Despite being evolutionary distant, plants and animals exhibit a shared phenomenon during the transition from somatic-to-reproductive cell fate marked by extensive structural and compositional changes in chromatin. This chromatin reprogramming occurs in the plant SMCs (Spore Mother Cells) and animal PGCs (primordial germ cells) and is initiated by the loss of linker histones (H1). H1 loss is essential to establish pluripotency in animal PGCs but its role is not known in plants. Here, we identified two regulatory pathways involving a citrullinase and an E3-ubiquitin ligase that contribute H1.1 loss in female SMCs in Arabidopsis. We also identified roles for two specific residues: an arginine, whose positive charge contributes to H1.1 destabilization from chromatin, and a lysine in the globular domain that is essential for H1.1 degradation. Ovules with impaired H1.1 loss in the SMC proceed through sporogenesis but fail to complete gametogenesis. We propose that a citrullination-ubiquitination pathway governs pre-meiotic H1 depletion as a critical mechanism for establishing post-meiotic competence in the Arabidopsis germline.
{"title":"Pre-meiotic H1.1 degradation is essential for Arabidopsis gametogenesis.","authors":"Yanru Li,Danli Fei,Jasmin Schubert,Kinga Rutowicz,Zuzanna Kaczmarska,Alberto Linares,Alejandro Giraldo Fonseca,Sylvain Bischof,Ueli Grossniklaus,Célia Baroux","doi":"10.1038/s44318-025-00671-2","DOIUrl":"https://doi.org/10.1038/s44318-025-00671-2","url":null,"abstract":"Despite being evolutionary distant, plants and animals exhibit a shared phenomenon during the transition from somatic-to-reproductive cell fate marked by extensive structural and compositional changes in chromatin. This chromatin reprogramming occurs in the plant SMCs (Spore Mother Cells) and animal PGCs (primordial germ cells) and is initiated by the loss of linker histones (H1). H1 loss is essential to establish pluripotency in animal PGCs but its role is not known in plants. Here, we identified two regulatory pathways involving a citrullinase and an E3-ubiquitin ligase that contribute H1.1 loss in female SMCs in Arabidopsis. We also identified roles for two specific residues: an arginine, whose positive charge contributes to H1.1 destabilization from chromatin, and a lysine in the globular domain that is essential for H1.1 degradation. Ovules with impaired H1.1 loss in the SMC proceed through sporogenesis but fail to complete gametogenesis. We propose that a citrullination-ubiquitination pathway governs pre-meiotic H1 depletion as a critical mechanism for establishing post-meiotic competence in the Arabidopsis germline.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-03DOI: 10.1038/s44318-025-00668-x
Jordan Costafrolaz,Laurence Degeorges,Gaël Panis,Simon-Ulysse Vallet,Manuel Velasco Gomariz,Fernando Teixeira Pinto Meireles,Matteo Dal Peraro,Kathrin S Fröhlich,Patrick H Viollier
Cytoplasmic pentapeptide repeat proteins (PRPs) protect bacterial DNA gyrase from quinolone antibiotics. While some secreted PRPs are essential upon quinolone exposure, their role in the regulation of antibiotic resistance remains to be fully characterized. We show that a YjbI-type secreted PRP regulates antibiotic sensitivity, bimodally for small or large molecules, via modulation of the Caulobacter crescentus outer membrane (OM). YjbI silences two converging envelope-stress pathways that globally reprogram the OM proteome via TonB-dependent receptors (TBDRs), periplasmic proteases, and AcrAB-NodT, a multidrug efflux pump whose induction by small molecules and antibiotics is lethal to yjbI mutant cells. Loss of YjbI also confers sensitivity to vancomycin and bacitracin, two large peptidoglycan-targeting and zinc-binding antibiotics that permeate the outer membrane via the previously uncharacterized TBDR BugA and its orthologs. Zinc stress triggers rapid proteolytic removal of Yjbl, activates expression of TBDRs, including BugA, and ultimately leads to replenishment of YjbI. Molecular dynamics simulations and reactive thiol probing imply an asymmetric surface disposition of YjbI, explaining the differential accessibility of its conserved cysteine pairs that flank the quadrilateral β-helix. Taken together, our findings identify a role of YjbI as a cell surface-regulator of outer membrane composition and antibiotic sensitivity in a Gram-negative bacterium.
