Nature Cell Biology最新文献_第10页

An overview of contemporary theories of ageing 当代老龄化理论概述

IF 19.1 1区生物学

Nature Cell Biology Pub Date : 2025-07-01 DOI: 10.1038/s41556-025-01698-7

João Pedro de Magalhães

{"title":"An overview of contemporary theories of ageing","authors":"João Pedro de Magalhães","doi":"10.1038/s41556-025-01698-7","DOIUrl":"10.1038/s41556-025-01698-7","url":null,"abstract":"Ageing is a complex biological process whose underlying mechanisms remain contentious. Nonetheless, due to an ageing global population and the rising incidence of age-related diseases, understanding why we age is one of the most important scientific questions of our time, with profound medical implications. Here, I explore the fundamental nature of the ageing process and provide an overview of modern mechanistic theories. I critically examine two main groups of ageing theories: error-based and program-based theories. I discuss the relevance of these theories in the context of ageing patterns, genetic manipulations and longevity drugs, highlighting how experimental challenges and technological limitations have hindered progress. Overall, there is a pressing and unmet need for a robust theoretical framework in ageing research. Elucidating the cellular and molecular mechanisms of ageing would be crucial for developing effective interventions that slow the ageing process and prevent its associated diseases. This Review provides an overview of modern mechanistic theories and critically examines two main groups of ageing theories—error and program based—in the context of ageing patterns, genetic manipulations and longevity drugs.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 7","pages":"1074-1082"},"PeriodicalIF":19.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520434","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

Emerging connections between myelin and Alzheimer’s disease 髓磷脂与阿尔茨海默病之间的新联系

IF 19.1 1区生物学

Nature Cell Biology Pub Date : 2025-07-01 DOI: 10.1038/s41556-025-01701-1

Anna Bright, Leyla Anne Akay, Joel Blanchard, Li-Huei Tsai

引用次数: 0

The Vps13-like protein BLTP2 regulates phosphatidylethanolamine levels to maintain plasma membrane fluidity and breast cancer aggressiveness vps13样蛋白BLTP2调节磷脂酰乙醇胺水平，维持质膜流动性和乳腺癌侵袭性

IF 19.1 1区生物学

Nature Cell Biology Pub Date : 2025-06-27 DOI: 10.1038/s41556-025-01672-3

Subhrajit Banerjee, Stephan Daetwyler, Xiaofei Bai, Morgane Michaud, Juliette Jouhet, Derk Binns, Shruthi Madhugiri, Emma Johnson, Chao-Wen Wang, Reto Fiolka, Alexandre Toulmay, William A. Prinz

{"title":"The Vps13-like protein BLTP2 regulates phosphatidylethanolamine levels to maintain plasma membrane fluidity and breast cancer aggressiveness","authors":"Subhrajit Banerjee, Stephan Daetwyler, Xiaofei Bai, Morgane Michaud, Juliette Jouhet, Derk Binns, Shruthi Madhugiri, Emma Johnson, Chao-Wen Wang, Reto Fiolka, Alexandre Toulmay, William A. Prinz","doi":"10.1038/s41556-025-01672-3","DOIUrl":"10.1038/s41556-025-01672-3","url":null,"abstract":"Lipid transport proteins (LTPs) facilitate non-vesicular lipid exchange between cellular compartments and have critical roles in lipid homeostasis. A recently identified family of bridge-like LTPs (BLTPs) is thought to form lipid-transporting conduits between organelles. One of these, BLTP2, is conserved across species but its function is not known. Here we show that BLTP2 regulates plasma membrane (PM) fluidity by increasing phosphatidylethanolamine (PE) levels in the PM. BLTP2 localizes to endoplasmic reticulum (ER)–PM contact sites, and transports PE in vivo, suggesting it drives PE movement from ER to PM. We find that BLTP2 works in parallel with another pathway that regulates intracellular PE distribution and PM fluidity. BLTP2 expression correlates with breast cancer aggressiveness. We found that BLTP2 facilitates growth of a triple negative breast cancer cell line and sustains its aggressiveness in an in vivo model of metastasis, suggesting maintenance of PM fluidity by BLTP2 may be critical for tumorigenesis in humans. Banerjee et al. report that the Vps13-like lipid transport protein BLTP2 regulates plasma membrane fluidity by maintaining phosphatidylethanolamine homeostasis. BLTP2 also facilitates breast cancer cell growth, suggesting a separate role in tumorigenesis.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 7","pages":"1125-1135"},"PeriodicalIF":19.1,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01672-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500446","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

