bims-ribost 2025-12-21 papers

bims-ribost

Biomed News

on Ribostasis and translation stress

Issue of 2025–12–21
eleven papers selected by
Cédric Chaveroux, CNRS

Identification of circular RNA hsa-PHACTR4_0009 as a new class of biomarker for transposition of the great arteries.
A single Musashi gene allele is sufficient to maintain mouse photoreceptor cells.
"Shape is everything: on proteins' functions": Author.
Indole sensing in host, microbiota, and pathogen interactions.
EVRCEPT: EV RNA Cargo Enrichment Prediction Tool to predict enrichment of RNA into Extracellular Vesicles.
The G3BP stress-granule proteins reinforce the integrated stress response translation programme.
Histones and nucleoid-associated proteins in Methanosarcina acetivorans mediate recovery from stress and stasis.
Protein-coding genes in humans and model mammals (mouse, rat and pig): gene identifiers and disambiguation of gene nomenclature retrieved from the Ensembl genome browser.
Reprogramming ribosomes during viral protein synthesis.
There and back again: a cell biologist's journey from organelles to molecules.
Ribosomal RNA Synthesis is a Lethal Vulnerability During Reductive Stress In C . elegans.

J Mol Cell Cardiol Plus. 2025 Dec;14 100830

Identification of circular RNA hsa-PHACTR4_0009 as a new class of biomarker for transposition of the great arteries.

Neha Rawal, Anmol Gurgela, Snigdha Kumari, Manoj Kumar Rohit, Ajay Bahl, Anupam Mittal.

  Dextro-Transposition of great arteries (d-TGA) is a cardiac birth anomaly with reversed anatomic position of the aorta and pulmonary artery, with a poor prognosis. The molecular aetiology of d-TGA remains elusive, possibly due to polygenic contributions and gene-environment interactions, suggesting the role of epigenetic components in d-TGA. Various non-coding RNAs, like circular RNA (circRNA), epigenetically regulate gene expression and may also serve as putative biomarkers because of their exceptionally high stability in plasma. In this study, we performed whole transcriptome analysis in the plasma of diseased and healthy neonates to identify circular RNA specifically dysregulated in the d-TGA condition. Our data suggested that a circular RNA, i.e., hsa-PHACTR4_0009, is significantly increased in the plasma of d-TGA neonates and has 85 % sensitivity and 80 % specificity with an AUC value of 0.900 with foetal echocardiography as the gold standard. Interestingly, d-TGA cases had a proportional increase of hsa-PHACTR4_0009 with the severity of the disease, as evident by comparably high levels in patients with intact interventricular and interatrial septa. Transcriptomics analysis further indicated that there is a dysregulation of the focal adhesion assembly genes like vimentin, profilin, gamma-actin and emerin, corroborating with hsa-PHACTR4_0009 expression. Notably, overexpression of hsa-PHACTR4_0009 led to increased cell migration in H9C2 cells, suggesting that defects in cell migration are involved in the development of d-TGA. Collectively, our study suggests hsa-PHACTR4_0009 as a potential biomarker of d-TGA and provides a highly valuable insight into the molecular pathogenesis of d-TGA from an unexplored perspective, enabling a better prognosis for these patients.

Keywords:  Biomarker; Circular RNA; Transposition of great arteries; Whole transcriptomics

DOI:  https://doi.org/10.1016/j.jmccpl.2025.100830
bioRxiv. 2025 Dec 01. pii: 2025.11.26.690869. [Epub ahead of print]

A single Musashi gene allele is sufficient to maintain mouse photoreceptor cells.

Bohye Jeong, Peter Stoilov.

In vertebrates, two genes, Musashi1 (Msi1) and Musashi2 (Msi2) , encode for highly similar Musashi protein paralogs. The Musashi proteins are known to bind to 3'-UTRs and control translation. In photoreceptor cells, the Musashi proteins promote the inclusion of photoreceptor-specific alternative exons by binding to the proximal downstream of their introns. While the Musashi proteins are expressed in various cell types, their role in regulating splicing appears to be confined to photoreceptor cells, where the two proteins have exceptionally high expression levels. To test if the photoreceptor-specific role of MSI1 and MSI2 in splicing is due to their expression levels in photoreceptor cells, we generated combined Msi1 and Msi2 knockouts that progressively reduced the number of Musashi alleles in photoreceptor cells. We analyzed the splicing of photoreceptor-specific exons in the Cc2d2a , Cep290 , Prom1 , and Ttc8 genes and the function of photoreceptor cells in the knockouts. We found that a single allele from either Msi1 or Msi2 is sufficient to maintain photoreceptor function and support high inclusion levels of the photoreceptor-specific exons.

