Nature Structural & Molecular Biology最新文献

{"title":"OGT prevents DNA demethylation and suppresses the expression of transposable elements in heterochromatin by restraining TET activity genome-wide","authors":"Hugo Sepulveda, Xiang Li, Leo J. Arteaga-Vazquez, Isaac F. López-Moyado, Melina Brunelli, Lot Hernández-Espinosa, Xiaojing Yue, J. Carlos Angel, Caitlin Brown, Zhen Dong, Natasha Jansz, Fabio Puddu, Aurélie Modat, Jamie Scotcher, Páidí Creed, Patrick H. Kennedy, Cindy Manriquez-Rodriguez, Samuel A. Myers, Robert Crawford, Geoffrey J. Faulkner, Anjana Rao","doi":"10.1038/s41594-025-01505-9","DOIUrl":"10.1038/s41594-025-01505-9","url":null,"abstract":"O-GlcNAc transferase (OGT) interacts robustly with all three mammalian TET methylcytosine dioxygenases. Here we show that deletion of the Ogt gene in mouse embryonic stem (mES) cells results in a widespread increase in the TET product 5-hydroxymethylcytosine in both euchromatic and heterochromatic compartments, with a concomitant reduction in the TET substrate 5-methylcytosine at the same genomic regions. mES cells treated with an OGT inhibitor also displayed increased 5-hydroxymethylcytosine, and attenuating the TET1–OGT interaction in mES cells resulted in a genome-wide decrease of 5-methylcytosine, indicating that OGT restrains TET activity and limits inappropriate DNA demethylation in a manner that requires the TET–OGT interaction and the catalytic activity of OGT. DNA hypomethylation in OGT-deficient cells was accompanied by derepression of transposable elements predominantly located in heterochromatin. We suggest that OGT protects the genome against TET-mediated DNA demethylation and loss of heterochromatin integrity, preventing the aberrant increase in transposable element expression noted in cancer, autoimmune-inflammatory diseases, cellular senescence and aging. Here the authors show that the disruption of OGT expression in mouse embryonic stem cells unleashes TET activity, causing genome-wide decreases in DNA methylation and increases in 5-hydroxymethylcytosine, leading to the derepression of transposable elements and, in certain cases, the activation of nearby genes.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 7","pages":"1282-1296"},"PeriodicalIF":10.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723815","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":"Small-molecule glues selectively restrict deubiquitylase activity and inflammatory signaling","authors":"","doi":"10.1038/s41594-025-01518-4","DOIUrl":"10.1038/s41594-025-01518-4","url":null,"abstract":"A new class of small molecular ‘glues’ selectively inhibit the BRISC deubiquitylase complex by stabilizing it in an inactive dimeric conformation. These compounds reduce inflammatory signaling by preventing deubiquitylation of an interferon receptor, and thereby offer a promising avenue for the treatment of type I interferon-driven diseases.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 9","pages":"1592-1593"},"PeriodicalIF":10.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703197","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":"Conformational changes in heat- and proton-sensing ion channel in centipedes","authors":"","doi":"10.1038/s41594-025-01526-4","DOIUrl":"10.1038/s41594-025-01526-4","url":null,"abstract":"Structural analyses, patch-clamp recordings and molecular dynamic simulations of the heat and proton sensor BRTNaC1 channel in centipedes reveal a ‘twist the wrist’ mechanism induced by proton activation. Heat induces broad conformational changes in BRTNaC1, including rotation and shift in the transmembrane helices to open this channel.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 6","pages":"966-967"},"PeriodicalIF":10.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695672","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":"Microtubule motors of opposite polarity cooperate rather than compete in cargo transport","authors":"Steven M. Markus","doi":"10.1038/s41594-025-01524-6","DOIUrl":"10.1038/s41594-025-01524-6","url":null,"abstract":"Microtubule-based cargo transport relies on the actions of dynein and kinesins, motors that walk in opposite directions yet act together to ensure appropriate distribution of cargos in cells. Research now provides mechanistic insights into how these seemingly antagonistic motors collaborate, rather than compete, to promote each other’s activities.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 4","pages":"595-597"},"PeriodicalIF":10.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695673","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":"Thylakoid membrane remodeling by VIPP1 ESCRT-III-like filaments","authors":"John McCullough, Wesley I. Sundquist","doi":"10.1038/s41594-025-01511-x","DOIUrl":"10.1038/s41594-025-01511-x","url":null,"abstract":"Three papers show that Vipp1, a plastid ESCRT-III protein, can form sheets, spirals and regular polygons on flat membranes and tubulate the membranes within stacked rings and helices. This work provides a framework for how Vipp1 can deliver lipids for thylakoid membrane biogenesis and protect and repair the membranes during photosynthesis.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 3","pages":"414-417"},"PeriodicalIF":12.