Autophagy-targeted NBR1–p62/SQSTM1 complexes promote breast cancer metastasis by sequestering ITCH 靶向自噬的NBR1-p62 /SQSTM1复合物通过隔离瘙痒促进乳腺癌转移

IF 19.1 1区生物学

Nature Cell Biology Pub Date : 2025-06-27 DOI: 10.1038/s41556-025-01689-8

Gourish Mondal, Hugo Gonzalez, Timothy Marsh, Andrew M. Leidal, Ariadne Vlahakis, Pravin R. Phadatare, Sofı́a Bustamante Eguiguren, Michael Bruck, Akul Naik, Mark Jesus M. Magbanua, Laura A. Huppert, Arun P. Wiita, Jeroen P. Roose, Jennifer M. Rosenbluth, Jayanta Debnath

{"title":"Autophagy-targeted NBR1–p62/SQSTM1 complexes promote breast cancer metastasis by sequestering ITCH","authors":"Gourish Mondal, Hugo Gonzalez, Timothy Marsh, Andrew M. Leidal, Ariadne Vlahakis, Pravin R. Phadatare, Sofı́a Bustamante Eguiguren, Michael Bruck, Akul Naik, Mark Jesus M. Magbanua, Laura A. Huppert, Arun P. Wiita, Jeroen P. Roose, Jennifer M. Rosenbluth, Jayanta Debnath","doi":"10.1038/s41556-025-01689-8","DOIUrl":"10.1038/s41556-025-01689-8","url":null,"abstract":"Autophagy deficiency in breast cancer promotes metastasis through the accumulation of the autophagy cargo receptor NBR1. Here we show that autophagy normally suppresses breast cancer metastasis by enabling the clearance of NBR1–p62/SQSTM1 complexes that instruct p63-mediated pro-metastatic basal differentiation programmes. When autophagy is inhibited, the autophagy cargo receptors NBR1 and p62/SQSTM1 accumulate within biomolecular condensates in cells, which drives basal differentiation in both mouse and human breast cancer models. Mechanistically, these NBR1–p62/SQSTM1 complexes sequester ITCH, a ubiquitin ligase that degrades and negatively regulates p63 in breast cancer cells, thereby stabilizing and activating p63. Accordingly, mutant forms of NBR1 unable to sequester ITCH into NBR1–p62/SQSTM1 complexes do not promote basal differentiation and metastasis in vivo. Overall, our findings illuminate how proteostatic defects arising in the setting of therapeutic autophagy inhibition modulate epithelial lineage fidelity and metastatic progression. Mondal et al. report that autophagy inhibition promotes p63 activation and metastasis in breast cancer. This process depends on NBR1, which forms cytoplasmic p62/SQSTM1 condensates that sequester the ITCH ubiquitin ligase and prevents p63 degradation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 7","pages":"1098-1113"},"PeriodicalIF":19.1,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500405","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

REM transcription factors and GDE1 shape the DNA methylation landscape through the recruitment of RNA polymerase IV transcription complexes REM转录因子和GDE1通过募集RNA聚合酶IV转录复合物来塑造DNA甲基化景观

IF 19.1 1区生物学

Nature Cell Biology Pub Date : 2025-06-27 DOI: 10.1038/s41556-025-01691-0

Zhongshou Wu, Yan Xue, Shuya Wang, Yuan-Hsin Shih, Zhenhui Zhong, Suhua Feng, Jonathan Draper, Allen Lu, Carsten A. Hoeke, Jihui Sha, Lu Li, James Wohlschlegel, Keqiang Wu, Steven E. Jacobsen

