bims-spribo 2026-09-27 papers

bims-spribo

Biomed News

on Specialized ribosomes

Issue of 2026–09–27
nine papers selected by
Maxim Bouvet, Università di Torino

A human cell-free translation screen identifies the NT-2 mycotoxin as a ribosomal inhibitor that binds the peptidyl transferase center.
Local translation couples synaptic activity to mitochondrial adaptation in dendrites.
RpS19a depletion alters the hematopoietic translatome to drive tissue overgrowth.
Activity-based profiling of bacterial RNA-modifying enzymes reveals species-specific 5-methyluridine modification in Bacillus subtilis 23S rRNA.
Nucleolar reorganization on stress depends on physicochemical changes due to reduced nascent rRNA synthesis.
Single-cell visual proteomics of a minimal bacterium reveals structural coordination of gene expression machineries.
Lsp2 links mTORC1 to TOP mRNA translation and lifespan in Drosophila.
In-cell structures visualize human pre-ribosome assembly in the nucleolus.
Macrophage Differentiation Selectively Downregulates RPS15A While Preserving RPL13A and RPL17 Expression in THP-1-Derived Macrophages.

Commun Biol. 2026 Sep 23. pii: 1237. [Epub ahead of print]9(1):

A human cell-free translation screen identifies the NT-2 mycotoxin as a ribosomal inhibitor that binds the peptidyl transferase center.

Nino Schwaller, Dominic Andenmatten, Jonas Luginbühl, Julius Rabl, Helena Baur, Marc Chambon, Jonathan Vesin, Gerardo Turcatti, Evangelos D Karousis.

Translation inhibitors are invaluable for probing ribosome function and therapeutic applications, but systematic discovery in human systems is limited by the lack of scalable, screening-compatible cell-free platforms. Here, we establish a robust high-throughput screening using human lysates that bypasses cellular cytotoxic effects. After screening ~28,000 small molecules, we identified known and a novel translation inhibitor, including NT-2, a trichothecene mycotoxin produced by the pathogenic Fusarium sporotrichioides. NT-2 suppressed protein synthesis in human cells and yeast lysates, while sparing translation in bacteria and intact yeast cells. Cryo-EM at 1.76 Å revealed NT-2 bound at the peptidyl transferase center of the human 60S ribosome. In addition, cryoEM classification of NT-2 treated cells shows ribosomes in an inactive eEF2/SERBP1-bound dormant state. Together, these results expose NT-2 as a previously unrecognized environmental inhibitor of mammalian protein synthesis and demonstrate the power of cell-free translation screening to reveal new inhibitors with unexpected ribosome fates.

DOI: https://doi.org/10.1038/s42003-026-10743-6
bioRxiv. 2026 Sep 20. pii: 2026.09.17.752159. [Epub ahead of print]

Local translation couples synaptic activity to mitochondrial adaptation in dendrites.

Madison T Jones, Natalie Noble, Robert B Darnell, Ezgi Hacisuleyman.

Neurons rely on localized protein synthesis to rapidly adapt synaptic function to activity, yet how dendritic translation regulates mitochondrial remodeling during synaptic plasticity remains poorly understood. Here, we show that neuronal activity engages a spatially restricted translational program that couples local protein synthesis to mitochondrial function through the non-canonical translation initiation factor eIF4G2. Using proximity labeling to profile the dendritic RNA interactome, translatome, and proteome, we identify a cohort of nuclear-encoded mitochondrial mRNAs that are selectively recruited for translation following depolarization and mGluR activation. This program drives activity-dependent increases in mitochondrial membrane potential, mitochondrial abundance, and oxygen consumption. Loss of eIF4G2 abolishes these responses, whereas dendrite-specific, but not soma-restricted, rescue restores mitochondrial remodeling, demonstrating that eIF4G2 functions locally at postsynaptic sites. Mechanistically, eIF4G2 binds the 5 prime or minute untranslated regions of activity-responsive mitochondrial transcripts and promotes translation of both upstream open reading frames (uORFs) and downstream coding sequences. Using a dendritically targeted split-GFP reporter, we further show that neuronal activity induces local uORF translation to generate previously unannotated micropeptides. Together, our findings identify eIF4G2-dependent local translation as a mechanism that establishes mitochondrial competence during synaptic activity by coordinating the production of mitochondrial proteins and uORF-encoded micropeptides.

