Nature Cell Biology最新文献_第4页

Batten disease protein CLN8 enables a non-canonical phospholipid synthesis pathway 巴顿病蛋白CLN8激活非规范磷脂合成途径。

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-09-15 DOI: 10.1038/s41556-026-02059-8

Johannes Breithofer, Nermeen Fawzy, Clara Zitta, Martin Tischitz, Dominik Bulfon, Clemens Hofmann, Lennart Hartig, Carina Wagner, Gernot F. Grabner, Anita Pirchheim, Achim Lass, Ulrike Taschler, Keira Turner, Kasparas Petkevicius, Ulrich Stelzl, Dagmar Kratky, Rolf Breinbauer, Robert Zimmermann

{"title":"Batten disease protein CLN8 enables a non-canonical phospholipid synthesis pathway","authors":"Johannes Breithofer, Nermeen Fawzy, Clara Zitta, Martin Tischitz, Dominik Bulfon, Clemens Hofmann, Lennart Hartig, Carina Wagner, Gernot F. Grabner, Anita Pirchheim, Achim Lass, Ulrike Taschler, Keira Turner, Kasparas Petkevicius, Ulrich Stelzl, Dagmar Kratky, Rolf Breinbauer, Robert Zimmermann","doi":"10.1038/s41556-026-02059-8","DOIUrl":"10.1038/s41556-026-02059-8","url":null,"abstract":"According to text book knowledge, de novo glycerophospholipid (GPL) synthesis begins with the acylation of glycerol-3-phosphate to form phosphatidic acid, the precursor of all other GPLs. Here we describe an alternative GPL synthesis pathway that starts with the acyl-CoA-dependent acylation of glycerophosphoglycerol, resulting in the formation of lysophosphatidylglycerol. The acyltransferase reaction is catalysed by the Batten disease-associated protein ceroid lipofuscinosis neuronal 8 (CLN8). Tracer studies revealed that CLN8-derived lysophosphatidylglycerol is selectively converted into bis(monoacylglycero)phosphate (BMP), a GPL essential for lysosomal lipid homeostasis but not into phosphatidylglycerol or cardiolipin. CLN8-knockout cells and mice cannot utilize glycerophosphoglycerol for BMP synthesis, resulting in BMP deficiency and excess accumulation of phospholipids in lysosomes. The lipid synthesis pathway described herein is relevant for understanding lysosomal lipid metabolism and the pathogenesis of neurodegenerative diseases. BMP deficiency may contribute to or even underlie lysosomal cargo accumulation in certain forms of Batten disease and other lysosomal storage disorders. Two studies show that the ER-associated protein CLN8 catalyses the acyl CoA-dependent acylation of glycerophosphoglycerol, producing lysophosphatidylglycerol, which is then converted into BMP. These results provide insight into CLN8 Batten disease.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 10","pages":"2078-2087"},"PeriodicalIF":22.7,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-026-02059-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977253","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

Gain-of-function suppressors restore microtubule dynamics and rescue dominant-negative tubulinopathies 功能获得抑制因子恢复微管动力学和拯救显性阴性微管病变

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-09-11 DOI: 10.1038/s41556-026-02066-9

Kaiming Xu, Zhengyang Guo, Jingyi Ke, Zihan Chen, Linfan Mao, Ranyu Sun, Mo Chen, Jie Na, Shanshan Xie, Tianhua Zhou, Jinxiang Zhang, Hui Wang, Song-Hai Shi, Wei Li, Guangshuo Ou