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646331","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":"Molecular glues that inhibit deubiquitylase activity and inflammatory signaling","authors":"Francesca Chandler, Poli Adi Narayana Reddy, Smita Bhutda, Rebecca L. Ross, Arindam Datta, Miriam Walden, Kieran Walker, Stefano Di Donato, Joel A. Cassel, Michael A. Prakesch, Ahmed Aman, Alessandro Datti, Lisa J. Campbell, Martina Foglizzo, Lillie Bell, Daniel N. Stein, James R. Ault, Rima S. Al-awar, Antonio N. Calabrese, Frank Sicheri, Francesco Del Galdo, Joseph M. Salvino, Roger A. Greenberg, Elton Zeqiraj","doi":"10.1038/s41594-025-01517-5","DOIUrl":"10.1038/s41594-025-01517-5","url":null,"abstract":"Deubiquitylases (DUBs) are crucial in cell signaling and are often regulated by interactions within protein complexes. The BRCC36 isopeptidase complex (BRISC) regulates inflammatory signaling by cleaving K63-linked polyubiquitin chains on type I interferon receptors (IFNAR1). As a Zn2+-dependent JAMM/MPN (JAB1, MOV34, MPR1, Pad1 N-terminal) DUB, BRCC36 is challenging to target with selective inhibitors. Here, we discover first-in-class inhibitors, termed BRISC molecular glues (BLUEs), which stabilize a 16-subunit human BRISC dimer in an autoinhibited conformation, blocking active sites and interactions with the targeting subunit, serine hydroxymethyltransferase 2. This unique mode of action results in selective inhibition of BRISC over related complexes with the same catalytic subunit, splice variants and other JAMM/MPN DUBs. BLUE treatment reduced interferon-stimulated gene expression in cells containing wild-type BRISC and this effect was abolished when using structure-guided, inhibitor-resistant BRISC mutants. Additionally, BLUEs increase IFNAR1 ubiquitylation and decrease IFNAR1 surface levels, offering a potential strategy to mitigate type I interferon-mediated diseases. Our approach also provides a template for designing selective inhibitors of large protein complexes by promoting rather than blocking protein–protein interactions. The BRCC36 isopeptidase complex (BRISC) is a deubiquitylase that stabilizes interferon receptors, driving inflammation. We discovered ‘BRISC molecular glue’ inhibitors (BLUEs) that selectively inactivate BRISC, promoting interferon receptor ubiquitylation and degradation to dampen immune responses.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 9","pages":"1812-1824"},"PeriodicalIF":10.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01517-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635705","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":"A nuclear pore-anchored condensate enables germ granule organization and transgenerational epigenetic inheritance","authors":"Pu Lu, Boyuan Deng, Xinru Li, Xufang Niu, Yanhong Qiu, Yuntao Liang, Yonglin Liang, Guorun Tang, Zhongping Yuan, Guanzheng Luo, Scott Kennedy, Gang Wan","doi":"10.1038/s41594-025-01515-7","DOIUrl":"10.1038/s41594-025-01515-7","url":null,"abstract":"Biomolecular condensates, such as stress and germ granules, often contain subcompartments. For instance, the Caenorhabditis elegans germ granule, which localizes near the outer nuclear membrane of germ cell nuclei, is composed of at least four ordered compartments, each housing distinct sets of proteins and RNAs. How these compartments form and why they are spatially ordered remains poorly understood. Here, we show that the conserved DEAD-box RNA helicase DDX-19 defines another compartment of the larger C. elegans germ granule, which we term the D compartment. The D compartment exhibits properties of a liquid condensate and forms between the outer nuclear pore filament and other compartments of the germ granule. Two nuclear pore proteins, NPP-14 and GLEL-1, are required for its formation, suggesting that the D compartment localizes adjacent to the outer nuclear membrane through interactions with the nuclear pore. The loss of DDX-19, NPP-14 or GLEL-1 leads to functional defects, including aberrant formation of the other four germ granule compartments, a loss of germline immortality and dysregulation of small RNA-based transgenerational epigenetic inheritance programs. Hence, we propose that a function of the D compartment is to anchor larger germ granules to nuclear pores, enabling germ granule compartmentalization and promoting transgenerational RNA surveillance. Lu et al. report a D compartment in Caenorhabditis elegans germ granules, formed by DEAD-box RNA helicase DDX-19 and nuclear pore proteins. This compartment anchors granules to nuclear pores, ensuring compartmentalization, RNA surveillance and germline immortality.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 7","pages":"1241-1254"},"PeriodicalIF":10.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607990","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":"Mutant tau filaments from some inherited frontotemporal dementias show the Alzheimer fold","authors":"","doi":"10.1038/s41594-025-01499-4","DOIUrl":"10.1038/s41594-025-01499-4","url":null,"abstract":"Frontotemporal dementias can be caused by mutations in MAPT, which encodes the protein tau; the mutant protein forms harmful aggregates in the brain. Cryo-electron microscopy of tau filaments from individuals with mutant V337M and R406W tau show the Alzheimer fold.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 7","pages":"1139-1140"},"PeriodicalIF":10.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599671","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":"TCAIM is linked to lipid metabolism","authors":"Michelle Korda","doi":"10.1038/s41594-025-01520-w","DOIUrl":"10.1038/s41594-025-01520-w","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 3","pages":"407-407"},"PeriodicalIF":12.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589614","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":"Presenilins balancing autophagy and extracellular vesicle secretion","authors":"Melina Casadio","doi":"10.1038/s41594-025-01513-9","DOIUrl":"10.1038/s41594-025-01513-9","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 3","pages":"407-407"},"PeriodicalIF":12.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589615","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}