduced by genetic knockdown or pharmacological inhibition of HER2/HER3-mediated signaling in both HER2-overexpressing SKBR3 and non-overexpressing MCF7 breast cancer cells. HER3 knockdown in SKBR3 cells also increased cell death during ER stress. Notably, depletion of HER3, likely occurring through ER stress-associated downregulation mechanisms, was accompanied by attenuation of ATF4 induction during sustained stress. These findings suggest that the HER3-ATF4 axis functions as a dynamically regulated mechanism for tuning the cellular stress response.
    Keywords:  ATF4; Breast cancer; HER2; HER3; Integrated stress response
    DOI:  https://doi.org/10.1016/j.bbrc.2025.153215
  17. Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2517258123
    Cotranslational assembly directs the biogenesis of the m6A methyltransferase complex.
    Xiang Wu, Haotian Zhang, Lingci Huang, Shiyin Zhang, Junjie He, Shen Wang, Wenli Zhu, Yu Li, Jun Zhou, Xiao-Min Liu.
      The chemical modification N6-methyladenosine (m6A) is catalyzed by the m6A methyltransferase complex (MTC) comprising METTL3 and METTL14 in the nucleus. Structural evidence reveals that METTL3 primarily functions as the catalytic core, while METTL14 serves as an RNA-binding scaffold. However, the mechanism directing the complex assembly in vivo remains enigmatic. Here, we demonstrate that MTC is formed by a cotranslational mechanism in which nascent METTL3 interacts with METTL14 polypeptide chain exposed from the ribosome exit tunnel. The methyltransferase domains in the subunits determine the specificity of their cotranslational interaction. In contrast, WTAP, the regulatory subunit of MTC, is recruited to the complex posttranslationally. We further identify CCT4, the key subunit of cytosolic chaperonin TCP-1, as an essential facilitator of the endogenous MTC assembly process. Depletion of CCT4 results in dramatic reduction of METTL3-METTL14 heterodimer formation. Remarkably, we engineer a cell-permeable peptide M14P1, which could disrupt cotranslational assembly of MTC, thereby impairing m6A deposition and significantly attenuating the proliferation of acute myeloid leukemia (AML) cells and promoting apoptosis. Collectively, our findings unravel intrinsic mechanisms governing the in vivo assembly of MTC, and provide a potential therapeutic strategy to disrupt oncogenic m6A pathways and impede AML progression.
    Keywords:  N6-methyladenosine; cotranslational assembly; interfering peptide; methyltransferase complex
    DOI:  https://doi.org/10.1073/pnas.2517258123
  18. Exp Suppl. 2026 ;115 1-29
    Noncoding RNAs: The Not So "Junk" DNA Is the Blueprint of the Transcriptional Landscape of the RNA World.
    Mohammad Fahad Ullah.
      In the past, the vast genomic DNA, encoding transcripts now known as noncoding RNAs were considered as "junk DNA." However, over the years, studies have demonstrated the critical roles of these noncoding RNAs in various biological functions, leading to a major transformation in our understanding of molecular biology. Noncoding RNAs (ncRNAs) have emerged as critical players in the regulation of gene expression, cellular processes, and the maintenance of genomic stability. It is the complex interplay of the RNA diversity rather than the number of proteins that seems to have a significant role in the developmental complexity of organisms. This chapter provides an in-depth exploration of various categories of ncRNAs, their biogenesis, mechanisms of action, and implications in health and disease. With technological advancements in genomic sequencing and bioinformatics, our understanding of ncRNAs has expanded significantly, revealing their vast potential as therapeutic targets and biomarkers.
    Keywords:  Gene regulation; Noncoding RNAs; Nucleases; RNA biogenesis; Spliceosome
    DOI:  https://doi.org/10.1007/978-3-032-06948-1_1
  19. Methods Mol Biol. 2026 ;3004 1-17
    Tip-Enhanced Raman Spectroscopy of RNAs.
    Sébastien Bonhommeau.
      Tip-enhanced Raman spectroscopy (TERS) has been widely used for the nanoscale chemical and structural analysis of biomolecules. TERS combines indeed the high molecular sensitivity of Raman spectroscopy with the high spatial resolution of scanning probe microscopies (SPM), by exploiting the intense electromagnetic field generated at the apex of a metal SPM tip at nanometer distance from the sample. While TERS studies on ribonucleic acid (RNA) nucleobases started more than two decades ago, several major scientific advances like the advent of a compelling TERS-based RNA sequencing method and the description of amyloid-like RNA-induced tau fibrils potentially implicated in Alzheimer's disease have been only achieved recently. In this chapter, after presenting these promising advances, we provide technical and methodological information allowing TERS maps of such RNA samples to be obtained, processed, and correctly interpreted in order to properly describe the chemical composition of RNA components and the structure of tau proteins interacting with them.
    Keywords:  Amino acids and protein secondary structures; Nanoscale chemical imaging; RNA nucleobases; RNA sequencing; Tip-enhanced Raman spectroscopy
    DOI:  https://doi.org/10.1007/978-1-0716-5084-4_1
  20. Biology (Basel). 2025 Nov 21. pii: 1634. [Epub ahead of print]14(12):
    The Effect of a Dominant Inhibitory p53 Protein on Stress Responses Induced by Toxic and Non-Toxic Concentrations of Anisomycin in PC12 Cells.
    Renáta Schipp, Judit Varga, Judit Bátor, Mónika Vecsernyés, Zita Árvai, Petra Kele-Morvai, József Szeberényi, Marianna Pap.
      Anisomycin, a ribotoxic compound, is an efficient inhibitor of eukaryotic translation: at toxic concentrations, it interferes with the function of ribosomal peptidyl transferase, blocks protein synthesis, and ultimately leads to apoptosis. The process is accompanied by the activation of various cellular stress mechanisms. Subinhibitory anysomycin concentrations, in contrast, do not inhibit translation and cause apoptosis, but still activate certain stress pathways. The present study aimed to compare the signaling effects of toxic (1 µg/mL) and non-toxic (10 ng/mL) anisomycin treatment in PC12 cells. In addition, the role of the p53 tumor suppressor protein in these processes was explored, using a PC12 cell line expressing a dominant inhibitory p53 protein. Apoptosis-mediating events (PKR cleavage; eIF2α phosphorylation; activation of caspase 3, 8, and 9 enzymes) were caused by high, but not low, anisomycin concentration in a p53-dependent manner. MAPK pathways (JNK, p38 MAPK, ERK) were stimulated by non-toxic anisomycin treatment, with a more complex p53 involvement. The apoptotic response of cells appeared to be supported by exosomal paracrine signaling.
    Keywords:  PC12 cell line; anisomycin; apoptosis; exosomes; p53 protein; stress signaling
    DOI:  https://doi.org/10.3390/biology14121634
  21. Islets. 2026 Dec 31. 18(1): 2610590
    Differential expression of mitomiRs in pancreatic islet cells associated with maternal protein restriction.