{"title":"REM transcription factors and GDE1 shape the DNA methylation landscape through the recruitment of RNA polymerase IV transcription complexes","authors":"Zhongshou Wu, Yan Xue, Shuya Wang, Yuan-Hsin Shih, Zhenhui Zhong, Suhua Feng, Jonathan Draper, Allen Lu, Carsten A. Hoeke, Jihui Sha, Lu Li, James Wohlschlegel, Keqiang Wu, Steven E. Jacobsen","doi":"10.1038/s41556-025-01691-0","DOIUrl":"10.1038/s41556-025-01691-0","url":null,"abstract":"In plants, the maintenance of DNA methylation is controlled by several self-reinforcing loops involving histone methylation and non-coding RNAs. However, how methylation is initially patterned at specific genomic loci is largely unknown. Here we describe four Arabidopsis REM transcription factors, VDD, VAL, REM12 and REM13, that recognize specific sequence regions and, together with the protein GENETICS DETERMINES EPIGENETICS1 (GDE1), recruit RNA polymerase IV transcription complexes. This targeted recruitment leads to the production of 24-nucleotide small interfering RNAs that guide DNA methylation to specific genomic sites in plant female reproductive tissues. In the absence of GDE1, polymerase IV transcription complexes are directed to loci bound by an alternative transcription factor, REM8, highlighting the role of REM transcription factors and GDE1 proteins as positional cues for epigenetic modulation. These findings establish a direct connection between sequence-specific transcription factors and the spatial regulation of siRNA production and DNA methylation, offering new insights into the genetic control of epigenetic patterning. Wu et al. demonstrate that REM transcription factors and GDE1 guide RNA polymerase IV to specific genomic loci, establishing a DNA sequence-dependent mechanism for siRNA biogenesis and DNA methylation patterning.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 7","pages":"1136-1147"},"PeriodicalIF":19.1,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01691-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500407","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

A lysosomal surveillance response to stress extends healthspan 对压力的溶酶体监测反应延长了健康寿命

IF 19.1 1区生物学

Nature Cell Biology Pub Date : 2025-06-26 DOI: 10.1038/s41556-025-01693-y

Terytty Yang Li, Arwen W. Gao, Rendan Yang, Yu Sun, Yuxuan Lei, Xiaoxu Li, Lin Chen, Yasmine J. Liu, Rachel N. Arey, Kimberly Morales, Raya B. Liu, Wenzheng Wang, Ang Zhou, Tong-jin Zhao, Weisha Li, Amélia Lalou, Qi Wang, Tanes Lima, Riekelt H. Houtkooper, Johan Auwerx

{"title":"A lysosomal surveillance response to stress extends healthspan","authors":"Terytty Yang Li, Arwen W. Gao, Rendan Yang, Yu Sun, Yuxuan Lei, Xiaoxu Li, Lin Chen, Yasmine J. Liu, Rachel N. Arey, Kimberly Morales, Raya B. Liu, Wenzheng Wang, Ang Zhou, Tong-jin Zhao, Weisha Li, Amélia Lalou, Qi Wang, Tanes Lima, Riekelt H. Houtkooper, Johan Auwerx","doi":"10.1038/s41556-025-01693-y","DOIUrl":"10.1038/s41556-025-01693-y","url":null,"abstract":"Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific vacuolar H+-ATPase subunits (for example, vha-6), which are essential for intestinal lumen acidification in Caenorhabditis elegans, extends lifespan by ~60%. This longevity phenotype can be explained by an adaptive transcriptional response typified by induction of a set of transcripts involved in lysosomal function and proteolysis, which we termed the lysosomal surveillance response (LySR). LySR activation is characterized by boosted lysosomal activity and enhanced clearance of protein aggregates in worm models of Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis, thereby improving fitness. The GATA transcription factor ELT-2 governs the LySR programme and its associated beneficial effects. Activating the LySR pathway may therefore represent an attractive mechanism to reduce proteotoxicity and, as such, potentially extend healthspan. Li et al. uncover a lysosomal surveillance response whereby intestinal lumen deacidification induces a transcriptional programme that boosts lysosomal activity and improves protein aggregate clearance in multiple worm disease models, extending healthspan.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 7","pages":"1083-1097"},"PeriodicalIF":19.1,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01693-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488383","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