DOI: https://doi.org/10.1101/2025.11.26.690869
Biol Philos. 2026 ;41(1): 3

"Shape is everything: on proteins' functions": Author.

Francesca Bellazzi.

  Proteins are often defined as the molecules that enable life thanks to the special functions they display. But what are proteins' functions? Despite their relevance in various debates, the answer to this question is often left implicit. This paper argues that a correct characterisation of proteins' functions must consider the native structure of the protein, building on Bellazzi's definition of biochemical functions: proteins' functions are dispositions associated to specific chemical and geometrical structural properties relevant for the tertiary and quaternary structure of proteins, and they contribute to specific evolved biological processes. Section 1 introduces the problem of protein's functions. Section 2 unpacks the "structure problem" and the "function problem", where the former inquiries into the function bearer of proteins' function and the second into the relevant account of function. Section 3 presents an answer to the structure problem by arguing that the focus should be on native structure. Section 4 and Sect. 5 focus on the function problem and the account defended. Section 5 also considers two specific case studies, haemoglobin and crystallins, and a critical evaluation of the account. Section 6 concludes.

Keywords:  Biochemical kinds; Proteins; Structure; Unctions

DOI:  https://doi.org/10.1007/s10539-025-10005-5
Curr Opin Immunol. 2025 Dec 16. pii: S0952-7915(25)00186-4. [Epub ahead of print]98 102710

Indole sensing in host, microbiota, and pathogen interactions.

Mehmet Ali Hoskan, Vanessa Sperandio.

Indole is an abundant metabolite in the mammalian gut. Both mammals and microorganisms sense it. Indole is a signal used to communicate and gauge the gut environment. Indole is produced by bacteria that encode the tryptophanase enzyme. However, indole sensing is not limited to the organisms that produce it; mammals, as well as microbes incapable of producing this molecule, have receptors for it. Indole signaling has varying activities, from contributing to intestinal barrier integrity, modifying brain signaling, and preventing aging. In microorganisms, it represses biofilm formation and modulates the virulence of enteric pathogens, among other phenotypes. Although there is a renaissance in indole research, comprehensive knowledge of its signaling pathways is limited. Here, we review indole signaling across species and kingdoms. By understanding the integration of the activity of indole at the host, microbiota, and pathogen interface, one may be able to develop novel dietary and therapeutic approaches.

DOI: https://doi.org/10.1016/j.coi.2025.102710
bioRxiv. 2025 Dec 11. pii: 2025.12.08.693008. [Epub ahead of print]

EVRCEPT: EV RNA Cargo Enrichment Prediction Tool to predict enrichment of RNA into Extracellular Vesicles.

Ahmed Abdelgawad, Jaysheel D Bhavsar, Shawn W Polson, Vijay Parashar, Mona Batish.

Extracellular vesicles (EVs) are small membrane-bound vesicles that are released by most cells. EVs have been shown to transport molecules including proteins and various types of RNAs between cells of even different types. Furthermore, EV RNAs are shown to modulate gene expression in physiological and pathological conditions in recipient cells which can be utilized in therapeutics by engineering cells to enrich RNA of interest in EVs. However, how specific RNA species are enriched in EVs is a long-standing question in the field. Here, we used sequence features of RNAs to predict its enrichment in EVs. These features include length, nucleotide and dinucleotide frequencies, secondary structure information, number of exons, coding probability for non-coding RNAs as well as RNA binding protein (RBP) motifs. The model achieved a performance (AU-ROC: 90%, 77%) for circRNAs and mRNAs, respectively. Here, we present a web tool called, EV RNA Cargo Enrichment Prediction Tool (EVRCEPT), that allows users to predict likelihood of input RNA to be enriched into EVs. This tool will also provide the list of RBPs that are likely to interact with the input RNA and works with both linear and circular RNAs. This webtool, which is freely accessible at https://euler.dbi.udel.edu/evrcept , will help understand extracellular RNA transport and guide the design of therapeutic RNAs to maximize their incorporation in EVs towards targeted personalized medicine.

DOI: https://doi.org/10.64898/2025.12.08.693008
Nat Cell Biol. 2025 Dec 19.

The G3BP stress-granule proteins reinforce the integrated stress response translation programme.

Jarrett Smith, David P Bartel.