    Cecile Jacovetti, Romano Regazzi.
       OBJECTIVE: Mitochondria are central to energy production and cellular homeostasis. Beyond importing diverse RNAs, they also encode hundreds of their own non-coding RNAs, contributing to a complex and dynamic RNA landscape. Early-life nutritional insults, such as fetal and postnatal protein deficiency, can impair mitochondrial function and increase the long-term diabetes risk. However, the mitochondrial non-coding transcriptome of pancreatic islets, particularly its responsiveness to nutritional cues, remains largely unexplored.
    METHODS: We performed RNA sequencing to profile small non-coding RNAs in mitochondrial fractions of islet cells from offspring of rats exposed to low-protein (LP) or control diets during gestation and lactation and employed mRNA-miRNA network analysis to explore the potential regulatory roles of differentially expressed mitomiRs in LP-exposed pups.
    RESULTS: Protein deficiency during gestation and lactation led to a profound remodeling of the small non-coding RNA landscape in whole islets, with microRNAs and piRNAs showing the most pronounced changes. In mitochondrial fractions, LP exposure resulted in a striking shift in microRNA composition, with 33 mitomiRs detected in control islets versus 23 in LP-exposed rats, and only 5 shared between groups. Notably, ten mitomiRs were selectively depleted from the cytosol and enriched in mitochondria of LP-exposed islets. Amongst these, miR-10a-5p and miR-126a-5p, are predicted to target genes involved in mitochondrial metabolism and structural organization.
    CONCLUSION: Early-life protein restriction triggers a highly selective reorganization of the mitomiR landscape in pancreatic islets. The identified mitomiRs may serve as regulators of mitochondrial function and intracellular signaling, potentially influencing β-cell metabolic coupling and contributing to diabetes susceptibility.
    Keywords:  Diabetes susceptibility; Mitochondrial non-coding transcriptome; Small non-coding RNAs; mitomiRs
    DOI:  https://doi.org/10.1080/19382014.2025.2610590
  22. J Extracell Vesicles. 2025 Dec;14(12): e70210
    NETosis-Like Response Triggered by Extracellular Vesicle (EV)-Delivered Viral Nucleic Acid, a Novel Cellular Immune Mechanism in Crustacean.
    Hang Hu, Chunyi Zhong, Xinshan Zhao, Cheng Yi, Yi Gong.
      As a novel identified manner of cell death, NETosis is widely regarded as an effective approach to resist pathogen infection but mainly focused on vertebrates with systematic cell typing. Besides, the role of extracellular vesicles (EVs), which are essential tools for intercellular information exchange, in regulating NETosis during pathogen infection has yet to be addressed. Here, we found that viral mRNA wsv271 could be packaged by EVs secreted by haemocytes during WSSV infection in mud crab, and delivered to the neutrophil-like cells, followed by translation into viral protein, and then interacted with the TIR domain of Toll4 to recruit MyD88, so as to activate P38-MAPK signal pathway and further facilitate PAD4 phosphorylation and nuclear translocation to mediate histone-H3 citrullination, which eventually activated NETosis-like response in haemocytes to suppress the spread of viral infection. Therefore, our research not only identified neutrophil-like cells from the haemocytes of a crustacean based on single-cell transcriptomics but also revealed a novel NETosis induction mechanism mediated by EVs-derived viral nucleic acid delivery.
    Keywords:  NETosis‐like response; P38‐MAPK signal pathway; extracellular vesicle; innate immunity; viral infection; wsv271
    DOI:  https://doi.org/10.1002/jev2.70210
  23. Vet Sci. 2025 Nov 27. pii: 1128. [Epub ahead of print]12(12):
    Comparison of the Regulatory Effects of Host Factors on Viral Internal Ribosomal Entry Sites.
    Rupaly Akhter, Kazi Anowar Hossain, Bouchra Kitab, Mohammad Enamul Hoque Kayesh, Kyoko Tsukiyama-Kohara.
      Host factors play critical roles in viral IRES-mediated translation by modulating the efficiency and specificity of viral protein synthesis. In this study, we used small interfering RNA (siRNA) treatment to silence and plasmid-based expression to overexpress PKD1L3 and USP31. Silencing PKD1L3 and USP31 suppressed IRES activity in FMDV and CSFV RNAs, whereas the overexpression of PKD1L3 did not have a significant effect, and USP31 overexpression resulted in only a modest increase in CSFV-IRES activity. Silencing PKD1L3 significantly reduced EMCV-IRES activity but had no significant effect on HCV- or DENV-IRES activity, and silencing USP31 had no significant effect on the activities of these three IRESs. Notably, the combined overexpression of PKD1L3 and USP31 significantly suppressed HCV-IRES activity, suggesting potential context-dependent interactions. These findings indicated that PKD1L3 and USP31 contribute more prominently to CSFV-, FMDV-, and EMCV-IRES-mediated translation than to HCV- or DENV-IRES-driven translation. Collectively, our results provide new insights into the host factors involved in IRES-mediated viral translation, establish a foundation for future in vivo studies to elucidate the specific roles of PKD1L3 and USP31 during viral infection, and indicate potential strategies for mitigating these viruses.
    Keywords:  classical swine fever virus (CSFV); dengue virus (DENV); encephalomyocarditis virus (EMCV); foot-and-mouth disease virus (FMDV); hepatitis C virus (HCV); internal ribosome entry site (IRES); polycystic kidney disease 1-like 3 (PKD1L3); ubiquitin-specific peptidase 31 (USP31)
    DOI:  https://doi.org/10.3390/vetsci12121128
  24. J Bacteriol. 2025 Dec 29. e0053125
    The roles of the Listeria monocytogenes post-translocation chaperones PrsA1 and PrsA2 in protein secretion and stress resistance.
    Jada L George, Leah F Cabo, Jon P Boyle, Nancy E Freitag, Laty A Cahoon.
      PrsA1 and PrsA2 are parvulin peptidyl-prolyl isomerases that function as post-translocation secretion chaperones in Listeria monocytogenes. To assess the contributions of PrsA1 and PrsA2 to overall L. monocytogenes protein secretion, we analyzed prsA1 and prsA2 deletion mutants and PrsA2 structural variants for altered secretion profiles when compared to wild-type bacteria using tandem mass-tagged mass spectrometry. We find that prsA1 and prsA2 deletion mutants have distinctly altered secretion profiles. In addition, among the subset of known secreted proteins with significantly altered secretion abundance were those with characterized functions in virulence, cell division and cell wall assembly, and stress response. To further identify common pathways and protein factors that are altered when PrsA homologs are absent, we conducted a meta-analysis comparing our data from L. monocytogenes to recently published quantitative proteomic secretome data of prsA deletion mutants from diverse gram-positive human pathogens, including Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus. We find that when PrsA homologs are absent in diverse gram-positive bacteria, several pathways are similarly affected, including those promoting bacterial virulence, cell division and cell wall assembly, and oxidative stress resistance. Moreover, we provide evidence of novel roles for L. monocytogenes PrsA1 and PrsA2 in oxidative stress resistance and cell morphology, and PrsA2 in thermo-osmotic stress resistance. Overall, this work suggests that gram-positive PrsA homologs serve in the maturation of multiple protein substrates with varied cellular functions.