{"title":"Asymmetric envelope surface disposition of secreted protein YjbI controls bimodal antibiotic susceptibilities in C. crescentus.","authors":"Jordan Costafrolaz,Laurence Degeorges,Gaël Panis,Simon-Ulysse Vallet,Manuel Velasco Gomariz,Fernando Teixeira Pinto Meireles,Matteo Dal Peraro,Kathrin S Fröhlich,Patrick H Viollier","doi":"10.1038/s44318-025-00668-x","DOIUrl":"https://doi.org/10.1038/s44318-025-00668-x","url":null,"abstract":"Cytoplasmic pentapeptide repeat proteins (PRPs) protect bacterial DNA gyrase from quinolone antibiotics. While some secreted PRPs are essential upon quinolone exposure, their role in the regulation of antibiotic resistance remains to be fully characterized. We show that a YjbI-type secreted PRP regulates antibiotic sensitivity, bimodally for small or large molecules, via modulation of the Caulobacter crescentus outer membrane (OM). YjbI silences two converging envelope-stress pathways that globally reprogram the OM proteome via TonB-dependent receptors (TBDRs), periplasmic proteases, and AcrAB-NodT, a multidrug efflux pump whose induction by small molecules and antibiotics is lethal to yjbI mutant cells. Loss of YjbI also confers sensitivity to vancomycin and bacitracin, two large peptidoglycan-targeting and zinc-binding antibiotics that permeate the outer membrane via the previously uncharacterized TBDR BugA and its orthologs. Zinc stress triggers rapid proteolytic removal of Yjbl, activates expression of TBDRs, including BugA, and ultimately leads to replenishment of YjbI. Molecular dynamics simulations and reactive thiol probing imply an asymmetric surface disposition of YjbI, explaining the differential accessibility of its conserved cysteine pairs that flank the quadrilateral β-helix. Taken together, our findings identify a role of YjbI as a cell surface-regulator of outer membrane composition and antibiotic sensitivity in a Gram-negative bacterium.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The architecture of actin networks at the cell surface is regulated by local membrane topology. However, how actin nucleation can respond sensitively to the degree of membrane curvature remains incompletely understood. Using nanolithography to precisely control local membrane curvature, we reconstituted the dynamic interplay of the tri-component Cdc42/FBP17/N-WASP system on a series of deformed membrane sites, resulting in differential actin nucleation. We found that high-curvature sensing is primarily mediated by FBP17 through its intrinsic BAR-domain activity, which then induces the hierarchical assembly of FBP17/N-WASP clusters to activate N-WASP in synergy with Cdc42. This nucleation boost is fine-tuned by modulating the FBP17-to-N-WASP stoichiometry within multivalent macromolecular assemblies according to local curvature radii. At lower-curvature regions, Cdc42 enhances basal FBP17 recruitment to the membrane, enabling detection of shallow curvatures and initiating actin polymerization before high-curvature effects dominate. This establishes a dynamic, curvature radius-dependent cooperativity that links geometric cues to the regulation of actin polymerization, highlighting their interplay in coordinating membrane and actin morphodynamics during complex cellular processes.