When mammalian cells are exposed to stress, they co-ordinate the condensation of stress granules (SGs) through the action of proteins G3BP1 and G3BP2 (G3BPs) and, simultaneously, undergo a massive reduction in translation. Although SGs and G3BPs have been linked to this translation response, their overall impact has been unclear. Here we investigate the question of how, and indeed whether, G3BPs and SGs shape the stress translation response. We find that SGs are enriched for mRNAs that are resistant to the stress-induced translation shutdown. Although the accurate recruitment of these stress-resistant mRNAs does require the context of stress, a combination of optogenetic tools and spike-normalized ribosome profiling demonstrates that G3BPs and SGs are necessary and sufficient to both help prioritize the translation of their enriched mRNAs and help suppress cytosolic translation. Together, these results support a model in which G3BPs and SGs reinforce the stress translation programme by prioritizing the translation of their resident mRNAs.

DOI: https://doi.org/10.1038/s41556-025-01834-3
bioRxiv. 2025 Nov 24. pii: 2025.11.24.690127. [Epub ahead of print]

Histones and nucleoid-associated proteins in Methanosarcina acetivorans mediate recovery from stress and stasis.

Alienor S Baskevitch, Dipti D Nayak.

Many archaea encode both histones and N ucleoid- A ssociated P roteins (NAPs), which we refer to collectively as archaeal D NA B inding P roteins (DBPs). Whether these DBPs jointly work to compact the genome or have distinct functions remains unknown. Here, we have developed the methanogen, Methanosarcina acetivorans, as a platform to study the function of archaeal DBPs in vivo. M. acetivorans encodes one archaeal histone, hmaA, and two copies of the archaea-specific NAP, mc1 ( mc1a & mc1b). We found that each DBP is individually dispensable, but at least one copy of mc1 appears to be required for growth. The growth of the single and double DBP deletion mutants was, by and large, like the parent strain under optimal growth conditions. However, after exposure to stresses or extended periods of incubation in stationary phase, the DBP deletion strains often recovered growth much faster than the parent strain. Conversely, over-expression of DBPs led to a delay in growth recovery that could be abrogated by introducing point mutations in DNA-binding residues. Together, our data suggest that histone and archaea-specific NAPs have partially overlapping roles in M. acetivorans and likely protect the genome after exposure to stress or during prolonged periods of growth stasis. Our findings emphasize that there is no unified function for histones across the tree of life and instead imply that archaeal histones join the ranks of other archaeal NAPs in having strain-specific functions.
Importance: Though it is known that many archaea encode histones in tandem with archaea-specific N ucleoid- A ssociated P roteins (NAPs), the interplay between these two classes of D NA- B inding P roteins (DBPs) in vivo is not known. Most studies on archaeal DBPs have focused either on archaea known to form histone-based chromatin, or on strains which lack histones and compact their genomes exclusively with archaea-specific NAPs. Our study, therefore, fills an important gap in the literature by characterizing DBPs in a model methanogen, Methanosarcina acetivorans , which encodes both histones and archaea-specific NAPs. While no DBP is essential, at least one copy of MC1 appears to be needed, likely for genome compaction. In addition, mutants lacking DBPs had a growth advantage after being subject to stresses or long periods of growth stasis, indicating that DBPs likely function in genome maintenance when growth has stalled or stopped.

DOI: https://doi.org/10.1101/2025.11.24.690127
BMC Genomics. 2025 Dec 17.

Protein-coding genes in humans and model mammals (mouse, rat and pig): gene identifiers and disambiguation of gene nomenclature retrieved from the Ensembl genome browser.

Grzegorz R Juszczak, Chandra S Pareek, Urszula Czarnik, Mariusz Pierzchała.

   BACKGROUND: Gene nomenclature contains current official symbols and various numbers of synonyms, which pose a challenge to integrating genomic data and increase the probability that different genes share the same symbol. Therefore, we retrieved identifiers assigned to all protein-coding genes in human, mouse, rat and pig genomes that are available in the Ensembl genome browser (release 113) to assess the number of genes, compare species and identify ambiguous symbols.
RESULTS: Our analysis revealed that the total number of symbols, both official symbols and synonyms, used to identify protein-coding genes ranges from 16,600 in pigs to 64,580 in mice. Furthermore, the gene nomenclature is not complete because there are also genes without an assigned symbol, which indicates gaps in understanding protein-coding genes, especially in pigs. We also found a large number of gene symbols that map to more than one gene. These symbols might complicate the identification of about 10% of rat and mouse genes and 18% of human protein-coding genes. A simple solution for this problem is the usage of stable gene IDs assigned by scientific institutions and committees (Ensembl, NCBI, RGD, HGNC and VGNC) provided that the genomic information associated with these IDs is retrieved directly from proprietary databases containing the most accurate data. Finally, although gene symbols may pose a problem with unequivocal identification of genes, there are instances when no other identifiers are available in the literature. Therefore, we have developed an R script performing search of the Ensembl database and integrating data to provide a single list of updated symbols with annotation about their ambiguity.
CONCLUSIONS: Gene symbols are not always reliable and should be reported together with stable IDs to enable unequivocal identification of genes. Therefore, data containing only gene symbols should be used cautiously to avoid misidentification of genes. A solution for this problem is our R script REgeness that performs a gene symbol update to current official versions combined with identification of ambiguous symbols and retrieval of other IDs from the Ensembl database.