    IMPORTANCE: Bacterial protein secretion is critical for functions ranging from cell physiology to virulence. Here, we examine the effect of deleting two Listeria monocytogenes secretion chaperones, PrsA1 and PrsA2, and find that in the absence of one or both chaperones, secretion of several proteins implicated in key biological processes was significantly disrupted. These results, coupled with phenotypic observations of chaperone deletion mutants, reveal that PrsA1 and PrsA2 have roles in bacterial physiology and stress resistance. Furthermore, our meta-analysis of prsA deletion mutants in Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus suggests that the contribution of PrsA to critical bacterial processes is well conserved in gram-positive pathogens. Our work lays the foundation for future inquiry investigating the client repertoire of these chaperones.
    Keywords:  Listeria monocytogenes; PPIase; PrsA1; PrsA2; chaperone; gram-positive secretion; parvulin; secretome; stress resistance
    DOI:  https://doi.org/10.1128/jb.00531-25
  25. bioRxiv. 2025 Dec 16. pii: 2025.12.15.694525. [Epub ahead of print]
    Translational Downregulation of 5' TOP mRNAs During T Cell Exhaustion.
    Erica S Pledger, Navya Ambavaram, Lucas Ferguson, Jamie H D Cate.
      T cell exhaustion is a dysfunctional state that arises during chronic infections and cancer, characterized by impaired effector functions and sustained expression of inhibitory receptors. While transcriptional, epigenetic, and metabolic rewiring have been well documented in exhausted T cells, a comprehensive understanding of how translation is regulated in this state remains incomplete. To address this gap, we performed ribosome profiling and RNA sequencing on exhausted human CD8+ T cells to globally assess translational control. Our analyses reveal a marked repression of 5' terminal oligopyrimidine (TOP) mRNAs during exhaustion. Unexpectedly, we demonstrate that this translational repression occurs despite evidence of elevated mTOR activity in exhausted T cells. These findings uncover a previously unknown layer of translational control in exhausted T cells.
    DOI:  https://doi.org/10.64898/2025.12.15.694525
  26. Methods Mol Biol. 2026 ;3004 193-210
    Crowding Effects in RNA Interactions.
    Francesco A Aprile, Annalisa Pastore.
      Molecular crowding refers to the excluded volume restriction of the space available to molecules in a solution due to the high concentration of other molecules, particularly macromolecules like proteins and nucleic acids. This restriction of space, or excluded volume effect, leads to changes in the behavior and properties of the crowded molecules. In this chapter, we discuss how RNA affects crowding and is affected by it and describe techniques that allow us to study these phenomena. We also discuss methods to extract granules that can then be used to understand their components.
    Keywords:  Biochemistry; Biophysics; Confinement; Crowding; Phase separation
    DOI:  https://doi.org/10.1007/978-1-0716-5084-4_14
  27. Cancer Med. 2026 Jan;15(1): e71438
    Exploring the Role of Long Noncoding RNAs in Breast Cancer Progression: A Comprehensive Study on Biomarkers and Therapeutic Approaches.
    Ramin Moeini, Amin AhsanAlkhat, Saeid Ghorbian.
       BACKGROUND: Among the many forms of cancer that plague women all over the globe, breast cancer (BC) is one of the most prevalent kinds. BC is a multifaceted disease that can manifest in many ways depending on the individual.
    AIMS: The identification of new biomarkers that may be used to diagnose and prognosis of the BC, as well as those that can aid in the creation of novel therapeutic approaches and the understanding of how to regulate multiple pathways in metastasis, may initiate the process of creating novel therapeutic interventions for cancer patients.
    MATERIALS AND METHODS: According to data from recent studies, long noncoding RNAs (LncRNAs) contribute to the development of BC via several distinct biochemical mechanisms. Remembering that long LncRNAs are longer than 200 nucleotides and do not encode proteins is essential.
    RESULTS: Through its interaction with the EGF, TGF-β, NF-κB, PI3K/AKT, and p53 pathways, the abnormal production of LncRNA has a substantial impact on the progression of BC.
    CONCLUSIONS: This research investigates the biological properties of LncRNAs to ascertain their role in regulating cell signaling pathways and the subsequent changes in cell survival, invasion, and proliferation components that characterize BC.
    Keywords:  LncRNA; breast cancer; metastasis; oncogene; prognosis; tumor suppressor
    DOI:  https://doi.org/10.1002/cam4.71438
  28. Neural Regen Res. 2025 Dec 30.
    Error-prone translation as a driver of proteostasis collapse and neurodegeneration.
    Rashid Akbergenov, David P Wolfer, Dennis Gillingham, Dimitri Shcherbakov.
      Error-prone translation, resulting in inaccuracies in protein synthesis, is increasingly recognized as a critical contributor to proteostasis disruption and the pathogenesis of age-related neurological disorders. In recent years, numerous studies have elucidated that stochastic errors during mRNA translation may act as a molecular "tipping point" initiating pathogenic protein misfolding. A detailed analysis of how translation errors lead to protein misfolding, aggregation, and subsequent neurotoxicity will facilitate the identification of promising therapeutic targets for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This article explores the contribution of mistranslation to proteostasis decline, focusing on the unique vulnerabilities of neuronal cells. We review the sources of translation errors, effects of ribosomal ambiguity and error-restrictive mutations, role of proteostatic mechanisms (such as molecular chaperones, ubiquitin-proteasome system, and unfolded protein response), and provide a unified perspective that links age-related translational infidelity to neurodegeneration. By synthesizing the most recent data obtained with genetically modified cellular and animal model studies, we highlight how age-associated decline in translational fidelity exacerbates proteostasis failure and propose potential therapeutic interventions targeting translation accuracy to mitigate neurodegeneration.
    Keywords:  aging; neurological disease; protein aggregation; protein misfolding; protein synthesis; proteostasis; ribosomal mistranslation; translation accuracy
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00795
  29. PLoS One. 2025 ;20(12): e0339572
    A methodology for calculating the rarity of diverse proteins based on functional specificity and thermodynamic stability.
    Brian J Miller.
      A key question in protein studies is the proportion of amino acid sequences that correspond to functional proteins, often called protein rarity. This issue underlies the relationship between mutations and disease, theories on the origin of proteins, and strategies for engineering new proteins. Recent literature has detailed how to employ estimates of protein rarity to evaluate the required biasing of functional sequences in sequence space to allow for evolutionary paths to connect distinct proteins. One challenge in addressing rarity has been an imprecise definition of function and a lack of consistency in methodology. This study introduces a new methodology, referred to as PRISM, to evaluate protein rarity based on the impact of mutations on stability. PRISM offers a suite of methods that are simpler than traditional approaches while providing accurate upper-bound rarity estimates. The specific method applied is determined by the protein's function and available empirical data on how accumulating mutations affect its stability and performance. PRISM is applied to several proteins, and the accuracy of the methods is demonstrated by comparing the results to rarity estimates from previous studies. The calculated rarities align with previous research that concludes functional sequences are often exceedingly rare. The application of PRISM is outlined for research in protein engineering, protein evolution, and pathology.