DOI: https://doi.org/10.64898/2026.09.17.752159
iScience. 2026 Oct 16. 29(10): 117515

RpS19a depletion alters the hematopoietic translatome to drive tissue overgrowth.

Naomi C Mitchell, Arjun Chahal, Tanya Javaid, Katrina Woodward, Ralf B Schittenhelm, Cheng Huang, Julie Lorent, Jiwon Lee, Melanie Rug, Amee J George, Ross D Hannan, Ola Larsson, Anthony W Purcell, Eduardo Eyras, Nikolay Shirokikh, Teresa T Bonello, Leonie M Quinn, Olga Zaytseva.

  Despite ribosomal protein loss correlating with increased tumor predisposition, direct mechanisms for the counterintuitive oncogenic effect of ribosomal protein depletion have not been reported. We used genetic models to investigate ribosomal protein S19a (RpS19a) depletion in the Drosophila blood organ, the lymph gland. Intriguingly, we demonstrate that RpS19a depletion directly drives excess proliferation and tissue overgrowth. Proteomic and differential translation analysis of RpS19a-depleted cells revealed altered stoichiometry of translation initiation factors and increased association of ribosomes with mRNAs encoding growth-promoting proteins. Furthermore, ribosomes in RpS19a-depleted cells are associated with mRNA encoding dNep1, a putative ribosomal RNA methyltransferase. Although uncharacterized in Drosophila, NEP1 is implicated in ribosomal RNA methylation and ribosome stability in yeast and humans, and its mutations underpin the ribosomopathy Bowen-Conradi syndrome. The RpS19a knockdown phenotype is suppressed by dNep1 co-depletion, altogether suggesting that dNep1 enables assembly of pro-proliferative ribosomes essential for blood lineage overgrowth driven by ribosomal protein loss.

Keywords:  Drosophila; NEP1; RpS19a; blood; growth control; lymph gland; protein translation; ribosomal protein; ribosomopathy

DOI:  https://doi.org/10.1016/j.isci.2026.117515
Proc Natl Acad Sci U S A. 2026 Sep 29. 123(39): e2613881123

Activity-based profiling of bacterial RNA-modifying enzymes reveals species-specific 5-methyluridine modification in Bacillus subtilis 23S rRNA.

Qais Z Jaber, Nathan J Yu, Isao Masuda, Ya-Ming Hou, Ralph E Kleiner.

  RNA modifications play an important role in biological processes. Mapping the diversity of RNA chemistry and studying the biological function of individual modifications remains an outstanding challenge in many organisms. In particular, RNA modifications remain poorly studied across most bacterial systems. Our group previously developed RNA-mediated activity-based protein profiling (RNABPP), a reactivity-based strategy employing metabolic labeling and quantitative proteomics to profile RNA modification writer enzymes in human cells. Here, we adapt this approach to characterize RNA-modifying enzymes in bacteria. We apply metabolic labeling with 5-fluoropyrimidine nucleosides and phase separation-based enrichment of RNA-protein complexes (RNABPP-PS) to profile RNA pyrimidine modifying enzymes in Escherichia coli and Bacillus subtilis. We identify known and putative bacterial pyrimidine C5 methyltransferases, pseudouridine synthases, and dihydrouridine synthases, demonstrating the utility of our approach. Further, we find the carboxymethylaminomethyluridine (cnmn5U)-forming enzyme MnmG (GidA), supporting the existence of a covalent protein-RNA intermediate during the catalytic cycle. Finally, we use RNABPP-PS in B. subtilis to identify YfjO, an uncharacterized protein that is homologous to 5-methyluridine (m5U) methyltransferases. We use nucleoside and oligonucleotide mass spectrometry to establish that YfjO (which we rename as RlmS) installs m5U620 in the 23S rRNA (U576 in E. coli), a modification specific to the B. subtilis ribosome. We characterize ΔyfjO B. subtilis, which exhibits impaired growth and protein translation, concomitant with a defect in 70S ribosome assembly. Taken together, our study establishes a versatile platform for RNA modifying enzyme discovery and characterization in bacteria and illuminates species-specific rRNA modification chemistry in B. subtilis.

Keywords:  RNA modifications; chemical proteomics; ribosome

DOI:  https://doi.org/10.1073/pnas.2613881123
EMBO Rep. 2026 Sep 22.

Nucleolar reorganization on stress depends on physicochemical changes due to reduced nascent rRNA synthesis.