{"title":"Membrane curvature initiates Cdc42-FBP17-N-WASP clustering and actin nucleation.","authors":"Kexin Zhu,Xiangfu Guo,Aravind Chandrasekaran,Xinwen Miao,Padmini Rangamani,Wenting Zhao,Yansong Miao","doi":"10.1038/s44318-025-00677-w","DOIUrl":"https://doi.org/10.1038/s44318-025-00677-w","url":null,"abstract":"The architecture of actin networks at the cell surface is regulated by local membrane topology. However, how actin nucleation can respond sensitively to the degree of membrane curvature remains incompletely understood. Using nanolithography to precisely control local membrane curvature, we reconstituted the dynamic interplay of the tri-component Cdc42/FBP17/N-WASP system on a series of deformed membrane sites, resulting in differential actin nucleation. We found that high-curvature sensing is primarily mediated by FBP17 through its intrinsic BAR-domain activity, which then induces the hierarchical assembly of FBP17/N-WASP clusters to activate N-WASP in synergy with Cdc42. This nucleation boost is fine-tuned by modulating the FBP17-to-N-WASP stoichiometry within multivalent macromolecular assemblies according to local curvature radii. At lower-curvature regions, Cdc42 enhances basal FBP17 recruitment to the membrane, enabling detection of shallow curvatures and initiating actin polymerization before high-curvature effects dominate. This establishes a dynamic, curvature radius-dependent cooperativity that links geometric cues to the regulation of actin polymerization, highlighting their interplay in coordinating membrane and actin morphodynamics during complex cellular processes.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-22DOI: 10.1038/s44318-025-00664-1
Zhong Zhang,Lingli Zhang,Bo Jiang,Shuqin Chen,Wenhui Xing,Peilong Wang,Lixiang Lou,Chunxiao Tang,Xuye Hu,Jinlong Suo,Bo O Zhou,Weiguo Zou,Lijun Wang
Bone fracture healing remains a significant challenge in orthopedics, as injury-responsive skeletal stem cell (SSC) populations and the regulatory mechanisms governing SSC activation during nonunion fracture repair remain poorly delineated. This study identifies zinc finger transcription factor basonuclin-2 (BNC2) as a skeletal fracture repair control factor in periosteal stem cells. BNC2 marks quiescent periosteal cells during homeostasis and is significantly upregulated upon injury in mice, driving endochondral ossification post-fracture via clonal expansion. Moreover, knockout of Bnc2 in Prx1-cre+ cells (not Ocn-cre+ osteoblasts or LepR-creER+ BMSCs) resulted in impaired fracture healing, suppressing SSC proliferation. Mechanistically, ATAC-seq revealed that BNC2 deletion reduced chromatin accessibility at promoter regions of proliferation genes, hindering transcriptional activation. Additionally, BNC2 regulates histone H3 acetylation by interacting with the NuRD complex. Pharmacologically inhibition of HDAC1/2 activity partially ameliorated the fracture repair defects observed in Prx1-cre; Bnc2f/f mice. Collectively, we identified BNC2+ cells as a rapidly expanding periosteal cell population inducing endochondral ossification niches during repair, providing potential therapeutic strategies for nonunion fractures.
{"title":"Basonuclin-2 promotes fracture repair through NuRD-dependent chromatin remodeling in periosteal stem cells.","authors":"Zhong Zhang,Lingli Zhang,Bo Jiang,Shuqin Chen,Wenhui Xing,Peilong Wang,Lixiang Lou,Chunxiao Tang,Xuye Hu,Jinlong Suo,Bo O Zhou,Weiguo Zou,Lijun Wang","doi":"10.1038/s44318-025-00664-1","DOIUrl":"https://doi.org/10.1038/s44318-025-00664-1","url":null,"abstract":"Bone fracture healing remains a significant challenge in orthopedics, as injury-responsive skeletal stem cell (SSC) populations and the regulatory mechanisms governing SSC activation during nonunion fracture repair remain poorly delineated. This study identifies zinc finger transcription factor basonuclin-2 (BNC2) as a skeletal fracture repair control factor in periosteal stem cells. BNC2 marks quiescent periosteal cells during homeostasis and is significantly upregulated upon injury in mice, driving endochondral ossification post-fracture via clonal expansion. Moreover, knockout of Bnc2 in Prx1-cre+ cells (not Ocn-cre+ osteoblasts or LepR-creER+ BMSCs) resulted in impaired fracture healing, suppressing SSC proliferation. Mechanistically, ATAC-seq revealed that BNC2 deletion reduced chromatin accessibility at promoter regions of proliferation genes, hindering transcriptional activation. Additionally, BNC2 regulates histone H3 acetylation by interacting with the NuRD complex. Pharmacologically inhibition of HDAC1/2 activity partially ameliorated the fracture repair defects observed in Prx1-cre; Bnc2f/f mice. Collectively, we identified BNC2+ cells as a rapidly expanding periosteal cell population inducing endochondral ossification niches during repair, providing potential therapeutic strategies for nonunion fractures.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145808021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alternative polyadenylation (APA) modulates gene expression by altering 3' untranslated region (3'UTR) length. Although 3'UTR lengthening typically accompanies cell differentiation, we unexpectedly observed preferential APA-mediated 3'UTR shortening events during muscle stem cell (satellite cell, SC) differentiation, coinciding with increased muscle-specific miRNAs (myomiRs) targeting at alternative 3'UTRs. Mechanistically, this shortening primarily results from reduced cleavage factor I (CFI) expression and allows transcripts to escape repression by differentiation-induced myomiRs. Interestingly, perturbation of mRNA 3'UTR shortening of multiple genes impairs myogenic differentiation. Focusing on Matr3-a gene linked to muscle disorders-we demonstrate that its APA-miRNA regulatory balance is critical for efficient SC differentiation in vitro. Genetically mutating Matr3 proximal polyadenylation site (pA site) impaired mouse muscle regeneration in vivo. Together, our findings reveal that APA-mediated 3'UTR shortening counteracts miRNA repression to orchestrate the gene expression program essential for robust muscle regeneration.
