Samuele Metti, Lucie Bracq, Matteo Signor, Nicola Facchinello, Lisa Gambarotto, Leonardo Nogara, Giulia Pigato, Laurence Abrami, Béatrice Kunz, Julien Duc, Patrizia Sabatelli, Aurora De Acutis, Gabriele Maria Fortunato, Giovanni Vozzi, Paola Braghetta, Bert Blaauw, F Gisou van der Goot, Paolo Bonaldo
{"title":"FAPs orchestrate ANTXR2-mediated fine-tuning of collagen VI to ensure skeletal muscle function.","authors":"Samuele Metti, Lucie Bracq, Matteo Signor, Nicola Facchinello, Lisa Gambarotto, Leonardo Nogara, Giulia Pigato, Laurence Abrami, Béatrice Kunz, Julien Duc, Patrizia Sabatelli, Aurora De Acutis, Gabriele Maria Fortunato, Giovanni Vozzi, Paola Braghetta, Bert Blaauw, F Gisou van der Goot, Paolo Bonaldo","doi":"10.1083/jcb.202606056","DOIUrl":"https://doi.org/10.1083/jcb.202606056","url":null,"abstract":"<p><p>Tissue function relies on the ECM, which surrounds cells and provides structural and biochemical support. Maintaining ECM homeostasis requires a tightly regulated balance between deposition and degradation of its components, and disruption of this equilibrium can lead to disease. Here, we examined the role of anthrax toxin receptor 2 (ANTXR2/CMG2), an ECM turnover receptor whose loss-of-function mutations cause hyaline fibromatosis syndrome (HFS), a multisystem connective tissue disorder. We show that ANTXR2 is expressed predominantly by fibro-adipogenic progenitors (FAPs) and mediates internalization of the major ECM component collagen VI (COL6). ANTXR2-null (Antxr2-/-) mice exhibit premature COL6 accumulation within intramuscular connective tissue, leading to tissue stiffening and progressive, maladaptive muscle hypertrophy with impaired locomotion and myopathic features. Using Antxr2-/-::Col6a1-/- double-knockout mice, we demonstrate that these phenotypes are COL6-dependent, highlighting the essential role of ANTXR2-mediated COL6 remodeling in preserving ECM homeostasis and skeletal muscle function and establishing a mechanistic basis for muscle pathology in HFS.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"225 11","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149193941","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}
Thomas D Williams, Christian Klose, Robert Ernst, Pedro Carvalho
{"title":"Lipid remodeling enables adaptation to chronic hyperosmotic stress.","authors":"Thomas D Williams, Christian Klose, Robert Ernst, Pedro Carvalho","doi":"10.1083/jcb.202603154","DOIUrl":"10.1083/jcb.202603154","url":null,"abstract":"<p><p>Lipid droplets (LDs) accumulate in response to diverse cellular stresses. However, their regulation and physiological roles remain poorly understood in most contexts. Here, we show that in budding yeast, chronic hyperosmotic stress induces sustained LD accumulation. Unlike the transient LD response observed during acute osmotic shock, chronic stress triggers prolonged, Dga1-dependent triacylglycerol synthesis. In the absence of triacylglycerol synthesis, cellular fitness is impaired. Lipidomic profiling reveals extensive membrane remodeling during chronic hyperosmotic stress, most notably an increase in phosphatidylcholine (PC) resulting in changes to membrane properties. In LD-deficient cells, the hyperosmotic stress-induced PC increase is blunted, while enhancing PC synthesis improves the fitness of triacylglycerol-deficient cells. Thus, LD accumulation and phospholipid remodeling underlie an adaptive response to chronic hyperosmotic stress.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"225 11","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136822","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}
{"title":"Avl9 defines a family of DENN domain GTPase-activating proteins.","authors":"Ryan C Vignogna, J Christopher Fromme","doi":"10.1083/jcb.202601003","DOIUrl":"10.1083/jcb.202601003","url":null,"abstract":"<p><p>Ras-related GTPases are molecular switches regulating hundreds of signaling and trafficking pathways in cells. Many GTPase regulators remain to be identified despite extensive genetic and biochemical screens. Here we present the results of computational protein-protein interaction screens and functional experiments identifying the DENN domain protein Avl9 as a GTPase-activating protein for Arf1. Avl9 is involved in secretion and cell migration, but its molecular function has not been characterized. We determined that Avl9 possesses robust Arf-GAP activity and is recruited to secretory vesicles by Rab8. We find that Avl9 GAP function is conserved in humans and enhances cell migration. We propose that several other DENN domain proteins are also candidate GAPs, and we demonstrate that one candidate previously characterized as a Rab-GEF, DENND6A, exhibits strong Arf-GAP activity toward ARL8B, explaining its role in lysosome positioning. Collectively, this work uncovers a family of monomeric \"DENN GAP\" proteins that regulate diverse cell biological pathways.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"225 11","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13580876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912055","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}
