EMBO Journal最新文献_第9页

Two FAM134B isoforms differentially regulate ER dynamics during myogenesis.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-02-01 Epub Date: 2025-01-06 DOI: 10.1038/s44318-024-00356-2

Viviana Buonomo, Kateryna Lohachova, Alessio Reggio, Sara Cano-Franco, Michele Cillo, Lucia Santorelli, Rossella Venditti, Elena Polishchuk, Ivana Peluso, Lorene Brunello, Carmine Cirillo, Sara Petrosino, Malan Silva, Rossella De Cegli, Sabrina Di Bartolomeo, Cesare Gargioli, Paolo Swuec, Mirko Cortese, Alexandra Stolz, Ramachandra M Bhaskara, Paolo Grumati

{"title":"Two FAM134B isoforms differentially regulate ER dynamics during myogenesis.","authors":"Viviana Buonomo, Kateryna Lohachova, Alessio Reggio, Sara Cano-Franco, Michele Cillo, Lucia Santorelli, Rossella Venditti, Elena Polishchuk, Ivana Peluso, Lorene Brunello, Carmine Cirillo, Sara Petrosino, Malan Silva, Rossella De Cegli, Sabrina Di Bartolomeo, Cesare Gargioli, Paolo Swuec, Mirko Cortese, Alexandra Stolz, Ramachandra M Bhaskara, Paolo Grumati","doi":"10.1038/s44318-024-00356-2","DOIUrl":"10.1038/s44318-024-00356-2","url":null,"abstract":"Endoplasmic reticulum (ER) plasticity and ER-phagy are intertwined processes essential for maintaining ER dynamics. We investigated the interplay between two isoforms of the ER-phagy receptor FAM134B in regulating ER remodeling in differentiating myoblasts. During myogenesis, the canonical FAM134B1 is degraded, while its isoform FAM134B2 is transcriptionally upregulated. The switch, favoring FAM134B2, is an important regulator of ER morphology during myogenesis. FAM134B2 partial reticulon homology domain, with its rigid conformational characteristics, enables efficient ER reshaping. FAM134B2 action increases in the active phase of differentiation leading to ER restructuring via ER-phagy, which then reverts to physiological levels when myotubes are mature and the ER is reorganized. Knocking out both FAM134B isoforms in myotubes results in an aberrant proteome landscape and the formation of dilated ER structures, both of which are rescued by FAM134B2 re-expression. Our results underscore how the fine-tuning of FAM134B isoforms and ER-phagy orchestrate the ER dynamics during myogenesis providing insights into the molecular mechanisms governing ER homeostasis in muscle cells.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":"44 4","pages":"1039-1073"},"PeriodicalIF":9.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442568","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}

引用次数: 0

qTAG: an adaptable plasmid scaffold for CRISPR-based endogenous tagging. qTAG：用于基于crispr的内源性标记的适应性质粒支架。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-02-01 Epub Date: 2024-12-12 DOI: 10.1038/s44318-024-00337-5

Reuben Philip, Amit Sharma, Laura Matellan, Anna C Erpf, Wen-Hsin Hsu, Johnny M Tkach, Haley D M Wyatt, Laurence Pelletier

{"title":"qTAG: an adaptable plasmid scaffold for CRISPR-based endogenous tagging.","authors":"Reuben Philip, Amit Sharma, Laura Matellan, Anna C Erpf, Wen-Hsin Hsu, Johnny M Tkach, Haley D M Wyatt, Laurence Pelletier","doi":"10.1038/s44318-024-00337-5","DOIUrl":"10.1038/s44318-024-00337-5","url":null,"abstract":"Endogenous tagging enables the study of proteins within their native regulatory context, typically using CRISPR to insert tag sequences directly into the gene sequence. Here, we introduce qTAG, a collection of repair cassettes that makes endogenous tagging more accessible. The cassettes support N- and C-terminal tagging with commonly used selectable markers and feature restriction sites for easy modification. Lox sites also enable the removal of the marker gene after successful integration. We demonstrate the utility of qTAG with a range of diverse tags for applications in fluorescence imaging, proximity labeling, epitope tagging, and targeted protein degradation. The system includes novel tags like mStayGold, offering enhanced brightness and photostability for live-cell imaging of native protein dynamics. Additionally, we explore alternative cassette designs for conditional expression tagging, selectable knockout tagging, and safe-harbor expression. The plasmid collection is available through Addgene, featuring ready-to-use constructs for common subcellular markers and tagging cassettes to target genes of interest. The qTAG system will serve as an open resource for researchers to adapt and tailor their own experiments.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"947-974"},"PeriodicalIF":9.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819793","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}

引用次数: 0

Molecular mechanism targeting condensin for chromosome condensation. 以凝集素为染色体凝聚靶标的分子机制