{"title":"3'UTR shortening alleviates miRNA repression of mRNAs critical for muscle stem cell differentiation.","authors":"Yi Zhu,Jianshu Wang,Deng Tong,Peixuan Jia,Suli Chen,Yangyang Li,Jiaying Fu,Qiming Li,Ping Hu,Yu Zhou,Hong Cheng","doi":"10.1038/s44318-025-00663-2","DOIUrl":"https://doi.org/10.1038/s44318-025-00663-2","url":null,"abstract":"Alternative polyadenylation (APA) modulates gene expression by altering 3' untranslated region (3'UTR) length. Although 3'UTR lengthening typically accompanies cell differentiation, we unexpectedly observed preferential APA-mediated 3'UTR shortening events during muscle stem cell (satellite cell, SC) differentiation, coinciding with increased muscle-specific miRNAs (myomiRs) targeting at alternative 3'UTRs. Mechanistically, this shortening primarily results from reduced cleavage factor I (CFI) expression and allows transcripts to escape repression by differentiation-induced myomiRs. Interestingly, perturbation of mRNA 3'UTR shortening of multiple genes impairs myogenic differentiation. Focusing on Matr3-a gene linked to muscle disorders-we demonstrate that its APA-miRNA regulatory balance is critical for efficient SC differentiation in vitro. Genetically mutating Matr3 proximal polyadenylation site (pA site) impaired mouse muscle regeneration in vivo. Together, our findings reveal that APA-mediated 3'UTR shortening counteracts miRNA repression to orchestrate the gene expression program essential for robust muscle regeneration.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145808019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-17DOI: 10.1038/s44318-025-00642-7
Niklas Herrle,Pedro F Malacarne,Timothy Warwick,Alfredo Cabrera-Orefice,Yiheng Chen,Maedeh Gheisari,Souradeep Chatterjee,Matthias S Leisegang,Tamim Sarakpi,Sarah Wionski,Melina Lopez,Carine Kader,Tom Teichmann,Maria-Kyriaki Drekolia,Ina Koch,Marcus Keßler,Sabine Klein,Frank Erhard Uschner,Jonel Trebicka,Steffen Brunst,Ewgenij Proschak,Stefan Günther,Mónica Rosas-Lemus,Nina Baumgarten,Stephan Klatt,Thimoteus Speer,Sofia-Iris Bibli,Marta Segarra,Amparo Acker-Palmer,Julian U G Wagner,Ilka Wittig,Stefanie Dimmeler,Marcel H Schulz,J B Richards,Ralf Gilsbach,Travis T Denton,Ingrid Fleming,Luciana Hannibal,Ralf P Brandes,Flávia Rezende
Oxidative stress is a major driver of cardiovascular disease; however, the fast changes in cellular metabolism caused by short-lived reactive oxygen species (ROS) remain ill-defined. Here, we characterized changes in the endothelial cell metabolome in response to acute oxidative challenges and identified novel redox-sensitive metabolic enzymes. H2O2 selectively increased the amount of α-ketoglutaramate (αKGM), a largely uncharacterized metabolite produced by glutamine transamination and an unrecognized intermediate of endothelial glutamine catabolism. In addition, H2O2 impaired the catalytic activity of nitrilase-like 2 ω-amidase (NIT2), the enzyme that converts αKGM to α-ketoglutarate (αKG), by the reversible oxidation of specific cysteine residues. Moreover, a NIT2 gene variant exhibited decreased expression in humans and was associated with increased plasma αKGM concentration. Endothelial-specific knockout of NIT2 in mice increased cellular αKGM levels and impaired angiogenesis. Further, NIT2 depletion impaired endothelial cell proliferation, sprouting, and induced senescence. In conclusion, we uncover NIT2 as a redox-sensitive enzyme of the glutamine transaminase-ω-amidase pathway that acts as a metabolic switch modulating endothelial glutamine metabolism in mice and humans.