{"title":"Gain-of-function suppressors restore microtubule dynamics and rescue dominant-negative tubulinopathies","authors":"Kaiming Xu, Zhengyang Guo, Jingyi Ke, Zihan Chen, Linfan Mao, Ranyu Sun, Mo Chen, Jie Na, Shanshan Xie, Tianhua Zhou, Jinxiang Zhang, Hui Wang, Song-Hai Shi, Wei Li, Guangshuo Ou","doi":"10.1038/s41556-026-02066-9","DOIUrl":"10.1038/s41556-026-02066-9","url":null,"abstract":"Missense mutations in tubulin-coding genes often exert dominant-negative effects on microtubule (MT) assembly, leading to developmental disorders collectively known as tubulinopathies. Here we performed suppressor screens in Caenorhabditis elegans and identified three functionally distinct classes of missense suppressors that counteract toxic α- and β-tubulin mutants. Intergenic suppressors—missense variants in the reciprocal tubulin gene—restore MT architecture via two distinct mechanisms: assembly-defective variants competitively exclude mutant tubulins, whereas assembly-competent variants modulate MT dynamics. These mechanisms are conserved and recapitulated in human cells and murine oocytes, where selected intergenic suppressors rescue pathogenic tubulin-induced MT defects and outperform wild-type tubulin supplementation. A systematic mutational analysis of TUBA1A further defines a landscape of gain-of-function assembly-competent suppressors, supported by molecular simulations showing restoration of protofilament geometry. Together, our results provide a structural and functional framework for tubulin suppression and highlight intergenic suppressors as potential candidates for precision therapeutics targeting dominant tubulinopathies. Xu, Guo et al. report suppressor screens in Caenorhabditis elegans to counteract tubulin mutants. They report several missense variants in tubulin genes that may restore microtubule architecture and dynamics, which may have some conservation in mammalian cells.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 10","pages":"2054-2067"},"PeriodicalIF":22.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148934008","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}

引用次数: 0

4D nucleome landscape reveals dissolution of bipartite active X chromosome in liver cancer development 四维核体显示肝癌发展过程中两部活性X染色体的溶解

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-09-11 DOI: 10.1038/s41556-026-02063-y

Xiaoli Xie, Delin Tan, Jingyun Mo, Yang Xu, Qingqiang Ni, Ting Liu, Huaiming Wang, Bingjie Chen, Yujia Liao, Yingnan Lin, Wanting Chen, Susu Luo, Qing Fang, Menglan Zhao, Yangyinhui Yu, Cunjing Zheng, Ruolin Cui, Jiaying Wang, Hong Chang, Qing Gong, Alfred Sze-Lok Cheng, Huiqing Jiang, Tingting Li, Jia Wang

{"title":"4D nucleome landscape reveals dissolution of bipartite active X chromosome in liver cancer development","authors":"Xiaoli Xie, Delin Tan, Jingyun Mo, Yang Xu, Qingqiang Ni, Ting Liu, Huaiming Wang, Bingjie Chen, Yujia Liao, Yingnan Lin, Wanting Chen, Susu Luo, Qing Fang, Menglan Zhao, Yangyinhui Yu, Cunjing Zheng, Ruolin Cui, Jiaying Wang, Hong Chang, Qing Gong, Alfred Sze-Lok Cheng, Huiqing Jiang, Tingting Li, Jia Wang","doi":"10.1038/s41556-026-02063-y","DOIUrl":"10.1038/s41556-026-02063-y","url":null,"abstract":"Changes of three-dimensional chromosome organization in cancers are well established, but little focus has been placed on the behaviour of X chromosome (chrX). Here we show that hepatic chrX of male mice exhibits chromosome segregation, which is attenuated during hepatocellular carcinoma (HCC) development. Using F1 hybrid mice, we find that both conformation change and gene activation on male active chrX (Xa) are more pronounced than those on female Xa, which is correlated with male bias in liver diseases. Of note, analysis of human hepatic tissues demonstrates that normal Xa possesses a bipartite mega-domain structure, which is dissolved in fibrotic and HCC tissues across both sexes. This bipartite Xa is liver-specific, and shows little correlation with ploidy status. Furthermore, deletion of the megabase-scale Xa boundary via CRISPR–Cas3 disrupts the bipartite Xa conformation and drives a premalignant transition. Together, this comprehensive analysis highlights a key role of Xa conformation change in promoting HCC development. Xie, Tan, Mo and colleagues show that a liver-specific bipartite structure of the active X chromosome is lost early in hepatocarcinogenesis in mice and humans, driving X-linked gene activation and premalignant transformation, particularly in males.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 10","pages":"2106-2118"},"PeriodicalIF":22.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148932674","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}

引用次数: 0

The periphery of nuclear speckles defines a spatially and temporally regulated compartment of long-lived intron-retained RNAs that resolves during mitosis 核斑点的外围定义了一个空间和时间上受调控的长寿命内含子保留rna的区室，在有丝分裂期间分解。

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-09-09 DOI: 10.1038/s41556-026-02040-5