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-02-01 Epub Date: 2024-12-17 DOI: 10.1038/s44318-024-00336-6

Menglu Wang, Daniel Robertson, Juan Zou, Christos Spanos, Juri Rappsilber, Adele L Marston

{"title":"Molecular mechanism targeting condensin for chromosome condensation.","authors":"Menglu Wang, Daniel Robertson, Juan Zou, Christos Spanos, Juri Rappsilber, Adele L Marston","doi":"10.1038/s44318-024-00336-6","DOIUrl":"10.1038/s44318-024-00336-6","url":null,"abstract":"Genomes are organised into DNA loops by the Structural Maintenance of Chromosomes (SMC) proteins. SMCs establish functional chromosomal sub-domains for DNA repair, gene expression and chromosome segregation, but how SMC activity is specifically targeted is unclear. Here, we define the molecular mechanism targeting the condensin SMC complex to specific chromosomal regions in budding yeast. A conserved pocket on the condensin HAWK subunit Ycg1 binds to chromosomal receptors carrying a related motif, CR1. In early mitosis, CR1 motifs in receptors Sgo1 and Lrs4 recruit condensin to pericentromeres and rDNA, to facilitate sister kinetochore biorientation and rDNA condensation, respectively. We additionally find that chromosome arm condensation begins as sister kinetochores come under tension, in a manner dependent on the Ycg1 pocket. We propose that multiple CR1-containing proteins recruit condensin to chromosomes and identify several additional candidates based on their sequence. Overall, we uncover the molecular mechanism that targets condensin to functionalise chromosomal domains to achieve accurate chromosome segregation during mitosis.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"705-735"},"PeriodicalIF":9.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11791182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847853","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}

引用次数: 0

MCTS2 and distinct eIF2D roles in uORF-dependent translation regulation revealed by in vitro re-initiation assays. MCTS2和eIF2D在uorf依赖的翻译调节中的独特作用通过体外再启动试验揭示。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-02-01 Epub Date: 2025-01-02 DOI: 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":"10.1038/s44318-024-00347-3","url":null,"abstract":"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.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"854-876"},"PeriodicalIF":9.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790910/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

FOXP1 phosphorylation antagonizes its O-GlcNAcylation in regulating ATR activation in response to replication stress. FOXP1磷酸化可拮抗其o - glcn酰化，从而调节ATR在复制胁迫下的激活。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-01-01 Epub Date: 2024-12-02 DOI: 10.1038/s44318-024-00323-x

Xuefei Zhu, Congwen Gao, Bin Peng, Jingwei Xue, Donghui Xia, Liu Yang, Jiexiang Zhang, Xinrui Gao, Yilin Hu, Shixian Lin, Peng Gong, Xingzhi Xu

{"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":"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.","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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729909/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In vivo HIV-1 nuclear condensates safeguard against cGAS and license reverse transcription. 体内HIV-1核凝析物对cGAS有保护作用并允许逆转录。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-01-01 Epub Date: 2024-12-02 DOI: 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":"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.","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}

引用次数: 0

Towards routine proteome profiling of FFPE tissue: insights from a 1,220-case pan-cancer study. 实现 FFPE 组织的常规蛋白质组分析：一项 1220 例泛癌症研究的启示。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-01-01 Epub Date: 2024-11-18 DOI: 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":"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.","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}

引用次数: 0

SNARE mimicry by the CD225 domain of IFITM3 enables regulation of homotypic late endosome fusion. IFITM3的CD225结构域的SNARE模仿能够调节同型晚期核内体融合。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-01-01 Epub Date: 2024-12-09 DOI: 10.1038/s44318-024-00334-8

Kazi Rahman, Isaiah Wilt, Abigail A Jolley, Bhabadeb Chowdhury, Siddhartha A K Datta, Alex A Compton

{"title":"SNARE mimicry by the CD225 domain of IFITM3 enables regulation of homotypic late endosome fusion.","authors":"Kazi Rahman, Isaiah Wilt, Abigail A Jolley, Bhabadeb Chowdhury, Siddhartha A K Datta, Alex A Compton","doi":"10.1038/s44318-024-00334-8","DOIUrl":"10.1038/s44318-024-00334-8","url":null,"abstract":"The CD225/Dispanin superfamily contains membrane proteins that regulate vesicular transport and membrane fusion events required for neurotransmission, glucose transport, and antiviral immunity. However, how the CD225 domain controls membrane trafficking has remained unknown. Here we show that the CD225 domain contains a SNARE-like motif that enables interaction with cellular SNARE fusogens. Proline-rich transmembrane protein 2 (PRRT2) encodes a SNARE-like motif that enables interaction with neuronal SNARE proteins; mutations in this region disrupt SNARE binding and are linked to neurological disease. Another CD225 member, interferon-induced transmembrane protein 3 (IFITM3), protects cells against influenza A virus infection. IFITM3 interacts with SNARE proteins that mediate late endosome-late endosome (homotypic) fusion and late endosome-lysosome (heterotypic) fusion. IFITM3 binds to syntaxin 7 (STX7) in cells and in vitro, and mutations that abrogate STX7 binding cause loss of antiviral activity against influenza A virus. Mechanistically, IFITM3 disrupts assembly of the SNARE complex controlling homotypic fusion and accelerates the trafficking of endosomal cargo to lysosomes. Our results suggest that SNARE modulation plays a previously unrecognized role in the diverse functions performed by CD225 proteins.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"534-562"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730294/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142803274","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}