{"title":"The transaminase-ω-amidase pathway senses oxidative stress to control glutamine metabolism and α-ketoglutarate levels in endothelial cells.","authors":"Niklas Herrle,Pedro F Malacarne,Timothy Warwick,Alfredo Cabrera-Orefice,Yiheng Chen,Maedeh Gheisari,Souradeep Chatterjee,Matthias S Leisegang,Tamim Sarakpi,Sarah Wionski,Melina Lopez,Carine Kader,Tom Teichmann,Maria-Kyriaki Drekolia,Ina Koch,Marcus Keßler,Sabine Klein,Frank Erhard Uschner,Jonel Trebicka,Steffen Brunst,Ewgenij Proschak,Stefan Günther,Mónica Rosas-Lemus,Nina Baumgarten,Stephan Klatt,Thimoteus Speer,Sofia-Iris Bibli,Marta Segarra,Amparo Acker-Palmer,Julian U G Wagner,Ilka Wittig,Stefanie Dimmeler,Marcel H Schulz,J B Richards,Ralf Gilsbach,Travis T Denton,Ingrid Fleming,Luciana Hannibal,Ralf P Brandes,Flávia Rezende","doi":"10.1038/s44318-025-00642-7","DOIUrl":"https://doi.org/10.1038/s44318-025-00642-7","url":null,"abstract":"Oxidative stress is a major driver of cardiovascular disease; however, the fast changes in cellular metabolism caused by short-lived reactive oxygen species (ROS) remain ill-defined. Here, we characterized changes in the endothelial cell metabolome in response to acute oxidative challenges and identified novel redox-sensitive metabolic enzymes. H2O2 selectively increased the amount of α-ketoglutaramate (αKGM), a largely uncharacterized metabolite produced by glutamine transamination and an unrecognized intermediate of endothelial glutamine catabolism. In addition, H2O2 impaired the catalytic activity of nitrilase-like 2 ω-amidase (NIT2), the enzyme that converts αKGM to α-ketoglutarate (αKG), by the reversible oxidation of specific cysteine residues. Moreover, a NIT2 gene variant exhibited decreased expression in humans and was associated with increased plasma αKGM concentration. Endothelial-specific knockout of NIT2 in mice increased cellular αKGM levels and impaired angiogenesis. Further, NIT2 depletion impaired endothelial cell proliferation, sprouting, and induced senescence. In conclusion, we uncover NIT2 as a redox-sensitive enzyme of the glutamine transaminase-ω-amidase pathway that acts as a metabolic switch modulating endothelial glutamine metabolism in mice and humans.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"87 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fat mass loss is a severe complication in cancer-associated cachexia, but its underlying mechanisms remain unclear. This study identifies the tumor-secreted chaperone clusterin (CLU) as a driver of white adipose tissue (WAT) depletion in triple-negative breast cancer (TNBC). CLU secretion is increased in the serum of cachectic TNBC patients. Mechanistically, extracellular clusterin scavenges 14-3-3 in human TNBC cells, inhibiting nucleocytoplasmic translocation of the molecular clock activator BMAL1, and perturbing the transcriptional repression of circadian rhythm genes, including PER3. In tumors, desmosomal protein plakophilin 3 (PKP3) controls CLU stability by competitively binding to its lysosomal receptor LRP2, increasing CLU distribution in plaques and inhibiting its lysosomal degradation. In advanced TNBC patients, increased amounts of secreted CLU, PKP3 and PER3 are associated with cachectic fat loss. Finally, a targeted reduction of PKP3 or CLU in the serum restores PER3 expression rhythmicity and inhibits cachectic adipose wasting in a TNBC mouse model. Taken together, our results identify a targetable a clinically accessible PKP3-clusterin axis that disrupts circadian gene expression in fat tissue in breast cancer.