Keywords:  Ensembl; Gene symbols; HGNC; Human; Mouse; NCBI; Pig; RGD; Rat; VGNC

DOI:  https://doi.org/10.1186/s12864-025-12329-8
Biochem (Lond). 2025 Sep 02. 47(4): 3-7

Reprogramming ribosomes during viral protein synthesis.

Jemma Betts, Chris H Hill, Ian Brierley.

It is estimated that ~1031 viruses exist on planet earth, and all are entirely dependent on host cell ribosomes for viral mRNA translation. Ribosomes, the engines of protein synthesis, can be regarded as the 'compilers' of life-responsible for interpreting the genetic instruction set in a consistent way and creating protein molecules with executive functions, each of which contributes towards the phenotype of the cell. Even subtle changes in how the ribosome normally operates can have dramatic consequences, as illustrated by the lethality of many antibiotics that target the protein synthesis machinery. For viruses, millions of years of evolutionary pressure have led to every possible avenue being explored to optimise the encoding of information within a (typically) small genome. This has led to the emergence of mechanisms to reprogram translation in a variety of ways, collectively termed 'recoding'. For example, elongating ribosomes can be induced to shift reading frame and access overlapping coding sequences or to continue elongating through a stop codon. Here, we review the discovery of these phenomena, explore the role of RNA structures in these processes, and outline mechanistic questions that remain unanswered.

DOI: https://doi.org/10.1042/bio_2025_136
Biol Chem. 2025 Dec 18.

There and back again: a cell biologist's journey from organelles to molecules.

Emma J Fenech, Yury S Bykov.

  Eukaryotic life is defined by the presence of organelles. Organelles, in turn, were classically defined as specialized membrane-bound compartments composed of a unique set of macromolecules which support specific functions. Over the last few decades, a concerted effort into uncovering which components are present in each organelle has shaped our view of cell biology. However, despite some organelles already being visualized over 100 years ago, we are still discovering new organelle residents. Furthermore, our concept of both 'organelles' and 'compartmentalization' has evolved together with our deepening understanding in a number of fields. These include: organelle substructure and organization; the network of contact sites which interconnects all organelles; and membraneless organelles and phase-separated condensates. This review explores how image- and mass spectrometry-based methods can be used to understand the spectrum of where components are localized: from complexes, to subdomains, and whole organelles. The components we mainly focus on are proteins of the mitochondria and secretory pathway organelles.

Keywords:  contact sites; mass spectrometry; microscopy; organelle subdomains; organelles; protein complexes

DOI:  https://doi.org/10.1515/hsz-2025-0185
bioRxiv. 2025 Nov 27. pii: 2025.11.24.690266. [Epub ahead of print]

Ribosomal RNA Synthesis is a Lethal Vulnerability During Reductive Stress In C . elegans.

Jen F Rotti, Fasih Ahsan, Nicole L Stuhr, Sinclair Emans, Alexander Soukas, Armen Yerevanian.

Reductive stress has remained underappreciated as a significant disrupter of redox homeostasis. Recent studies have begun to link the accumulation of NADH and NADPH to the development and progression of metabolic diseases such as cancer, cardiac disease, and diabetes. Further research is needed to understand how cellular responses to reductive stress are governed. In this study we use the nematode Caenorhabditis elegans to examine the phenomenon of catastrophic reductive-death caused by combined biguanide treatment and fasn-1 deficiency. This process of synergistic reductive stress correlates with aberrant alternations in nucleolar morphology. The absence of fasn-1 activity blocks phenformin-mediated reduction in nucleolar size in the hypodermis, potentially resulting in enhanced translation. We find that loss-of-function and RNAi-based knockdown of the catalytic RNA exosome subunit crn-3 significantly increases resistance to toxic reductive stress. Multiple other genes involved in rRNA synthesis recapitulate this phenotype. We postulate that this reversal of reductive death can be attributed to impaired ribosomal RNA biogenesis that promotes tolerance of the accumulation of reducing equivalents NADPH and NADH and preventing the accumulation of GSH. Overall, we identify a novel mechanism by which pathologic states of reductive stress-related diseases can be ameliorated.

DOI: https://doi.org/10.1101/2025.11.24.690266