Nature structural & molecular biology最新文献_第3页

Heritable maintenance of chromatin modifications confers transcriptional memory of interferon-γ signaling 染色质修饰的可遗传维持赋予干扰素-γ信号的转录记忆

Nature structural & molecular biology Pub Date : 2025-04-04 DOI: 10.1038/s41594-025-01522-8

Pawel Mikulski, Sahar S. H. Tehrani, Anna Kogan, Izma Abdul-Zani, Emer Shell, Louise James, Brent J. Ryan, Lars E. T. Jansen

{"title":"Heritable maintenance of chromatin modifications confers transcriptional memory of interferon-γ signaling","authors":"Pawel Mikulski, Sahar S. H. Tehrani, Anna Kogan, Izma Abdul-Zani, Emer Shell, Louise James, Brent J. Ryan, Lars E. T. Jansen","doi":"10.1038/s41594-025-01522-8","DOIUrl":"https://doi.org/10.1038/s41594-025-01522-8","url":null,"abstract":"Interferon-γ (IFNγ) transiently activates genes related to inflammation and innate immunity. A subset of targets retain a mitotically heritable memory of prior IFNγ exposure, resulting in hyperactivation upon re-exposure through poorly understood mechanisms. Here, we discover that the transcriptionally permissive chromatin marks H3K4me1, H3K14ac and H4K16ac are established during IFNγ priming and are selectively maintained on a cluster of guanylate-binding protein (GBP) genes in dividing human cells in the absence of transcription. The histone acetyltransferase KAT7 is required for H3K14ac deposition at GBP genes and for accelerated GBP reactivation upon re-exposure to IFNγ. In naive cells, the GBP cluster is maintained in a low-level repressive chromatin state, marked by H3K27me3, limiting priming through a PRC2-dependent mechanism. Unexpectedly, IFNγ priming results in transient accumulation of this repressive mark despite active gene expression. However, during the memory phase, H3K27 methylation is selectively depleted from primed GBP genes, facilitating hyperactivation. Furthermore, we identified a cis-regulatory element that forms transient, long-range contacts across the GBP cluster and acts as a repressor, curbing hyperactivation of previously IFNγ-primed cells. Our results provide insight into the chromatin basis for the long-term transcriptional memory of IFNγ signaling, which might contribute to enhanced innate immunity.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775688","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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O-GlcNAc transferase is a key regulator of DNA methylation and transposon silencing O-GlcNAc转移酶是DNA甲基化和转座子沉默的关键调控因子

Nature structural & molecular biology Pub Date : 2025-04-02 DOI: 10.1038/s41594-025-01507-7

引用次数: 0

Structural basis for membrane remodeling by the AP5–SPG11–SPG15 complex AP5-SPG11-SPG15复合物重塑膜的结构基础

Nature structural & molecular biology Pub Date : 2025-04-02 DOI: 10.1038/s41594-025-01500-0

Xinyi Mai, Yang Wang, Xi Wang, Ming Liu, Fei Teng, Zheng Liu, Ming-Yuan Su, Goran Stjepanovic

引用次数: 0

OGT prevents DNA demethylation and suppresses the expression of transposable elements in heterochromatin by restraining TET activity genome-wide OGT通过抑制TET活性在全基因组范围内阻止DNA去甲基化并抑制异染色质中转座因子的表达

Nature structural & molecular biology Pub Date : 2025-03-28 DOI: 10.1038/s41594-025-01505-9

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

{"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":"https://doi.org/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.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"47 1","pages":""},"PeriodicalIF":0.0,"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":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Small-molecule glues selectively restrict deubiquitylase activity and inflammatory signaling 小分子胶选择性地限制去泛素化酶活性和炎症信号

Nature structural & molecular biology Pub Date : 2025-03-25 DOI: 10.1038/s41594-025-01518-4

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Conformational changes in heat- and proton-sensing ion channel in centipedes 蜈蚣体内热感应和质子感应离子通道的构象变化

Nature structural & molecular biology Pub Date : 2025-03-25 DOI: 10.1038/s41594-025-01526-4

引用次数: 0

Microtubule motors of opposite polarity cooperate rather than compete in cargo transport 相反极性的微管电机在货物运输中合作而不是竞争

Nature structural & molecular biology Pub Date : 2025-03-25 DOI: 10.1038/s41594-025-01524-6

Steven M. Markus

引用次数: 0

Molecular glues that inhibit deubiquitylase activity and inflammatory signaling 抑制去泛素化酶活性和炎症信号传导的分子粘合剂

Nature structural & molecular biology Pub Date : 2025-03-17 DOI: 10.1038/s41594-025-01517-5

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

{"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":"https://doi.org/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.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"55 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635705","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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A nuclear pore-anchored condensate enables germ granule organization and transgenerational epigenetic inheritance 核孔锚定凝聚使胚芽颗粒组织和跨代表观遗传

Nature structural & molecular biology Pub Date : 2025-03-13 DOI: 10.1038/s41594-025-01515-7

Pu Lu, Boyuan Deng, Xinru Li, Xufang Niu, Yanhong Qiu, Yuntao Liang, Yonglin Liang, Guorun Tang, Zhongping Yuan, Guanzheng Luo, Scott Kennedy, Gang Wan

{"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":"https://doi.org/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.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"54 1","pages":""},"PeriodicalIF":0.0,"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":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mutant tau filaments from some inherited frontotemporal dementias show the Alzheimer fold 来自某些遗传性额颞叶痴呆的突变tau纤维显示阿尔茨海默氏褶皱

Nature structural & molecular biology Pub Date : 2025-03-12 DOI: 10.1038/s41594-025-01499-4

引用次数: 0