{"title":"Tumor-secreted clusterin promotes cachectic fat wasting via disrupting circadian gene expression and adipogenesis.","authors":"Yan Liu,Yehui Zhou,Mengmeng Zhang,Jin Zhang,Jiahui Chen,Long Chen,Jia Tian,Xiang Lv,Xinxing Ma,Jing Xu,Jingwei Shi,Liming Chen","doi":"10.1038/s44318-025-00661-4","DOIUrl":"https://doi.org/10.1038/s44318-025-00661-4","url":null,"abstract":"Fat mass loss is a severe complication in cancer-associated cachexia, but its underlying mechanisms remain unclear. This study identifies the tumor-secreted chaperone clusterin (CLU) as a driver of white adipose tissue (WAT) depletion in triple-negative breast cancer (TNBC). CLU secretion is increased in the serum of cachectic TNBC patients. Mechanistically, extracellular clusterin scavenges 14-3-3 in human TNBC cells, inhibiting nucleocytoplasmic translocation of the molecular clock activator BMAL1, and perturbing the transcriptional repression of circadian rhythm genes, including PER3. In tumors, desmosomal protein plakophilin 3 (PKP3) controls CLU stability by competitively binding to its lysosomal receptor LRP2, increasing CLU distribution in plaques and inhibiting its lysosomal degradation. In advanced TNBC patients, increased amounts of secreted CLU, PKP3 and PER3 are associated with cachectic fat loss. Finally, a targeted reduction of PKP3 or CLU in the serum restores PER3 expression rhythmicity and inhibits cachectic adipose wasting in a TNBC mouse model. Taken together, our results identify a targetable a clinically accessible PKP3-clusterin axis that disrupts circadian gene expression in fat tissue in breast cancer.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"154 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-16DOI: 10.1038/s44318-025-00612-z
Alexander Dorr,Veronique Kiermer,Angelika Pedal,Hans-Richard Rackwitz,Peter Henklein,Ulrich Schubert,Ming-Ming Zhou,Eric Verdin,Melanie Ott
{"title":"Author Correction: Transcriptional synergy between Tat and PCAF is dependent on the binding of acetylated Tat to the PCAF bromodomain.","authors":"Alexander Dorr,Veronique Kiermer,Angelika Pedal,Hans-Richard Rackwitz,Peter Henklein,Ulrich Schubert,Ming-Ming Zhou,Eric Verdin,Melanie Ott","doi":"10.1038/s44318-025-00612-z","DOIUrl":"https://doi.org/10.1038/s44318-025-00612-z","url":null,"abstract":"","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1038/s44318-025-00640-9
Bianca Bartl,Ursula E Schoeberl,Renan Valieris,Johanna Fitz,Konstantin Roeder,Kutti R Vinothkumar,Benjamin Gundinger,Israel Tojal Da Silva,Rushad Pavri
Somatic hypermutation (SHM) in variable regions of immunoglobulin genes by activation-induced deaminase (AID) is essential for the maturation of protective antibodies against pathogen and vaccine antigens. AID preferentially mutates cytosines within WRCH motifs (wherein W = A/T, R = A/G, and H = A/C/T) in single-stranded DNA, yet these motifs show large but reproducible variation in mutation frequency, suggesting a crucial role for sequences flanking the WRCH motifs (i.e., a sequence grammar) in determining mutational outcomes. However, the nature of this sequence grammar is poorly understood. Here, we demonstrate that identical sequence contexts can exert significantly varying effects on the mutagenesis of different WRCH motifs. Molecular dynamics simulations reveal that both the sequence context and the specific WRCH motif modulate AID activity by altering the mode and strength of AID's interactions with single-stranded DNA. Repositioning a motif and its context within the variable region significantly alters its mutability. Therefore, the mutability of AID target cytosines is determined by a motif-specific sequence grammar that determines, in part, how activation-induced deaminase binds single-stranded DNA, as well as the motif position.