    DOI:  https://doi.org/10.1371/journal.pone.0339572
  30. Nat Commun. 2025 Dec 30.
    Autonomous biogenesis of all thirty proteins of the Escherichia coli translation machinery.
    Matthaeus Schwarz-Schilling, Ilan Cohen, Aurore Dupin, Noa Avidan, Yoav Barak, Yoshihiro Shimizu, Shirley S Daube, Roy H Bar-Ziv.
      The cell-free biogenesis of the protein translation machinery is essential for the creation of a self-regenerating synthetic cell. Here, we demonstrate the autonomous and simultaneous biogenesis of all thirty proteins of the translation machinery of E. coli in a reconstituted transcription-translation system. We first establish self-regeneration of every translation protein by determining the threshold concentration required for its own synthesis from a synthetic gene coding for the protein, thereby demonstrating the functionality of all nascent proteins, separately. Simultaneous biogenesis of multiple translation proteins at their threshold results in delayed synthesis below detection levels. To achieve self-regeneration of multiple translation proteins, we induce boundary-free compartmentalization of the reaction by immobilizing the genes on a surface at high density. The co-localization of genes, molecular machinery, messenger RNA and nascent proteins at the surface create sufficient conditions to catalyze the simultaneous self-regeneration of sub-groups up to all thirty translation proteins, as measured by total internal reflection fluorescence on the surface. Our approach provides mechanistic insight and presents a general methodology for the biogenesis of cellular machines toward autonomous synthetic systems.
    DOI:  https://doi.org/10.1038/s41467-025-67772-8
  31. J Cell Biol. 2026 Apr 06. pii: e202504003. [Epub ahead of print]225(4):
    Cell type-specific spatiotemporal control of GFP-tagged protein degradation in mice.
    Alexandra Prado-Mantilla, Joseph Sheheen, Julie Underwood, Terry Lechler.
      Loss-of-function studies are a central approach to understanding gene/protein function. In mice, this often relies upon heritable recombination at the DNA level. This approach is slow and nonreversible, which limits both spatial and temporal resolution of analysis. Recently, degron techniques that directly target proteins for degradation have been successfully used to quickly and reversibly knock down proteins. Currently, these systems have been limited by lack of tissue/cell type specificity. Here, we generated mice that allow spatial and temporal control of GFP-tagged protein degradation. This DegronGFP line leads to degradation of GFP-tagged proteins in different cellular compartments and in distinct cell types. Further, it is rapid and reversible. We used DegronGFP to probe the function of the glucocorticoid receptor in the epidermis and demonstrate that it has distinct functions in proliferative and differentiated cells-an analysis that would not have been possible with traditional recombination approaches. We propose that the ability to use GFP knock-in lines for loss-of-function analysis will provide additional motivation for generation of these useful tools.
    DOI:  https://doi.org/10.1083/jcb.202504003
  32. Aging Cell. 2026 Jan;25(1): e70334
    Loss of p62 Binding Allows TIF-IA Accumulation in Senescence, Which Promotes Phenotypic Changes to Nucleoli and the Senescence Associated Secretory Phenotype.
    Hazel C Thoms, Tyler S Brant, Katie Duckett, Yizheng Yang, Jinxi Dong, Hongfei Wang, Freya Derby, Oluwatumilara F Akeke, Faizah Al-Alayeen, Amy Newell, Piotr Manasterski, Aishwarya Gopalakrishnan, Derek Mann, Fraser R Millar, Alex Von Kriegsheim, Juan Carlos Acosta, Fiona Oakley, Lesley A Stark.
      A key characteristic of senescent and ageing cells is a reduction in number and increase in size of nucleoli. Although a number of pathways have been suggested, the mechanisms underlying this altered nucleolar phenotype, and the downstream consequences, remain poorly understood. The PolI complex component, TIF-IA, has previously been implicated in regulating this characteristic nucleolar phenotype in response to stress. Here we explored the role of TIF-IA in senescence and ageing. We show that TIF-IA accumulation, particularly in the nucleus and nucleolus, is an early response to oncogene- and therapy-induced senescence (OIS and TIS) in vitro. Using multiple mouse models, we also demonstrate accumulation of TIF-IA in response to senescence induction and ageing in vivo. We demonstrate that TIF-IA accumulation is not required for cell cycle arrest but that in OIS and TIS, it is essential for phenotypic changes to nucleoli, the senescence-associated secretory phenotype (SASP) and establishment of stable senescence. We demonstrate that in proliferating cells, TIF-IA binds the cargo receptor, p62 (SQSTM1), and that accumulation in senescence occurs as a consequence of ATM activation, which disrupts this interaction. Finally, we show that TIF-IA accumulation causes an increase in reactive oxygen species (ROS) levels. Together, these results establish TIF-IA accumulation as a key regulator of the nucleolar phenotype and the SASP in senescence and uncover a novel, p62-dependent mechanism driving this process. These findings offer significant new insights into nucleolar size regulation in senescence and ageing, and suggest a potential relationship with the inflammatory phenotype.
    Keywords:  ATM; DNA damage; PolI complex; ROS; inflammation; nucleolar; nucleolus; p62; senescence
    DOI:  https://doi.org/10.1111/acel.70334
  33. Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2517995123
    Legionella effector Ceg10 acetylates RPS20 to inhibit host translation and induce cell cycle arrest.
    Jiajia Gao, Wenwen Xu, Ziyi Zhou, Lixin Lu, Zhenhuang Ge, Weiqiang Wang, Yongjun Lu, Honghua Ge.
      Legionella pneumophila, the causative agent of Legionnaires' disease, utilizes a type IV secretion system (T4SS) to translocate effectors into host cells, modulating diverse cellular processes to create a replication-permissive niche. Here, we characterize Ceg10, a T4SS-translocated effector, as a nucleus-targeting acetyltransferase that interferes with host ribosome biogenesis and cell cycle progression. Structural analysis reveals that Ceg10 harbors a conserved Cys-His-Asp (CHD) catalytic triad required for its acetyltransferase activity. Upon nuclear import mediated by the host transport adaptor HEATR3, Ceg10 selectively acetylates the ribosomal protein RPS20 at Thr64, Thr65, and Arg66, which have not been annotated as posttranslational modification sites. This acetylation impairs RPS20's interaction with RPS29 and 18S rRNA, two components critical for 40S ribosomal subunit assembly, leading to translation inhibition and G1/S cell cycle arrest. These host perturbations are essential for efficient early-stage intracellular replication of L. pneumophila. Our findings identify a distinct mechanism by which a bacterial effector co-opts nuclear import machinery and directly modifies ribosomal proteins to subvert host biosynthesis and cell cycle control, highlighting ribosomal protein acetylation as a hitherto unrecognized role in host-pathogen interactions.