引用次数: 0

An EpCAM/Trop2 mechanostat differentially regulates collective behaviour of human carcinoma cells. EpCAM/Trop2机械调节器可对人类癌细胞的集体行为进行不同程度的调节。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-01-01 Epub Date: 2024-11-21 DOI: 10.1038/s44318-024-00309-9

Azam Aslemarz, Marie Fagotto-Kaufmann, Artur Ruppel, Christine Fagotto-Kaufmann, Martial Balland, Paul Lasko, François Fagotto

{"title":"An EpCAM/Trop2 mechanostat differentially regulates collective behaviour of human carcinoma cells.","authors":"Azam Aslemarz, Marie Fagotto-Kaufmann, Artur Ruppel, Christine Fagotto-Kaufmann, Martial Balland, Paul Lasko, François Fagotto","doi":"10.1038/s44318-024-00309-9","DOIUrl":"10.1038/s44318-024-00309-9","url":null,"abstract":"EpCAM and its close relative Trop2 are well-known cell surface markers of carcinoma, but their potential role in cancer metastasis remains unclear. They are known, however, to downregulate myosin-dependent contractility, a key parameter involved in adhesion and migration. We investigate here the morphogenetic impact of the high EpCAM and Trop2 levels typically found in epithelial breast cancer cells, using spheroids of MCF7 cells as an in vitro model. Intriguingly, EpCAM depletion stimulated spheroid cohesive spreading, while Trop2 depletion had the opposite effect. Combining cell biological and biophysical approaches, we demonstrate that while EpCAM and Trop2 both contribute to moderate cell contractility, their depletions differentially impact on the process of \"wetting\" a substrate, here both matrix and neighboring cells, by affecting the balance of cortical tension at cell and tissue interfaces. These distinct phenotypes can be explained by partial enrichment at specific interfaces. Our data are consistent with the EpCAM-Trop2 pair acting as a mechanostat that tunes adhesive and migratory behaviours.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"75-106"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689445","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}

引用次数: 0

How J-chain ensures the assembly of immunoglobulin IgM pentamers. j链如何保证免疫球蛋白IgM五聚体的组装。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-01-01 Epub Date: 2024-12-04 DOI: 10.1038/s44318-024-00317-9

Chiara Giannone, Xenia Mess, Ruiming He, Maria Rita Chelazzi, Annika Mayer, Anush Bakunts, Tuan Nguyen, Yevheniia Bushman, Andrea Orsi, Benedikt Gansen, Massimo Degano, Johannes Buchner, Roberto Sitia

{"title":"How J-chain ensures the assembly of immunoglobulin IgM pentamers.","authors":"Chiara Giannone, Xenia Mess, Ruiming He, Maria Rita Chelazzi, Annika Mayer, Anush Bakunts, Tuan Nguyen, Yevheniia Bushman, Andrea Orsi, Benedikt Gansen, Massimo Degano, Johannes Buchner, Roberto Sitia","doi":"10.1038/s44318-024-00317-9","DOIUrl":"10.1038/s44318-024-00317-9","url":null,"abstract":"Polymeric IgM immunoglobulins have high avidity for antigen and complement, and dominate primary antibody responses. They are produced either as assemblies of six µ2L2 subunits (i.e., hexamers), or as pentamers of two µ2L2 subunits and an additional protein termed J-chain (JC), which allows transcytosis across epithelia. The molecular mechanism of IgM assembly with the desired stoichiometry remained unknown. Here, we show in vitro and in cellula that JC outcompetes the sixth IgM subunit during assembly. Before insertion into IgM, JC exists as an ensemble of largely unstructured, protease-sensitive species with heterogeneous, non-native disulfide bonds. The J-chain interacts with the hydrophobic β-sheets selectively exposed by nascent pentamers. Completion of an amyloid-like core triggers JC folding and drives disulfide rearrangements that covalently stabilize JC-containing pentamers. In cells, the quality control factor ERp44 surveys IgM assembly and prevents the secretion of aberrant conformers. This mechanism allows the efficient production of high-avidity IgM for systemic or mucosal immunity.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"505-533"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781753","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}

引用次数: 0