Josep Biayna, Artem Baranovskii, Anusha Chaudhuri, Marta Paladin, Berkay Erdem, Luise-Elektra Keller, A. Rasim Barutcu, Stefanie Dimmeler, Annalisa Marsico, Gabrijela Dumbović

{"title":"The periphery of nuclear speckles defines a spatially and temporally regulated compartment of long-lived intron-retained RNAs that resolves during mitosis","authors":"Josep Biayna, Artem Baranovskii, Anusha Chaudhuri, Marta Paladin, Berkay Erdem, Luise-Elektra Keller, A. Rasim Barutcu, Stefanie Dimmeler, Annalisa Marsico, Gabrijela Dumbović","doi":"10.1038/s41556-026-02040-5","DOIUrl":"10.1038/s41556-026-02040-5","url":null,"abstract":"RNA localization adds a fundamental layer to gene expression by determining when and where translation-ready mRNAs become available, yet how this timing is coordinated with nuclear architecture and cell-cycle progression remains unclear. Here we identify a subnuclear RNA niche at the nuclear speckle periphery that couples intron retention to cell-cycle-timed RNA release. Using compartment-resolved transcriptional inhibition, sequence-based deep learning and single-molecule and super-resolution RNA imaging in human pluripotent stem cells, we define a class of nuclear RNAs with long-lived retained introns that persist for hours and are enriched in transcripts encoding regulators of genome maintenance and mitosis, including centromere and kinetochore assembly, DNA repair and telomere maintenance. Long-lived retained introns exhibit elevated GC content, predicted structural stability and enrichment for nuclear speckle-associated RNA-binding proteins. In interphase, these RNAs localize to a distinct nuclear speckle-peripheral RNA niche in a spatial arrangement conserved across cell types. During mitotic remodelling, they undergo coordinated, kinase-dependent splicing and are released into the cytoplasm of early G1 daughter cells. Together, these findings link cis-encoded intronic features, subnuclear organization and mitotic remodelling to temporal control of RNA fate. Biayna, Baranovskii and colleagues report that intron-retained RNAs derived from cell cycle- and genome maintenance-related genes are pooled at the periphery of nuclear speckles and undergo synchronous splicing at mitosis, thereby contributing to their temporal regulation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 9","pages":"1857-1874"},"PeriodicalIF":22.7,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-026-02040-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920635","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

DYRK1B at processing bodies DYRK1B处理体。

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-09-09 DOI: 10.1038/s41556-026-02073-w

Daryl J. V. David

引用次数: 0

Reining in immune responses with MDM2 用MDM2控制免疫反应。

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-09-09 DOI: 10.1038/s41556-026-02072-x

Petra Gross

引用次数: 0

Keeping time with protein turnover 与蛋白质周转保持同步。

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-09-09 DOI: 10.1038/s41556-026-02071-y

Evan S. Bardot

引用次数: 0

Tissue flow acts as a guidance cue for immune cell polarization and directional migration 组织流动是免疫细胞极化和定向迁移的引导信号

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-09-07 DOI: 10.1038/s41556-026-02058-9

Hoang Anh Le, Jonas Hartmann, Ricard Alert, Roberto Mayor

{"title":"Tissue flow acts as a guidance cue for immune cell polarization and directional migration","authors":"Hoang Anh Le, Jonas Hartmann, Ricard Alert, Roberto Mayor","doi":"10.1038/s41556-026-02058-9","DOIUrl":"10.1038/s41556-026-02058-9","url":null,"abstract":"Embryonic myeloid (EM) cells are the first immune-cell population to emerge during development and must disperse throughout the embryo to act as the first line of defence against infection. Although EM cells migrate directionally toward wounds, how they navigate through unwounded tissues during early colonization remains unclear. Here we show that EM cell dispersion in Xenopus embryos is driven, at least in part, by cell-on-cell migration, an important yet underappreciated phenomenon, guided by dynamic tissue flows. We have established a new ex vivo EM cell migration system that allows for live imaging, computational analyses and optogenetic manipulation. We find that local ectodermal tissue flows repolarize EM cell protrusions and bias their directional migration. Disrupting these flows, both ex vivo and in vivo, either genetically or mechanically, impairs EM cell dispersion. Our findings reveal that mechanical cues generated by surrounding tissue flows coordinate immune-cell migration during development, highlighting an overlooked mechanism by which collective tissue dynamics guide individual cell behaviour. Le et al. show that in Xenopus embryos, local ectodermal tissue flows provide a directional cue that polarizes and guides embryonic myeloid cells migration via cell-on-cell interactions.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 10","pages":"2008-2026"},"PeriodicalIF":22.7,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-026-02058-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148899593","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