    Keywords:  Legionella pneumophila; cell cycle arrest; protein acetylation; ribosomal protein RPS20; type IV secretion system
    DOI:  https://doi.org/10.1073/pnas.2517995123
  34. Cancers (Basel). 2025 Dec 05. pii: 3900. [Epub ahead of print]17(24):
    Fibrillarin Contributes to the Oncogenic Characteristics of Colorectal Cancer Cells and Reduces Sensitivity to 5-Fluorouracil.
    Ting Wu, Mounira Chalabi-Dchar, Wei Xiong, Lucie Arnould, Eliezer Aimontche, Sabine Beaumel, Charles Dumontet, Virginie Marcel, Tanguy Fenouil, Jean-Jacques Diaz, Marie Alexandra Albaret, Hichem Claude Mertani.
       BACKGROUND/OBJECTIVES: Fibrillarin (FBL) is a key nucleolar methyltransferase involved in ribosome biogenesis through 2'-O-ribose methylation of rRNA. While its oncogenic role has been reported in several cancer types, its expression and function in human colorectal cancer (CRC) have remained largely unexplored. This study aims to investigate the expression of FBL in human CRC tissues and cell lines and to determine its functional role in tumor progression and metastasis.
    METHODS: We examined FBL expression in paired human CRC primary tumors and liver metastases using immunohistochemistry. Functional studies were performed using SW-480 (primary tumor) and SW-620 (lymph node metastasis) CRC cell lines derived from the same patient. Cell migration, invasion, and 3D spheroid growth were analyzed following FBL downregulation. In vivo tumor growth was assessed in SCID mice xenografted with FBL-deficient cells. Molecular changes were explored through phosphorylation arrays and Western blotting.
    RESULTS: FBL expression was significantly higher in human metastatic lesions than in primary tumors. FBL downregulation impaired migration, invasion, and spheroid growth in SW-480 and SW-620 cells and reduced tumor growth in vivo. Mechanistically, FBL inhibition decreased activation of MAPK/ERK, PI3K/AKT, and JNK/p38 pathways and reduced phosphorylation of the transcription factor CREB.
    CONCLUSIONS: Our study identifies FBL as a potential contributor to colorectal cancer progression, with elevated expression associated particularly with metastatic disease. By demonstrating that FBL expression is elevated in patient-derived metastatic tissues and functionally promotes migration, invasion, and tumor growth, our findings expand the role of ribosome biogenesis factors beyond protein synthesis. The observed suppression of key oncogenic pathways and CREB phosphorylation upon FBL inhibition suggests that FBL integrates ribosomal regulation with cancer cell signaling. These insights open new avenues for targeting nucleolar activity in advanced CRC and highlight FBL as a potential biomarker and therapeutic target in metastatic disease.
    Keywords:  colorectal cancer; fibrillarin; metastasis; ribosome biogenesis
    DOI:  https://doi.org/10.3390/cancers17243900
  35. Dev Dyn. 2025 Dec 30.
    Bridging maternal effects and epitranscriptomics: A novel perspective in developmental biology.
    Ehsan Pashay Ahi.
      Maternal effects, encompassing both genetic (maternally expressed gene products) and non-genetic (maternal state) influences, are powerful determinants of offspring phenotype, yet their RNA-level mechanisms remain incompletely resolved. In parallel, epitranscriptomics, an emerging field centered on chemical modifications to RNA, has revealed new layers of gene regulation with implications for cell fate, plasticity, and response to environmental cues. In this perspective article, a conceptual link is proposed between maternal effects and epitranscriptomic mechanisms, focusing on how maternal environments may shape offspring phenotypes through RNA modifications. Evidence is examined from diverse systems, including maternal deposition of modified RNAs, environmental modulation of RNA-modifying enzymes, and early developmental windows sensitive to maternal inputs. A clear distinction is drawn between placenta-mediated pathways that reprogram trophoblast/placental epitranscriptomics and direct fetal-tissue routes that act within developing organs. Although causal demonstrations are still emerging, convergent observations indicate that maternal environments can tune the offspring epitranscriptome with lasting phenotypic consequences. To articulate this emerging connection, the concept of "maternal RNA imprinting" is proposed, the idea that offspring development is shaped by maternal cues via targeted RNA modifications. This article aims not only to synthesize emerging insights across fields but also to stimulate interdisciplinary discussion and encourage investigation into the unexplored intersections of maternal biology and RNA regulation.
    Keywords:  RNA modifications; developmental programming; epitranscriptomics; maternal effects; non‐genetic inheritance
    DOI:  https://doi.org/10.1002/dvdy.70111
  36. Exp Suppl. 2026 ;115 111-122
    Reconnaissance of the Good, the Bad, and the Ugly Role of tRNAs in Carcinogenesis and Metastasis.
    Malik Ali Asghar, Mehraj Abbasov, Rukset Attar, Ammad Ahmad Farooqi.
      Our current knowledge of the translational mechanisms and the detailed structural insights of its components have highlighted the characteristically exclusive role of tRNAs and aminoacyl-tRNA synthetase diversity in the evolution of the genetic codes. Phenomenal advancements in mass spectrometry and high-throughput sequencing have enabled the researchers in developing a better understanding of the complex landscape of tRNA modifications. Emerging evidence has started to shed light on linchpin role of tRNAs in carcinogenesis and metastatic dissemination. In this chapter, we have provided an overview of the role of tRNAs, aminoacyl-tRNA synthetases, and tRNA-derived small RNAs in the onset and progression of cancer.
    Keywords:  Carcinogenesis; Metastasis; Noncoding RNA; tRNAs
    DOI:  https://doi.org/10.1007/978-3-032-06948-1_4
  37. J Biol Rhythms. 2025 Dec 30. 7487304251393577
    Rhythmicity of TOR (Target of Rapamycin) Activity Supports Circadian Function in Neurospora crassa.
    Golnoush Akhtari, Milad Falahat Chian, Ethan Myles Sooklal, Patricia Lakin-Thomas.
