{"title":"A phosphorylation-regulated NPF transporter determines salt tolerance by mediating chloride uptake in soybean plants.","authors":"Yunzhen Wu, Jingya Yuan, Like Shen, Qinxue Li, Zhuomeng Li, Hongwei Cao, Lin Zhu, Dan Liu, Yalu Sun, Qianru Jia, Huatao Chen, Wubin Wang, Jörg Kudla, Wenhua Zhang, Junyi Gai, Qun Zhang","doi":"10.1038/s44318-024-00357-1","DOIUrl":"https://doi.org/10.1038/s44318-024-00357-1","url":null,"abstract":"<p><p>Chloride (Cl<sup>-</sup>) ions cause major damage to crops in saline soils. Understanding the key factors that influence Cl<sup>-</sup> uptake and translocation will aid the breeding of more salt-tolerant crops. Here, using genome-wide association study and transcriptomic analysis, we identified a NITRATE TRANSPORTER 1 (NRT1)/PEPTIDE TRANSPORTER family (NPF) protein, GmNPF7.5, as the dominant gene locus influencing Cl<sup>-</sup> homeostasis in soybean (Glycine max). A natural SNP variation resulted in two haplotypes (GmNPF7.5<sup>HapA</sup> and GmNPF7.5<sup>HapB</sup>), which was associated with Cl<sup>-</sup> content. GmNPF7.5<sup>HapA</sup> mediated Cl<sup>-</sup> or nitrate (NO<sub>3</sub><sup>-</sup>) uptake in a pH-dependent manner and exhibited higher permeability for Cl<sup>-</sup> over NO<sub>3</sub><sup>-</sup>. The suppression of GmNPF7.5<sup>HapA</sup> expression decreased Cl<sup>-</sup> accumulation and salt damage in plants, whereas its overexpression showed the opposite effects. The elite haplotype GmNPF7.5<sup>HapB</sup> diminished Cl<sup>-</sup> transport activity independently from NO<sub>3</sub><sup>-</sup> permeability, thus enhancing soybean salt tolerance. Furthermore, the protein kinase GmPI4Kγ4 could phosphorylate GmNPF7.5, which repressed Cl<sup>-</sup> uptake without affecting NO<sub>3</sub><sup>-</sup> permeability. Our findings define a regulatory mechanism for Cl<sup>-</sup> control under NaCl stress, providing a strategy for the improvement of salt tolerance in soybean plants.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO JournalPub Date : 2025-01-03DOI: 10.1038/s44318-024-00355-3
Pawel K Lysyganicz, Antonio D Barbosa, Shoily Khondker, Nicolas A Stewart, George M Carman, Phillip J Stansfeld, Marcus K Dymond, Symeon Siniossoglou
{"title":"Partitioning of fatty acids between membrane and storage lipids controls ER membrane expansion.","authors":"Pawel K Lysyganicz, Antonio D Barbosa, Shoily Khondker, Nicolas A Stewart, George M Carman, Phillip J Stansfeld, Marcus K Dymond, Symeon Siniossoglou","doi":"10.1038/s44318-024-00355-3","DOIUrl":"10.1038/s44318-024-00355-3","url":null,"abstract":"<p><p>Biogenesis of membrane-bound organelles involves the synthesis, remodeling, and degradation of their constituent phospholipids. How these pathways regulate organelle size remains poorly understood. Here we demonstrate that a lipid-degradation pathway inhibits expansion of the endoplasmic reticulum (ER) membrane. Phospholipid diacylglycerol acyltransferases (PDATs) use endogenous phospholipids as fatty-acyl donors to generate triglyceride stored in lipid droplets. The significance of this non-canonical triglyceride biosynthesis pathway has remained elusive. We find that the activity of the yeast PDAT Lro1 is regulated by a membrane-proximal helical segment facing the luminal side of the ER bilayer. To reveal the biological roles of PDATs, we engineered an Lro1 variant with derepressed activity. We show that active Lro1 mediates retraction of ER membrane expansion driven by phospholipid synthesis. Furthermore, subcellular distribution and membrane turnover activity of Lro1 are controlled by diacylglycerol produced by the activity of Pah1, a conserved member of the lipin family. Collectively, our findings reveal a lipid-metabolic network that regulates endoplasmic reticulum biogenesis by converting phospholipids into storage lipids.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO JournalPub Date : 2025-01-03DOI: 10.1038/s44318-024-00335-7