{"title":"The Ral small GTPase is an essential regulator of exocyst complex function in secretion","authors":"You Wu,David J. Reiner","doi":"10.1083/jcb.202508181","DOIUrl":"https://doi.org/10.1083/jcb.202508181","url":null,"abstract":"Ral GTPases have long been proposed as regulators of the metazoan exocyst, a conserved secretory vesicle-tethering complex, but direct evidence for this role has been scarce. In contrast, the well-studied yeast exocyst relies on multiple Rab GTPases to regulate function, but yeast do not encode Ral. Using Caenorhabditis elegans, we demonstrate that endogenous RAL-1 directly engages the exocyst through conserved binding sites in its subunits. Loss of RAL-1 disrupts dendritic arborization of PVD sensory neurons, impairs vesicle trafficking, and causes broad developmental defects, acting both cell autonomously in neurons and non-autonomously through supporting epithelial cells. Structure-guided genome editing of RAL-1–exocyst interfaces produced synthetic phenotypes, underscoring the physiological importance of these contacts. Taken together, our findings establish RAL-1 as a bona fide regulator of the metazoan exocyst in vivo and suggest that Ral–exocyst interactions operate in parallel with other secretory pathways. More broadly, this work positions C. elegans as a powerful system to dissect Ral–exocyst mechanisms across molecular, cellular, and developmental scales.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"284 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090096","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}
Zhenjie Wang, Yuxuan Qian, Xuan Wang, Qianyu Ng, Hanxi Zhang, Yang Wu, Zhen Liu, Zhe Feng
{"title":"Ana1/Cep295 regulates centriole elongation via Cep135 and microtubules.","authors":"Zhenjie Wang, Yuxuan Qian, Xuan Wang, Qianyu Ng, Hanxi Zhang, Yang Wu, Zhen Liu, Zhe Feng","doi":"10.1083/jcb.202504094","DOIUrl":"10.1083/jcb.202504094","url":null,"abstract":"<p><p>Centrioles are essential for centrosome and cilium formation. In fly spermatocytes, they undergo dramatic elongation to form giant centrioles that support sperm development. The conserved centriole protein Ana1/Cep295 is known to promote this elongation, yet the underlying mechanism remains poorly understood. Here, we show that Ana1 regulates centriole length through two distinct mechanisms. It directly interacts with Cep135 to promote centriole elongation and to recruit Cep135 into the proximal centriole-like structure. Ana1 also binds and bundles microtubules in vitro, and this activity is required for centriole elongation in vivo. Importantly, these two interactions are not mutually exclusive and both contribute to Ana1-induced centriole overelongation. Together, our findings reveal that Ana1 is involved in centriole elongation through interactions with distinct centriolar components during fly spermatogenesis.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"225 10","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13422256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620232","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}
{"title":"Differential contributions of β-tubulin isotypes to acentrosomal oocyte meiosis in C. elegans.","authors":"Emmanuel T Nsamba, Anne M Villeneuve","doi":"10.1083/jcb.202511199","DOIUrl":"10.1083/jcb.202511199","url":null,"abstract":"<p><p>Oocyte meiotic spindles must achieve bipolarity and segregate chromosomes in the absence of centrosomes. Here, we use high-resolution immunofluorescence microscopy and live imaging to investigate the differential contributions of β-tubulin isotypes (TBB-1 and TBB-2) to assembly and function of acentrosomal spindles in Caenorhabditis elegans oocytes. By combining strains with altered β-tubulin isotype composition with mutations affecting microtubule-crosslinking motor KLP-18 and/or mutations affecting katanin-mediated microtubule severing, we show that TBB-1 and TBB-2 make distinct contributions to promoting spindle bipolarity. Further, by measuring multiple spindle features in wild-type and β-tubulin isotype substitution strains, we reveal contributions of isotype composition to spindle morphology, kinetics of anaphase chromosome separation, and maintenance of spindle structural integrity under stress. Together, our data support a model in which β-tubulin isotype composition helps to maintain a balance between microtubule-crosslinking and severing activities during oocyte meiosis. We further propose that this balance is crucial for establishing spindle bipolarity, maintaining spindle structures, and modulating the dynamics of chromosome separation.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"225 10","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13455592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148701306","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}