      Circadian (24 h) rhythmicity is a nearly-ubiquitous property of eukaryotic cells, and the mechanisms that generate this rhythmicity have been studied in a number of organisms for many years. However, there are still gaps in our understanding of the generation and regulation of rhythms. Although transcription/translation feedback loops (TTFLs) are said to be essential to generating rhythmicity in eukaryotes, there are many examples of rhythmicity seen in organisms without functioning TTFLs. Our lab previously found that two genes that function in the TOR (Target of Rapamycin) pathway, vta and gtr2, are essential for non-TTFL rhythmicity in the fungus Neurospora crassa. These two mutants were also shown to dampen the output rhythm of spore-formation (conidiation) and the rhythm of the TTFL component protein FRQ, and dampen the amplitude of the underlying oscillator in strains with functioning TTFLs. Therefore, we are interested in the role of TOR in generating and/or sustaining rhythmicity in both the presence and absence of a functioning TTFL. Here we report the development and validation of an improved assay for TOR activity in Neurospora, and using this assay we demonstrate that TOR activity displays circadian rhythmicity in strains with functioning TTFLs. The period of TOR rhythmicity is affected by a long-period mutation in a TTFL component (frq7), and the TOR rhythm is dampened in the vta and gtr2 knockouts. The mean level of TOR activity (mesor) in the vta and gtr2 knockout mutants is within the range of the TOR rhythm in wild type, indicating that it is rhythmicity of TOR, not a constant level of activity, that is required to sustain output rhythmicity. These results establish Neurospora as a valuable model for investigating the role of TOR in circadian rhythmicity and implicate TOR activity as a rhythmic state variable of the circadian system.
    Keywords:  Neurospora; RPS6; circadian; oscillators; target of rapamycin
    DOI:  https://doi.org/10.1177/07487304251393577
  38. IUBMB Life. 2026 Jan;78(1): e70081
    Capturing the Variations in Mutant p53-Driven Regulatory Networks in Breast Cancer Subtypes, Its Clinical Relevance and a Novel Association With Androgen Receptor and EMT.
    Aastha Singh, Rahul Gupta, Ritu Kulshreshtha.
      The tumour suppressor TP53 is frequently mutated in breast cancer and drives poor outcomes. The impact of mutant p53 (mutp53) on subtype-specific gene and non-coding RNA networks, and their clinical significance, remains largely underexplored. Here, using TCGA-BRCA data, we have delineated subtype-specific mRNA, lncRNA, and microRNA signatures, pathways, co-expression/interaction networks, and prognosis associated with hotspot mutp53 or wildtype p53 tumours. Our study shows that mutp53 deregulates the genes related to EMT, chemoresistance, and prognosis in a subtype-specific manner. The EMT-associated signature was able to stratify HER2 and Basal patients by their p53 status. Construction of lncRNA-mRNA-miRNA interaction networks led to the identification of various feedback loops and hub genes with prognostic relevance that possess binding sites for p53 and EMT-TFs within their promoters. In the basal mutp53 tumours, we found Androgen Receptor (AR) to be a downregulated EMT-associated gene, with its higher levels linked to a better prognosis. We validated that mutp53 breast cancer cell lines show reduced levels of AR and its predicted transcriptional target, miR-196a-5p. Overexpression of WTp53 resulted in the upregulation of AR and miR-196a-5p, while mutp53 (R175H) suppressed their expression. Basal mutp53 tumours with low AR displayed higher EMT scores. Enforced expression of AR led to suppression of mesenchymal markers in basal cell lines. Overall, we have identified novel prognostically relevant RNA signatures and networks that may serve as attractive therapeutic targets in mutp53 breast cancer patients in a subtype-specific manner. Additionally, we have discovered a novel AR:mutp53 association that may be implicated in EMT and chemoresistance.
    Keywords:  EMT; TCGA; breast cancer; lncRNAs; miRNAs; p53
    DOI:  https://doi.org/10.1002/iub.70081
  39. Mol Microbiol. 2026 Jan 02.
    An Improved Description of the Small RNA Landscape of the Human Fungal Pathogen Aspergillus fumigatus.
    Xiaoqing Pan, Abdulrahman A Kelani, Lukas Schrettenbrunner, Swatika Prabakar, Bhawana Israni, Matthew G Blango.
      Aspergillus fumigatus is a ubiquitous filamentous fungus and dangerous human pathogen that produces a limited pool of small RNAs under standard laboratory conditions. To better understand the rules of small RNA production in A. fumigatus, we induced canonical RNA interference (RNAi) via overexpression of two separate inverted-repeat transgenes. We observed production of predominantly 20-nt, 5' uridine-containing small RNAs from the 3' end of each transgene nearest to the loop region and dependent on dicer-like B RNase III enzyme. Using this refined knowledge, we assessed small RNA biogenesis by sRNA-seq in three double knockout strains of the RNAi pathway, namely the dicer-like proteins (ΔdclA/B), argonautes (ΔppdA/B), and RNA-dependent RNA polymerases (ΔrrpA/B). In each case, we found limited evidence for production of 5' U-containing small RNAs reliant on the RNAi machinery under standard laboratory conditions. We did observe 5' U-containing small RNAs amongst the abundant tRNA-derived RNAs (tDRs); however, biogenesis of tDRs was predominantly Dicer-like independent. To more accurately define the complex tDR repertoire, we employed a cutting-edge tDR-sequencing approach that improved tRNA-half detection and revealed qualitative morphotype-specific changes in the small RNA fraction of conidia relative to mycelium. Finally, leveraging the limited sRNA repertoire of A. fumigatus, we tested the consequences of inverted-repeat transgene overexpression in the ΔdclA/B double knockout, which revealed growth inhibition even in the absence of double-stranded RNA (dsRNA) processing and small RNA production. We hypothesize that the RNAi substrate-limited landscape of A. fumigatus facilitates sensitivity to increases in dsRNA, offering an intriguing system for future studies of dsRNA metabolism.
    Keywords:  double‐stranded RNA; filamentous fungi; fungal pathogen; small RNA; tRNA‐derived RNAs
    DOI:  https://doi.org/10.1111/mmi.70042
  40. Front Oncol. 2025 ;15 1687984
    LncRNA ZFHX4-AS1 initiates an oncogenic axis involving a ZFHX4/SOX2 positive feedback loop to accelerate glioma progression.
    Hongshan Yan, Xue Wang, Zongmao Zhao.
       Introduction: The long non-coding RNA ZFHX4-AS1 is a recently identified transcript with an unknown role in glioma. Here, we demonstrate that ZFHX4-AS1 and its neighboring protein-coding gene, ZFHX4, are both significantly upregulated in glioma, and their high expression correlates with poor patient prognosis.
    Methods: We integrated pan-cancer and glioma transcriptomic datasets from TCGA to assess ZFHX4-AS1 and ZFHX4 expression patterns and their prognostic relevance. We analyzed the expression of ZFHX4-AS1 and its neighboring gene ZFHX4 in human glioma tissues and correlated it with patient prognosis. Functional assays, including cell proliferation, migration, and invasion tests, were conducted in vitro, and tumor growth was assessed in vivo. Additional mechanistic assays-including RNA-FISH, subcellular fractionation, and co-immunoprecipitation-were performed to determine the localization and molecular interactions of ZFHX4-AS1. The mechanistic interactions between ZFHX4-AS1, ZFHX4, SOX2, and the JAK-STAT pathway were investigated using gene expression analysis, protein-protein interaction studies, and signaling pathway activation assays.