Sabita Chourasia, Christopher Petucci, Clarissa Shoffler, Dina Abbasian, Hu Wang, Xianlin Han, Ehud Sivan, Alexander Brandis, Tevie Mehlman, Sergey Malitsky, Maxim Itkin, Ayala Sharp, Ron Rotkopf, Bareket Dassa, Limor Regev, Yehudit Zaltsman, Atan Gross
{"title":"MTCH2 controls energy demand and expenditure to fuel anabolism during adipogenesis.","authors":"Sabita Chourasia, Christopher Petucci, Clarissa Shoffler, Dina Abbasian, Hu Wang, Xianlin Han, Ehud Sivan, Alexander Brandis, Tevie Mehlman, Sergey Malitsky, Maxim Itkin, Ayala Sharp, Ron Rotkopf, Bareket Dassa, Limor Regev, Yehudit Zaltsman, Atan Gross","doi":"10.1038/s44318-024-00335-7","DOIUrl":"https://doi.org/10.1038/s44318-024-00335-7","url":null,"abstract":"<p><p>Mitochondrial carrier homolog 2 (MTCH2) is a regulator of apoptosis, mitochondrial dynamics, and metabolism. Loss of MTCH2 results in mitochondrial fragmentation, an increase in whole-body energy utilization, and protection against diet-induced obesity. In this study, we used temporal metabolomics on HeLa cells to show that MTCH2 deletion results in a high ATP demand, an oxidized cellular environment, and elevated utilization of lipids, amino acids, and carbohydrates, accompanied by a decrease in several metabolites. Lipidomics analysis revealed a strategic adaptive reduction in membrane lipids and an increase in storage lipids in MTCH2 knockout cells. Importantly, MTCH2 knockout cells showed an increase in mitochondrial oxidative function, which may explain the higher energy demand. Interestingly, this imbalance in energy metabolism and reductive potential triggered by MTCH2-deletion prevents NIH3T3L1 preadipocytes from differentiating into mature adipocytes, an energy consuming reductive biosynthetic process. In summary, the loss of MTCH2 leads to increased mitochondrial oxidative activity and energy demand, creating a catabolic and oxidative environment that fails to fuel the anabolic processes required for lipid accumulation and adipocyte differentiation.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO JournalPub Date : 2025-01-03DOI: 10.1038/s44318-024-00319-7
Hala Estephan, Arun Tailor, Robert Parker, McKenzie Kreamer, Ioanna Papandreou, Leticia Campo, Alistair Easton, Eui Jung Moon, Nicholas C Denko, Nicola Ternette, Ester M Hammond, Amato J Giaccia
{"title":"Hypoxia promotes tumor immune evasion by suppressing MHC-I expression and antigen presentation.","authors":"Hala Estephan, Arun Tailor, Robert Parker, McKenzie Kreamer, Ioanna Papandreou, Leticia Campo, Alistair Easton, Eui Jung Moon, Nicholas C Denko, Nicola Ternette, Ester M Hammond, Amato J Giaccia","doi":"10.1038/s44318-024-00319-7","DOIUrl":"https://doi.org/10.1038/s44318-024-00319-7","url":null,"abstract":"<p><p>Hypoxia is a common feature of solid tumors that has previously been linked to resistance to radiotherapy and chemotherapy, and more recently to immunotherapy. In particular, hypoxic tumors exclude T cells and inhibit their activity, suggesting that tumor cells acquire a mechanism to evade T-cell recognition and killing. Our analysis of hypoxic tumors indicates that hypoxia downregulates the expression of MHC class I and its bound peptides (i.e., the immunopeptidome). Hypoxia decreases MHC-I expression in an oxygen-dependent manner, via activation of autophagy through the PERK arm of the unfolded protein response. Using an immunopeptidomics-based LC-MS approach, we find a significant reduction of presented antigens under hypoxia. Inhibition of autophagy under hypoxia enhances antigen presentation. In experimental tumors, reducing mitochondrial metabolism through a respiratory complex-I inhibitor increases tumor oxygenation, as well as MHC-I levels and the immunopeptidome. These data explain the molecular basis of tumor immune evasion in hypoxic conditions, and have implications for future therapeutic interventions targeting hypoxia-induced alterations in antigen presentation.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO JournalPub Date : 2025-01-02DOI: 10.1038/s44318-024-00348-2
Wen Tang, Lorenzo Costantino, Roman Stocsits, Gordana Wutz, Rene Ladurner, Otto Hudecz, Karl Mechtler, Jan-Michael Peters