激活诱导脱氨酶（AID）在免疫球蛋白基因可变区域的体细胞超突变（SHM）是针对病原体和疫苗抗原的保护性抗体成熟的必要条件。AID优先突变单链DNA中WRCH基序内的胞嘧啶（其中W = A/T, R = A/G, H = A/C/T），然而这些基序在突变频率上显示出巨大但可重复的变化，这表明WRCH基序两侧的序列（即序列语法）在决定突变结果方面起着至关重要的作用。然而，人们对这种序列语法的本质知之甚少。在这里，我们证明了相同的序列上下文可以对不同WRCH基序的诱变产生显著不同的影响。分子动力学模拟表明，序列背景和特定的WRCH基序通过改变AID与单链DNA相互作用的模式和强度来调节AID的活性。在可变区域内重新定位一个基序及其上下文可显著改变其可变性。因此，AID靶胞嘧啶的易变性是由基序特异性序列语法决定的，该语法在一定程度上决定了激活诱导的脱氨酶如何结合单链DNA以及基序位置。
{"title":"Somatic hypermutation patterns are shaped by both motif position and sequence grammar.","authors":"Bianca Bartl,Ursula E Schoeberl,Renan Valieris,Johanna Fitz,Konstantin Roeder,Kutti R Vinothkumar,Benjamin Gundinger,Israel Tojal Da Silva,Rushad Pavri","doi":"10.1038/s44318-025-00640-9","DOIUrl":"https://doi.org/10.1038/s44318-025-00640-9","url":null,"abstract":"Somatic hypermutation (SHM) in variable regions of immunoglobulin genes by activation-induced deaminase (AID) is essential for the maturation of protective antibodies against pathogen and vaccine antigens. AID preferentially mutates cytosines within WRCH motifs (wherein W = A/T, R = A/G, and H = A/C/T) in single-stranded DNA, yet these motifs show large but reproducible variation in mutation frequency, suggesting a crucial role for sequences flanking the WRCH motifs (i.e., a sequence grammar) in determining mutational outcomes. However, the nature of this sequence grammar is poorly understood. Here, we demonstrate that identical sequence contexts can exert significantly varying effects on the mutagenesis of different WRCH motifs. Molecular dynamics simulations reveal that both the sequence context and the specific WRCH motif modulate AID activity by altering the mode and strength of AID's interactions with single-stranded DNA. Repositioning a motif and its context within the variable region significantly alters its mutability. Therefore, the mutability of AID target cytosines is determined by a motif-specific sequence grammar that determines, in part, how activation-induced deaminase binds single-stranded DNA, as well as the motif position.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1038/s44318-025-00658-z
Aygul Subkhangulova,Marina Mikhaylova
The Golgi apparatus is the central hub of secretory and endosomal pathways in a eukaryotic cell. Despite having a conserved basic organization, the Golgi varies greatly in structure and operation mode between different cell types, ranging from dispersed cisternae in the budding yeast to the ribbon of cisternae stacks in most mammalian cells. Cell shape and secretory demands dictate structural and functional properties of the Golgi. Neurons are a particularly interesting type of secretory cells that have a highly polarized architecture and a large and diverse secretome. The neuronal Golgi complex evolved into an elaborate set of compartmentalized organelles that process and sort diverse neuronal cargos, including synaptic proteins, neuropeptides, and neurotrophic factors. In this review, we describe the structural adaptations of the Golgi to neuronal architecture and discuss the principles of neuronal cargo sorting. We also highlight structural rearrangements of the neuronal Golgi in neurodegenerative diseases and discuss the role of mutations in Golgi-related proteins in neurodevelopment.
{"title":"The Golgi apparatus: adaptations to neuronal shape and functions.","authors":"Aygul Subkhangulova,Marina Mikhaylova","doi":"10.1038/s44318-025-00658-z","DOIUrl":"https://doi.org/10.1038/s44318-025-00658-z","url":null,"abstract":"The Golgi apparatus is the central hub of secretory and endosomal pathways in a eukaryotic cell. Despite having a conserved basic organization, the Golgi varies greatly in structure and operation mode between different cell types, ranging from dispersed cisternae in the budding yeast to the ribbon of cisternae stacks in most mammalian cells. Cell shape and secretory demands dictate structural and functional properties of the Golgi. Neurons are a particularly interesting type of secretory cells that have a highly polarized architecture and a large and diverse secretome. The neuronal Golgi complex evolved into an elaborate set of compartmentalized organelles that process and sort diverse neuronal cargos, including synaptic proteins, neuropeptides, and neurotrophic factors. In this review, we describe the structural adaptations of the Golgi to neuronal architecture and discuss the principles of neuronal cargo sorting. We also highlight structural rearrangements of the neuronal Golgi in neurodegenerative diseases and discuss the role of mutations in Golgi-related proteins in neurodevelopment.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"366 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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