Sinjini Ghosh, Souvik Sen, Aprotim Mazumder.

Successive maturation of ribosomal subunits occurs through multilayered phase-separated structures of the cell nucleolus. The spatio-functional relationship between transcription of rRNA and nucleolar substructures, and how this adapts to cellular stress remain incompletely understood. In this study, we resolve the sub nucleolar structures using expansion microscopy to reveal ordered structures of fibrillar center (FC) and dense fibrillar component (DFC) domains as nested shells, which are reorganized upon cellular stress like DNA damage or RNA polymerase I (RNAPI) inhibition. Direct visualization of nascent (5' ETS) and mature (28S or 18S) rRNA suggests that rRNA synthesis is a critical regulator of nucleolar size and organization. Nucleolar reorganization upon stress emerges to be a direct function of nascent rRNA levels. Stress-induced transcription inhibition can remodel the sub-nucleolar compartments to a low mobility state and perturbs the nucleolar pH gradient due to the missing rRNA scaffold and other factors. We show that rather than signaling to mediate rDNA repair, nucleolar reorganization arises naturally from reduced rRNA levels and the resultant biophysical restructuring of the nucleolus under cellular stress.

DOI: https://doi.org/10.1038/s44319-026-00932-z
Cell. 2026 Sep 25. pii: S0092-8674(26)01065-2. [Epub ahead of print]

Single-cell visual proteomics of a minimal bacterium reveals structural coordination of gene expression machineries.

Joseph M Dobbs, Rasmus K Jensen, Julia Mahamid.

  Translation is a central process in gene expression. Its regulation is complex, depends on factors that include cell state and the subcellular environment, and is subject to modulation via crosstalk to processes such as transcription or translocation. Here, we used cryo-electron tomography of native and antibiotic-perturbed Mycoplasma pneumoniae cells to resolve 140 maps that recapitulate bacterial translation during the initiation, elongation, and recycling phases. We visualized multiple transcription-translation complexes, allowing us to propose a threading-based translation reinitiation mechanism and to provide structural evidence for a long-hypothesized supercomplex that coordinates transcription, translation, and membrane attachment. We resolved abundant membrane-associated large ribosomal subunits and suggest that dissociation from membranes depends on the conditional initiation of new translation, consistent with a potentially conserved mechanism in mammalian cells. This work visualizes the multilayered control of bacterial translation and demonstrates the power of in-cell structural biology to investigate regulatory circuits in gene expression.

Keywords:  Mycoplasma pneumoniae; RNA polymerase; SecDF; cryo-electron tomography; expressome; ribosome; subtomogram analysis; transcription-translation coupling; transertion

DOI:  https://doi.org/10.1016/j.cell.2026.08.054
Nature. 2026 Sep 23.

Lsp2 links mTORC1 to TOP mRNA translation and lifespan in Drosophila.

Jun Wang, Zixin Cai, Jiaojiao Gu, Shiqi Xiong, Jianhan Yi, Meng Yang, Kexin Chang, Xinrui Ning, Yilin Wen, Yan Yan, Jiongming Lu, Yirong Wang, Zongzhao Zhai.

Mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability to orchestrate metabolic processes that are crucial for physiological homeostasis and ageing1. mTORC1 preferentially regulates the translation of 5'-terminal oligopyrimidine (TOP) motif-containing mRNAs (which encode mainly ribosomal proteins) through the 4E-BP translational repressor2; however, this function of mTORC1 is resistant to rapamycin inhibition3. TOP mRNAs are exceptionally abundant, and thus impose a major translational burden on cells, but how their translation is physiologically tuned and linked with lifespan remains unclear. Here we show that Lsp2, which was previously known to be a storage protein4, is also an adipose effector and feedback activator of mTORC1 that modulates lifespan in Drosophila. Expression of Lsp2 is induced by essential amino acids through mTORC1 and is gated by additional signals of nutrient sufficiency. Genetic ablation of Lsp2 robustly extends lifespan without impairing key life history traits such as reproduction. Translatomic profiling shows that loss of Lsp2 selectively reduces global TOP mRNA translation in a 4E-BP-dependent manner, thereby extending lifespan through a mechanism distinct from the effects of rapamycin. Evolutionarily, TOP motifs co-emerged with 4E-BP and are present in nearly all Drosophila ribosomal protein mRNAs. Moreover, we show that the role of TOP motifs in translational control extends to Drosophila. Collectively, our findings reveal a nutrient-induced physiological factor that amplifies mTORC1 output in TOP mRNA translation and regulates organismal longevity.