{"title":"Cohesin positions the epigenetic reader Phf2 within the genome.","authors":"Wen Tang, Lorenzo Costantino, Roman Stocsits, Gordana Wutz, Rene Ladurner, Otto Hudecz, Karl Mechtler, Jan-Michael Peters","doi":"10.1038/s44318-024-00348-2","DOIUrl":"https://doi.org/10.1038/s44318-024-00348-2","url":null,"abstract":"<p><p>Genomic DNA is assembled into chromatin by histones, and extruded into loops by cohesin. These mechanisms control important genomic functions, but whether histones and cohesin cooperate in genome regulation is poorly understood. Here we identify Phf2, a member of the Jumonji-C family of histone demethylases, as a cohesin-interacting protein. Phf2 binds to H3K4me3 nucleosomes at active transcription start sites (TSSs), but also co-localizes with cohesin. Cohesin depletion reduces Phf2 binding at sites lacking H3K4me3, and depletion of Wapl and CTCF re-positions Phf2 together with cohesin in the genome, resulting in the accumulation of both proteins in chromosomal regions called vermicelli and cohesin islands. Conversely, Phf2 depletion reduces cohesin binding at TSSs lacking CTCF and decreases the number of short cohesin loops, while increasing the length of heterochromatic B compartments. These results suggest that Phf2 is an 'epigenetic reader', which is translocated through the genome by cohesin-mediated DNA loop extrusion, and which recruits cohesin to active TSSs and limits the size of B compartments. These findings reveal an unexpected degree of cooperativity between epigenetic and architectural mechanisms of eukaryotic genome regulation.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142923905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO JournalPub Date : 2025-01-02DOI: 10.1038/s44318-024-00344-6
Caroline Dalgliesh, Saad Aldalaqan, Christian Atallah, Andrew Best, Emma Scott, Ingrid Ehrmann, George Merces, Joel Mannion, Barbora Badurova, Raveen Sandher, Ylva Illing, Brunhilde Wirth, Sara Wells, Gemma Codner, Lydia Teboul, Graham R Smith, Ann Hedley, Mary Herbert, Dirk G de Rooij, Colin Miles, Louise N Reynard, David J Elliott
{"title":"An ultra-conserved poison exon in the Tra2b gene encoding a splicing activator is essential for male fertility and meiotic cell division.","authors":"Caroline Dalgliesh, Saad Aldalaqan, Christian Atallah, Andrew Best, Emma Scott, Ingrid Ehrmann, George Merces, Joel Mannion, Barbora Badurova, Raveen Sandher, Ylva Illing, Brunhilde Wirth, Sara Wells, Gemma Codner, Lydia Teboul, Graham R Smith, Ann Hedley, Mary Herbert, Dirk G de Rooij, Colin Miles, Louise N Reynard, David J Elliott","doi":"10.1038/s44318-024-00344-6","DOIUrl":"https://doi.org/10.1038/s44318-024-00344-6","url":null,"abstract":"<p><p>The cellular concentrations of splicing factors (SFs) are critical for controlling alternative splicing. Most serine and arginine-enriched (SR) protein SFs regulate their own concentration via a homeostatic feedback mechanism that involves regulation of inclusion of non-coding 'poison exons' (PEs) that target transcripts for nonsense-mediated decay. The importance of SR protein PE splicing during animal development is largely unknown despite PE ultra-conservation across animal genomes. To address this, we used mouse genetics to disrupt an ultra-conserved PE in the Tra2b gene encoding the SR protein Tra2β. Focussing on germ cell development, we found that Tra2b PE deletion causes azoospermia due to catastrophic cell death during meiotic prophase. Failure to proceed through meiosis was associated with increased Tra2b expression sufficient to drive aberrant Tra2β protein hyper-responsive splice patterns. Although critical for meiotic prophase, Tra2b PE deletion spared earlier mitotically active germ cells, even though these still required Tra2b gene function. Our data indicate that PE splicing control prevents the accumulation of toxic levels of Tra2β protein that are incompatible with meiotic prophase. This unexpected connection with male fertility helps explain Tra2b PE ultra-conservation and indicates the importance of evaluating PE function in animal models.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142923904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO JournalPub Date : 2025-01-02DOI: 10.1038/s44318-024-00347-3