{"title":"Myosin1D directs circumferential F-actin flow to define cell chirality.","authors":"Asuka Yamaguchi, Takeshi Sasamura, Kohei Yoshimura, Hiroki Taniguchi, Daisuke Kurisu, Takamasa Higashi, Yasuhiko Sato, Florian L Neugebauer, Shuya Ishii, Makito Miyazaki, Mikiko Inaki, Yasuhiro Inoue, Masakazu Akiyama, Takeshi Haraguchi, Kohji Ito, Kenji Matsuno","doi":"10.1083/jcb.202509125","DOIUrl":"10.1083/jcb.202509125","url":null,"abstract":"<p><p>Eukaryotic cells possess intrinsic chirality in their structure, motility, and intracellular dynamics, known as cell chirality, which contributes to left-right asymmetric morphogenesis. However, the mechanisms underlying its formation remain elusive. In Drosophila, Myosin1D (Myo1D) and Myosin1C (Myo1C), respectively, dictate right-handed or left-handed chirality of the cell shape and body. Here, we report that Myo1D and Myo1C, respectively, directed clockwise and counterclockwise circumferential F-actin flows in Drosophila macrophages collaborating with Myosin2 (Myo2). Furthermore, Myo1C induced a random F-actin flow in an in vitro motility assay, whereas Myo1D triggered the self-organization of the F-actin ring rotating clockwise in the same conditions, implying that Myo1D assembles F-actin into a circular arrangement with barbed-end-to-pointed-end polarity aligned in a specific direction. We propose a model in which Myo1D induces the formation of F-actin structures aligned in such a polarized fashion within macrophages, and Myo2 rotates them clockwise. This model provides a molecular basis for the formation of cell and organ chirality.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"225 10","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148813029","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":"When push comes to shove: How chromosomes absorb spindle forces without losing grip.","authors":"Geert J P L Kops","doi":"10.1083/jcb.202608030","DOIUrl":"https://doi.org/10.1083/jcb.202608030","url":null,"abstract":"<p><p>Chromosomes withstand substantial forces from spindle microtubules prior to their segregation in mitosis. Using super resolution live imaging, Tran, Dumont, and colleagues (https://doi.org/10.1083/jcb.202512154) find that stiff linkages between chromosomes and microtubules coupled with pliable underlying centromeres enables force absorption while maintaining a robust grip on microtubules.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"225 10","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148900664","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}
Olivia P L Dalby, Efstratios Kirtsios, Hale-Seda Radoykova, Cecilia Zaza, Megan D Joseph, Persis J Amrolia, Alice Giustacchini, Sabrina Simoncelli
{"title":"Super-resolution imaging reveals altered actin architecture at CAR-T cell immune synapses.","authors":"Olivia P L Dalby, Efstratios Kirtsios, Hale-Seda Radoykova, Cecilia Zaza, Megan D Joseph, Persis J Amrolia, Alice Giustacchini, Sabrina Simoncelli","doi":"10.1083/jcb.202506119","DOIUrl":"10.1083/jcb.202506119","url":null,"abstract":"<p><p>The actin cytoskeleton plays a key integrative role in immunological synapse (IS) formation during T cell activation, but how these dynamics are altered in chimeric antigen receptor (CAR)-T cells remains unclear. Here, we used stimulated emission depletion (STED) microscopy to perform the first super-resolution analysis of actin remodeling at the IS in single- and dual (CD19/CD22) CAR-T cells, activated on supported lipid bilayers across different time points. Quantitative imaging reveals that CAR-T cells form structurally distinct synapses to untransduced cells, characterized by reduced actin-depleted regions, fewer actin foci, and persistent microvilli-like protrusions. These features indicate incomplete cytoskeletal contraction and impaired actin network reorganization, leading to partial synapse maturation. Our findings highlight fundamental differences in actin dynamics between CAR- and TCR-mediated signaling and suggest that defective actin remodeling may contribute to unstable synapse formation, altered signaling integration, and dysregulated responses or off-target effects. These insights could inform future CAR-T engineering strategies to enhance safety and efficacy.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"225 10","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148678463","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}
Leah M Plasek-Hegde, Yeolhoe Kim, Rahul V Gupta, Emily A Dangelmaier, Sigrid Nachtergaele, Nadya Dimitrova
{"title":"Cell cycle-dependent translation-mediated turnover of the long noncoding RNA Malat1.","authors":"Leah M Plasek-Hegde, Yeolhoe Kim, Rahul V Gupta, Emily A Dangelmaier, Sigrid Nachtergaele, Nadya Dimitrova","doi":"10.1083/jcb.202512059","DOIUrl":"10.1083/jcb.202512059","url":null,"abstract":"<p><p>Increased abundance of the nuclear long noncoding RNA (lncRNA) Malat1 drives metastatic progression and is a strong predictor of poor patient prognosis. Although the mechanism that stabilizes Malat1 through processing of its 3' terminus is well-characterized, the pathways governing its turnover remain poorly understood. Here, we show that upon exit from mitosis, Malat1 localizes to the cytoplasm, where it is degraded during early G1, resetting its abundance at the start of each cell cycle. Mechanistically, we demonstrate that Malat1 turnover is mediated by a translation- and Smg1-dependent decay pathway and triggered by redundant elements. Importantly, failure to reset Malat1 levels in early G1, due to decay inhibition or in the absence of progression through mitosis, results in Malat1 accumulation. These findings uncover a cell cycle-dependent mechanism that harnesses the translation machinery to regulate Malat1 abundance and identify cancer cell dormancy as a potential mechanism underlying the widespread overexpression of Malat1 in cancer.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"225 10","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13505482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148813000","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}