    Results: Functionally, both ZFHX4-AS1 and ZFHX4 promote glioma cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Mechanistically, ZFHX4-AS1 acts in cis to positively regulate the expression of ZFHX4. Crucially, we identified the stemness factor SOX2 as a key functional partner of ZFHX4. ZFHX4 and SOX2 physically interact and form a positive feedback loop, where each protein promotes the other's expression. This regulatory circuit serves to amplify the oncogenic signal, robustly driving the malignant phenotype. Finally, we demonstrate that this signaling axis converges on the activation of the JAK-STAT pathway.
    Discussion: In conclusion, our study significantly expands upon the understanding of the ZFHX4-AS1 pathway in glioma. We demonstrate that ZFHX4-AS1 initiates an oncogenic signal which is powerfully amplified by a previously unidentified ZFHX4/SOX2 positive feedback loop. We further establish that this entire axis ultimately converges on the activation of the JAK-STAT pathway. This detailed ZFHX4-AS1/ZFHX4/SOX2/JAK-STAT axis represents a promising set of therapeutic targets for glioma treatment.
    Keywords:  SOX2; ZFHX4; ZFHX4-AS1; glioma; long non-coding RNA
    DOI:  https://doi.org/10.3389/fonc.2025.1687984
  41. Int J Mol Sci. 2025 Dec 18. pii: 12164. [Epub ahead of print]26(24):
    The Role of miRNAs in Parkinson's Disease: A Systematic Review.
    Michalis Chrysanthou, Christiana C Christodoulou, Eleni Zamba Papanicolaou.
      Over the years, there has been extensive research conducted on Parkinson's Disease (PD), a neurodegenerative disorder known for causing motor impairment and behavioral changes. In more recent years, the roles of dysregulated microRNAs (miRNAs) in PD pathology have been studied in the hopes of developing new diagnostic methods or even treatments. This systematic review pinpoints and examines studies between 2010 and 2024 that have identified significant dysregulation of miRNAs in patients with PD. Upon filtering out the search results by a series of exclusion criteria, this review was conducted using 56 relevant studies. These studies revealed a vast array of significantly dysregulated miRNAs identified in the samples of patients with PD, when compared to healthy controls. A number of these miRNAs, such as miR-29c-3p, are likely biomarkers for more accurate PD diagnosis, and many, such as miR-485-3p, were found to be involved in PD pathogenesis. With further research, miRNAs could become a helpful diagnostic and prognostic tool for PD, with some of them even being candidate therapeutic targets for future treatments.
    Keywords:  Parkinson’s Disease; biomarker; miRNA; systematic review
    DOI:  https://doi.org/10.3390/ijms262412164
  42. Mol Med Rep. 2026 02;pii: 75. [Epub ahead of print]33(2):
    [Expression of Concern] MicroRNA-29c inhibits proliferation and promotes apoptosis in non-small cell lung cancer cells by targeting VEGFA.
    Shijuan Zhan, Chunfeng Wang, Fangqing Yin.
      Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that western blot data appeared to have been assembled incorrectly in Fig. 4A on p. 6709. In this case, there was an apparent inversion of the p‑PI3K bands, and inclusion of one of these bands as a unique band (upside down) for the Control experiment in the p‑Akt row of data, purportedly showing the results of a different set of experiments. The authors were contacted by the Editorial Office to offer an explanation for this apparent anomaly in the presentation of the data in this paper; however, up to this time, no response from them has been forthcoming. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [Molecular Medicine Reports 17: 6705-6710, 2018; DOI: 10.3892/mmr.2018.8678].
    Keywords:  microRNA-29c; non-small cell lung cancer; vascular endothelial growth factor A
    DOI:  https://doi.org/10.3892/mmr.2025.13785
  43. bioRxiv. 2025 Dec 16. pii: 2025.12.15.694494. [Epub ahead of print]
    Functional diversification of the cephalopod proteome by RNA-editing.
    Jack M Moen, Alicia L Richards, Einar K Krogsaeter, Benjamin Polacco, Martin Gordon, Erica Stevenson, Rhiana Boyles, Maximilien Burq, Dejan Stepec, Bryan Crampton, Peter Cimermancic, Joshua J C Rosenthal, Nevan J Krogan, Danielle L Swaney.
      Coleoid cephalopods exhibit the highest levels of ADAR-mediated RNA editing of any known animal, yet the functional consequences of most recoding events remain largely unknown. We integrate proteomics with biochemical and cellular assays to characterize thousands of recoding events across the Doryteuthis pealeii proteome. Using quantitative and functional mass spectrometry, we show that RNA edit-driven recoding reshapes the cellular proteome to alter protein stability, subcellular localization, post-translational modifications, and enzymatic activity. -Recoding can regulate post-translational modifications through their creation or ablation, and this has direct effects on protein function and protein-protein interactions. Recoding of the E3 ligase MARCHF5 drives widespread changes in substrate ubiquitylation and perturbs mitochondrial homeostasis, illustrating how RNA editing can influence organelle function. These data provide the first proteome-scale view of how extensive RNA recoding diversifies protein function in coleoid cephalopods and offers a new framework for understanding how RNA-level plasticity shapes protein function and cellular physiology.
    DOI:  https://doi.org/10.64898/2025.12.15.694494
  44. Life (Basel). 2025 Dec 10. pii: 1888. [Epub ahead of print]15(12):
    Advances in Quantitative Techniques for Mapping RNA Modifications.
    Ling Tian, Bharathi Vallabhaneni, Yie-Hwa Chang.
      RNA modifications are essential regulators of gene expression and cellular function, modulating RNA stability, splicing, translation, and localization. Dysregulation of these modifications has been linked to cancer, neurodegenerative disorders, viral infections, and other diseases. Precise quantification and mapping of RNA modifications are crucial for understanding their biological roles. This review summarizes current and emerging methodologies for RNA modification analysis, including mass spectrometry, antibody-based and non-antibody-based approaches, PCR- and NMR-based detection, chemical- and enzyme-assisted sequencing, and nanopore direct RNA sequencing. We also highlight advanced techniques for single-cell and single-molecule imaging, enabling the study of modification dynamics and cellular heterogeneity. The advantages, limitations, and challenges of each method are discussed, providing a framework for selecting appropriate analytical strategies. Future perspectives emphasize high-throughput, multiplexed, and single-cell approaches, integrating multiple technologies to decode the epitranscriptome. These approaches form a robust toolkit for uncovering RNA modification functions, discovering biomarkers, and developing novel therapeutic strategies.
    Keywords:  RNA modifications; biomarker discovery; chemical-assisted sequencing; epitranscriptomics; mass spectrometry; nanopore direct RNA sequencing; single-cell analysis; single-molecule imaging
    DOI:  https://doi.org/10.3390/life15121888
  45. Ageing Res Rev. 2025 Dec 29. pii: S1568-1637(25)00352-6. [Epub ahead of print] 103006
    RNA G-quadruplexes Mediated Protein Aggregation in Neurodegenerative Diseases.
    Tu Chen Guan, Li Zeng, Mei Liu, Yan Liu, Yun Cheng Wu, Yu Guan Mu, Eng King Tan, Zhi Dong Zhou.