Romane Meurs, Mara De Matos, Adrian Bothe, Nicolas Guex, Tobias Weber, Aurelio A Teleman, Nenad Ban, David Gatfield
{"title":"MCTS2 and distinct eIF2D roles in uORF-dependent translation regulation revealed by in vitro re-initiation assays.","authors":"Romane Meurs, Mara De Matos, Adrian Bothe, Nicolas Guex, Tobias Weber, Aurelio A Teleman, Nenad Ban, David Gatfield","doi":"10.1038/s44318-024-00347-3","DOIUrl":"https://doi.org/10.1038/s44318-024-00347-3","url":null,"abstract":"<p><p>Ribosomes scanning from the mRNA 5' cap to the start codon may initiate at upstream open reading frames (uORFs), decreasing protein biosynthesis. Termination at a uORF can lead to re-initiation, where 40S subunits resume scanning and initiate another translation event downstream. The noncanonical translation factors MCTS1-DENR participate in re-initiation at specific uORFs, but knowledge of other trans-acting factors or uORF features influencing re-initiation is limited. Here, we establish a cell-free re-initiation assay using HeLa lysates to address this question. Comparing in vivo and in vitro re-initiation on uORF-containing reporters, we validate MCTS1-DENR-dependent re-initiation in vitro. Using this system and ribosome profiling in cells, we found that knockdown of the MCTS1-DENR homolog eIF2D causes widespread gene deregulation unrelated to uORF translation, and thus distinct to MCTS1-DENR-dependent re-initiation regulation. Additionally, we identified MCTS2, encoded by an Mcts1 retrogene, as a DENR partner promoting re-initiation in vitro, providing a plausible explanation for clinical differences associated with DENR vs. MCTS1 mutations in humans.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142923906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"FOXP1 phosphorylation antagonizes its O-GlcNAcylation in regulating ATR activation in response to replication stress.","authors":"Xuefei Zhu, Congwen Gao, Bin Peng, Jingwei Xue, Donghui Xia, Liu Yang, Jiexiang Zhang, Xinrui Gao, Yilin Hu, Shixian Lin, Peng Gong, Xingzhi Xu","doi":"10.1038/s44318-024-00323-x","DOIUrl":"10.1038/s44318-024-00323-x","url":null,"abstract":"<p><p>ATR signaling is essential in sensing and responding to the replication stress; as such, any defects can impair cellular function and survival. ATR itself is activated via tightly regulated mechanisms. Here, we identify FOXP1, a forkhead-box-containing transcription factor, as a regulator coordinating ATR activation. We show that, unlike its role as a transcription factor, FOXP1 functions as a scaffold and directly binds to RPA-ssDNA and ATR-ATRIP complexes, facilitating the recruitment and activation of ATR. This process is regulated by FOXP1 O-GlcNAcylation, which represses its interaction with ATR, while CHK1-mediated phosphorylation of FOXP1 inhibits its O-GlcNAcylation upon replication stress. Supporting the physiological relevance of this loop, we find pathogenic FOXP1 mutants identified in various tumor tissues with compromised ATR activation and stalled replication fork stability. We thus conclude that FOXP1 may serve as a potential chemotherapeutic target in related tumors.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"457-483"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO JournalPub Date : 2025-01-01Epub Date: 2024-11-18DOI: 10.1038/s44318-024-00289-w
Johanna Tüshaus, Stephan Eckert, Marius Schliemann, Yuxiang Zhou, Pauline Pfeiffer, Christiane Halves, Federico Fusco, Johannes Weigel, Lisa Hönikl, Vicki Butenschön, Rumyana Todorova, Hilka Rauert-Wunderlich, Matthew The, Andreas Rosenwald, Volker Heinemann, Julian Holch, Katja Steiger, Claire Delbridge, Bernhard Meyer, Wilko Weichert, Carolin Mogler, Peer-Hendrik Kuhn, Bernhard Kuster