DOI: https://doi.org/10.1038/s41586-026-11029-x
Science. 2026 Sep 24. eaej0483

In-cell structures visualize human pre-ribosome assembly in the nucleolus.

Xiaohan Zhao, Yuki Hayashi, Herman K H Fung, Sara Cuylen-Haering, Julia Mahamid, Christoph W Müller.

In eukaryotes, ribosome biogenesis initiates within the nucleolus, a hallmark multilayered compartment of the nucleus. Structures of pre-ribosomes have been characterized ex situ, but their assembly pathways within human nucleoli have not been described. Here, we used cryogenic correlative light and electron tomography to visualize molecular landscapes within HeLa cell nucleoli and obtained in-cell structural snapshots of both ribosomal subunit precursors, the SSU processome and the pre-60S. These recapitulate major states resolved previously ex situ and reveal additional critical interaction partners, including the RNA exosome, rixosome, and nuclear export receptor CRM1-RanGTP. We further show how pre-ribosome assembly landscapes are altered upon RNA polymerase I inhibition. Our study combines molecular structures with cellular context to elucidate the spatiotemporal assembly pathway of the human ribosome.

DOI: https://doi.org/10.1126/science.aej0483
J Cardiovasc Dev Dis. 2026 Sep 09. pii: 450. [Epub ahead of print]13(9):

Macrophage Differentiation Selectively Downregulates RPS15A While Preserving RPL13A and RPL17 Expression in THP-1-Derived Macrophages.

Joeline Dreik, Nouha Hamoui, Samer Bazzi, Mira Sabat, Zeina Nasr, Jalil Daher.

  Atherosclerosis is a chronic inflammatory condition that is considered a major contributor to cardiovascular disease (CVD). Atherosclerosis is linked to multiple risk factors, including dyslipidemia, particularly elevated levels of low-density lipoprotein (LDL), which can infiltrate the arterial intima and contribute to disease initiation. Modification of LDL into its oxidized form by myeloperoxidase has been proposed as a physiologically relevant model for LDL oxidation that reflects what happens during the initiation and progression of atherosclerosis. Interestingly, the latter form of oxidized LDL has been shown to induce a myriad of inflammatory reactions within a variety of cells that are involved in atherogenesis. In macrophages (Mφ), accumulation of modified LDL leads to the formation of foam cells which constitute the hallmark of atherosclerosis. Remarkably, Mφs exhibit considerable plasticity and can adopt different phenotypes in response to microenvironmental stimuli. Classically activated M1 macrophages are generally associated with pro-inflammatory responses, whereas alternatively activated M2 macrophages are associated with anti-inflammatory and tissue-repair functions. On the other hand, ribosomal proteins (RPs) have been associated with a range of extra-ribosomal functions that extend beyond their well-recognized role in translation. Notably, multiple RPs, including RPS3, RPL13A, RPS15A and RPL17, have been involved in CVD, playing contrasting roles in the pathogenesis of the disease. In our present study, we investigated, for the first time, the effect of Mφ differentiation, polarization, and Mox-LDL treatment on the expression levels of ribosomal proteins RPS3, RPL13A, RPS15A and RPL17 by using the THP-1 cell model in an effort to reveal potential roles of these ribosomal proteins in Mφ pathobiology. Our study showed that differentiation and polarization significantly downregulate RPS15A expression in THP-1 M0-, M1- and M2-Mφs, whereas differentiation leads to a non-significant trend toward reduced RPS3 expression in M1-Mφs compared with monocytes (p = 0.059), while no significant changes in RPL13A and RPL17 expression have been reported under our experimental conditions. These findings indicate that THP-1 monocyte differentiation and macrophage polarization are associated with selective downregulation of RPS15A, whereas the expression of the other investigated ribosomal proteins is largely preserved. Further studies, particularly in primary human macrophages and using functional approaches, are warranted to validate these findings and determine their biological significance and potential relevance to atherosclerosis.

Keywords:  RPL13A; RPL17; RPS15A; RPS3; THP-1; atherosclerosis; cardiovascular disease; macrophages; ribosomal proteins

DOI:  https://doi.org/10.3390/jcdd13090450