      RNA G-quadruplexes (rG4s) are stable secondary structures formed by guanine-rich RNA sequences that have emerged as critical regulators of RNA metabolism. The rG4s are widespread in both coding and noncoding RNAs and have been implicated in regulation multiple post-transcriptional processes, including RNA stability, splicing, polyadenylation, nuclear export, localization, and translation. Recent findings real that rG4s play pathological roles in neurodegenerative diseases (NDs), including Alzheimer's disease (AD) and Parkinson's disease (PD). The rG4s function in stress granule dynamics, aberrant phase separation, and the nucleation of pathological protein assemblies, which is implicated in protein co-aggregation and pathological protein aggregation in NDs. Here, we provide an integrated synthesis of how rG4s influence protein aggregation through biophysical, cellular, and molecular mechanisms, with particular emphasis on rG4-driven perturbations of phase separation and aggregation pathways. The rG4s relevant disease pathogenesis, biomarker development, and therapeutic interventions in NDs are discussed. Furthermore, we highlight emerging translational opportunities, including the potential of rG4-targeting small molecules such as 5-aminolevulinic acid and other modulators, which may open new avenues for combating neurodegeneration.
    Keywords:  RNA G-quadruplexes; biomarkers; neurodegeneration; protein aggregation; therapeutics
    DOI:  https://doi.org/10.1016/j.arr.2025.103006
  46. Nat Rev Cardiol. 2026 Jan 02.
    Cardiac epigenome in heart development and disease.
    Patrick Laurette, Ralf Gilsbach.
      Genetic and acquired forms of heart disease are leading causes of death worldwide. The epigenome, which governs cellular identity by modulating the accessibility of genetic regulatory elements, is established during development by transcription factors and has a pivotal role in the execution of cellular programmes. The epigenetic layers include DNA methylation, histone modifications and chromatin accessibility, which are dynamically regulated during development and in response to stress. Advances in single-cell and cell type-resolved epigenome analyses have provided unprecedented insights into the heterocellular nature of organs such as the heart, via the identification of epigenetic mechanisms and disease-associated epigenetic alterations in cardiomyocytes and other cardiac cell types. Chromatin remodelling, driven by specific modifiers, transcription factors and chaperones, orchestrates cardiac gene expression and contributes to disease manifestation and progression. Understanding how to modulate these epigenetic pathways in a cell type-specific manner offers promising avenues for therapeutic intervention, including epigenome editing for targeted modulation of regulatory elements. In this Review, we highlight studies decoding the various layers of the cardiac epigenome, emphasizing the interplay between cell type-specific mechanisms, describe emerging methods to study the cardiac epigenome, and discuss the translational potential of targeting epigenetic mechanisms for the prevention and treatment of cardiac diseases.
    DOI:  https://doi.org/10.1038/s41569-025-01223-1
  47. Mol Biomed. 2025 Dec 29. 6(1): 150
    Activated oligoadenylate synthetase-ribonuclease L pathway promotes endothelial pyroptosis and impairs diabetic wound healing via thioredoxin-interacting protein m6A methylation.
    Peng Zhou, Yating Huang, Zezheng Wang, Dianxi Chen, Binbin Long, Peiliang Qin, Yiqing Li, Chao Yang, Qin Li.
      In diabetic skin, even in the absence of infection, the antiviral enzymes 2'-5'-oligoadenylate synthetase (OAS) and ribonuclease L (RNase L) demonstrate abnormally heightened activity. This dysregulation triggers a state of cellular stress, which not only suppresses intracellular protein synthesis but also activates innate immune responses-particularly upon pathogenic bacterial invasion. Whether the sustained activation of the OAS-RNase L pathway in diabetic skin tissue critically contributes to impaired wound healing remains to be determined. We have investigated the pyroptosis changes in human umbilical vein endothelial cells (HUVECs) treated with Lipopolysaccharide (LPS) under high glucose by RNase L small interfering RNA (siRNA) to down-regulate RNase L expression. Under high glucose conditions, we observed abnormal activation of the OAS/RNase L pathway in HUVECs, which further exacerbated cellular pyroptosis upon LPS stimulation. Abnormally activated RNase L, which reduces the expression of methyltransferase 3 (METTL3), led to decreased m6A methylation of thioredoxin-interacting protein mRNA (TXNIP mRNA). The decreased degradation of TXNIP mRNA by the hypomethylation leads to increased TXNIP expression, which in turn enhances pyroptosis.. In vitro experiments, the impact of RNase L inhibitor Ellagic acid (EA) on diabetic wound healing in STZ (streptozotocin)-induced diabetic mice was evaluated. We found a reduction in skin pyroptosis and improved wound healing when EA was administered orally. Our results demonstrate that hyperglycemia-induced OAS/RNase L activation increases endothelial cell susceptibility to pyroptosis and inflammatory responses during infection. These findings provide valuable insights for developing novel therapeutic strategies for diabetic wound management.
    Keywords:  Diabetic wound; LPS; M6A methylation; OAS/RNase L; Pyroptosis; TXNIP
    DOI:  https://doi.org/10.1186/s43556-025-00399-9
  48. Genes (Basel). 2025 Nov 26. pii: 1408. [Epub ahead of print]16(12):
    Heat Shock Protein 104 (Hsp104) in the Marine Diatom Ditylum brightwellii: Identification and Transcriptional Responses to Environmental Stress.
    Han-Sol Kim, Jong-Won Lee, Jang-Seu Ki.
       BACKGROUNDS: The marine diatom Ditylum brightwellii has been widely used as a model species for ecotoxicological assessments in marine environments. Heat shock proteins (Hsps) function as molecular chaperones that protect cells under diverse stress conditions. Of them, Hsp104 participates in the protein restoration system by reversing protein aggregation.
    METHODS: In the present study, we determined the full-length sequence of DbHsp104 in D. brightwellii using transcriptome sequencing and gene cloning.
    RESULTS: The open reading frame (ORF) was 2745 bp in length, encoding a protein of 915 amino acids (101.15 kDa). Phylogenetic and domain structural analysis revealed that DbHsp104 possesses conserved features of eukaryotic Hsp104. In addition, transcriptional responses of the gene were evaluated after exposures to thermal stress at 20, 25, and 30 °C, and heavy metals and endocrine-disrupting chemicals (EDCs) for 24 h. Relative gene expression analysis showed that DbHsp104 was significantly up-regulated under thermal stress and copper exposures, peaking at 4.87- and 5.55-fold (p < 0.001) increases, respectively. In contrast, no significant changes were observed in response to nickel, bisphenol A (BPA), polychlorinated biphenyl (PCB), and endosulfan (EDS) treatments.
    CONCLUSIONS: These results suggest that DbHsp104 is specifically responsive to acute stress induced by thermal stress and copper, highlighting its potential as a molecular biomarker in marine environments.
    Keywords:  Ditylum brightwellii; biomarker; diatom; environmental stress; heat shock protein 104
    DOI:  https://doi.org/10.3390/genes16121408
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