Multi-stromal organoid co-culture modelling reveals epithelial–fibroblast heterogeneity in pancreatic cancer and pancreatitis 多基质类器官共培养模型揭示胰腺癌和胰腺炎的上皮-成纤维细胞异质性。

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-09-02 DOI: 10.1038/s41556-026-02057-w

Wenlong Li, Muntadher Jihad, Eloise G. Lloyd, Marta Zaccaria, Gianluca Mucciolo, Gideon Nsubuga, Alwin Koonan-Lonappan, Joaquín Araos Henríquez, Priscilla S. W. Cheng, Sneha Harish, Sally Mills, Paul M. Johnson, Weike Luo, Alejandro Alonso Montero, Rebecca Brais, Alex Deamer, Ania M. Piskorz, Julia Jones, Jodi L. Miller, Bristi Basu, Paul D. W. Kirk, Mireia Vallespinos, Giulia Biffi

{"title":"Multi-stromal organoid co-culture modelling reveals epithelial–fibroblast heterogeneity in pancreatic cancer and pancreatitis","authors":"Wenlong Li, Muntadher Jihad, Eloise G. Lloyd, Marta Zaccaria, Gianluca Mucciolo, Gideon Nsubuga, Alwin Koonan-Lonappan, Joaquín Araos Henríquez, Priscilla S. W. Cheng, Sneha Harish, Sally Mills, Paul M. Johnson, Weike Luo, Alejandro Alonso Montero, Rebecca Brais, Alex Deamer, Ania M. Piskorz, Julia Jones, Jodi L. Miller, Bristi Basu, Paul D. W. Kirk, Mireia Vallespinos, Giulia Biffi","doi":"10.1038/s41556-026-02057-w","DOIUrl":"10.1038/s41556-026-02057-w","url":null,"abstract":"Interactions between epithelial cells and fibroblasts influence disease progression and treatment response in pancreatic ductal adenocarcinoma (PDAC). While the diversity of fibroblasts in PDAC is increasingly recognized, it remains unclear how these cells differ from fibroblasts found in pancreatic inflammation. Chronic pancreatitis is a stroma-rich inflammatory disease and a risk factor for PDAC, making it a useful setting to study how epithelial cells and fibroblasts change during disease. Here we compare fibroblast diversity and epithelial–stromal interactions in pancreatitis and PDAC using human samples, mouse models and mouse pancreatitis-derived epithelial organoids. We also developed pancreatitis and PDAC organoid co-cultures containing pancreatic stellate cells, fibroblasts and mesothelial cells. Combining in vitro and in vivo models better reflected human disease than mouse models alone. Overall, our findings reveal distinct epithelial and fibroblast features in pancreatitis and PDAC and provide models to identify disease-specific markers and therapeutic vulnerabilities. Li, Jihad and colleagues develop an organoid co-culture system, alongside patient tissue and mouse model analyses, to model, characterize and compare cellular interactions between epithelia and stroma in pancreatitis versus pancreatic ductal adenocarcinoma.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 10","pages":"2119-2137"},"PeriodicalIF":22.7,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-026-02057-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881358","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

Author Correction: Characterizing the metabolomes of microglia, astrocytes and neurons in ageing and Alzheimer’s brains 作者更正：表征衰老和阿尔茨海默氏症大脑中小胶质细胞、星形胶质细胞和神经元的代谢组。

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-09-01 DOI: 10.1038/s41556-026-02078-5

Jie Yu, Fengzhi Li, Xing-jun Chen, Chenye Mou, Di Yao, Zhanying Bi, Xiaoli Chen, Lulu Du, Ziyan Feng, Xinshuang Zhang, Xiaoqian Yu, Lauren G. Zacharias, Ralph J. DeBerardinis, Li Zhang, Zhen Li, Benyan Luo, Xiao-Ling Hu, Woo-ping Ge

引用次数: 0