{"title":"Towards routine proteome profiling of FFPE tissue: insights from a 1,220-case pan-cancer study.","authors":"Johanna Tüshaus, Stephan Eckert, Marius Schliemann, Yuxiang Zhou, Pauline Pfeiffer, Christiane Halves, Federico Fusco, Johannes Weigel, Lisa Hönikl, Vicki Butenschön, Rumyana Todorova, Hilka Rauert-Wunderlich, Matthew The, Andreas Rosenwald, Volker Heinemann, Julian Holch, Katja Steiger, Claire Delbridge, Bernhard Meyer, Wilko Weichert, Carolin Mogler, Peer-Hendrik Kuhn, Bernhard Kuster","doi":"10.1038/s44318-024-00289-w","DOIUrl":"10.1038/s44318-024-00289-w","url":null,"abstract":"<p><p>Proteome profiling of formalin-fixed paraffin-embedded (FFPE) specimens has gained traction for the analysis of cancer tissue for the discovery of molecular biomarkers. However, reports so far focused on single cancer entities, comprised relatively few cases and did not assess the long-term performance of experimental workflows. In this study, we analyze 1220 tumors from six cancer entities processed over the course of three years. Key findings include the need for a new normalization method ensuring equal and reproducible sample loading for LC-MS/MS analysis across cohorts, showing that tumors can, on average, be profiled to a depth of >4000 proteins and discovering that current software fails to process such large ion mobility-based online fractionated datasets. We report the first comprehensive pan-cancer proteome expression resource for FFPE material comprising 11,000 proteins which is of immediate utility to the scientific community, and can be explored via a web resource. It enables a range of analyses including quantitative comparisons of proteins between patients and cohorts, the discovery of protein fingerprints representing the tissue of origin or proteins enriched in certain cancer entities.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"304-329"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO JournalPub Date : 2025-01-01Epub Date: 2024-12-02DOI: 10.1038/s44318-024-00316-w
Selen Ay, Julien Burlaud-Gaillard, Anastasia Gazi, Yevgeniy Tatirovsky, Celine Cuche, Jean-Sebastien Diana, Viviana Scoca, James P Di Santo, Philippe Roingeard, Fabrizio Mammano, Francesca Di Nunzio
{"title":"In vivo HIV-1 nuclear condensates safeguard against cGAS and license reverse transcription.","authors":"Selen Ay, Julien Burlaud-Gaillard, Anastasia Gazi, Yevgeniy Tatirovsky, Celine Cuche, Jean-Sebastien Diana, Viviana Scoca, James P Di Santo, Philippe Roingeard, Fabrizio Mammano, Francesca Di Nunzio","doi":"10.1038/s44318-024-00316-w","DOIUrl":"10.1038/s44318-024-00316-w","url":null,"abstract":"<p><p>Entry of viral capsids into the nucleus induces the formation of biomolecular condensates called HIV-1 membraneless organelles (HIV-1-MLOs). Several questions remain about their persistence, in vivo formation, composition, and function. Our study reveals that HIV-1-MLOs persisted for several weeks in infected cells, and their abundance correlated with viral infectivity. Using an appropriate animal model, we show that HIV-1-MLOs were formed in vivo during acute infection. To explore the viral structures present within these biomolecular condensates, we used a combination of double immunogold labeling, electron microscopy and tomography, and unveiled a diverse array of viral core structures. Our functional analyses showed that HIV-1-MLOs remained stable during treatment with a reverse transcriptase inhibitor, maintaining the virus in a dormant state. Drug withdrawal restored reverse transcription, promoting efficient virus replication akin to that observed in latently infected patients on antiretroviral therapy. However, when HIV-1 MLOs were deliberately disassembled by pharmacological treatment, we observed a complete loss of viral infectivity. Our findings show that HIV-1 MLOs shield the final reverse transcription product from host immune detection.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"166-199"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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