SEL1L–HRD1-mediated ERAD in mammals sel1l - hrd1介导的哺乳动物ERAD

IF 19.1 1区生物学

Nature Cell Biology Pub Date : 2025-06-25 DOI: 10.1038/s41556-025-01690-1

Huilun Helen Wang, Ida Biunno, Shengyi Sun, Ling Qi

{"title":"SEL1L–HRD1-mediated ERAD in mammals","authors":"Huilun Helen Wang, Ida Biunno, Shengyi Sun, Ling Qi","doi":"10.1038/s41556-025-01690-1","DOIUrl":"10.1038/s41556-025-01690-1","url":null,"abstract":"Endoplasmic reticulum-associated degradation (ERAD) is a critical quality control mechanism responsible for eliminating misfolded or unassembled proteins. It maintains endoplasmic reticulum homeostasis, ensures a proper folding environment and regulates substrate protein levels. Following its discovery in the late 1980s and early 1990s, research on ERAD in mammals—particularly that mediated by the conserved protein complex comprising suppressor/enhancer of Lin-12-like protein 1-like (SEL1L) and HMG-CoA reductase degradation protein 1 (HRD1)—has advanced substantially over the past decade. SEL1L–HRD1-mediated ERAD is now recognized as a fundamental process in mammals that governs various physiological functions largely in a substrate-specific manner. In humans, mutations in this complex have been causally linked to ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) and ENDI-agammaglobulinaemia. This Review highlights the SEL1L–HRD1-mediated ERAD pathway, exploring its machinery, molecular mechanism and physiological relevance and potential therapeutic strategies targeting this system. This Review discusses emerging insights into SEL1L–HRD1-mediated endoplasmic reticulum-associated degradation, including the underlying molecular mechanisms, physiological relevance for human disease and potential therapeutic opportunities.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 7","pages":"1063-1073"},"PeriodicalIF":19.1,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478991","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}

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Author Correction: A two-step mechanism for epigenetic specification of centromere identity and function 作者更正：着丝粒身份和功能的两步表观遗传规范机制

IF 19.1 1区生物学

Nature Cell Biology Pub Date : 2025-06-23 DOI: 10.1038/s41556-025-01718-6

Daniele Fachinetti, H. Diego Folco, Yael Nechemia-Arbely, Luis P. Valente, Kristen Nguyen, Alex J. Wong, Quan Zhu, Andrew J. Holland, Arshad Desai, Lars E. T. Jansen, Don W. Cleveland

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YAP maintains the dynamics of TDP-43 condensates and antagonizes TDP-43 pathological aggregates YAP维持TDP-43凝聚体的动力学，并拮抗TDP-43病理聚集体

IF 19.1 1区生物学

Nature Cell Biology Pub Date : 2025-06-20 DOI: 10.1038/s41556-025-01685-y

Jiaqi Zhang, Jiaojiao Hu, Ruogu Liu, Tian Zhou, Xuewei Luo, Peigang Liang, Zaichao Xie, Qinyue Zhao, Yan Chen, Dan Du, Cong Liu, Yiming Zheng, Dan Li, Bo Wang

{"title":"YAP maintains the dynamics of TDP-43 condensates and antagonizes TDP-43 pathological aggregates","authors":"Jiaqi Zhang, Jiaojiao Hu, Ruogu Liu, Tian Zhou, Xuewei Luo, Peigang Liang, Zaichao Xie, Qinyue Zhao, Yan Chen, Dan Du, Cong Liu, Yiming Zheng, Dan Li, Bo Wang","doi":"10.1038/s41556-025-01685-y","DOIUrl":"10.1038/s41556-025-01685-y","url":null,"abstract":"Recent studies exploring the underlying pathomechanisms of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder, have focused on biomolecular condensates. Here we reveal an unexpected function for YAP, a central component of the Hippo pathway, in regulating the dynamic behaviour of stress granules and TDP-43 condensates, a role that is independent of its transcriptional activity in the Hippo pathway. YAP directly binds to TDP-43. This interaction directly promotes the homotypic multimerization and phase separation of TDP-43 while inhibiting its hyperphosphorylation and solidification under stress conditions. Remarkably, YAP, whose messenger RNA levels are reduced in patients with ALS, is found to co-localize with pathological hyperphosphorylated TDP-43 aggregates in the brains of patients with ALS. In addition, elevation of YAP/Yorkie (a fly homologue of mammalian YAP) expression substantially reduces TDP-43 toxicity in primary neuron and transgenic fly models of ALS. Our findings highlight an unexpected role of YAP in managing ALS-associated biomolecular condensates, presenting important implications for potential ALS treatments. Zhang et al. show that YAP binds to TDP-43 to promote TDP-43 multimerization and phase separation. YAP and TDP-43 may co-localize in multiple cell types in oxidative stress and in brain samples from individuals with amyotrophic lateral sclerosis.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 7","pages":"1148-1160"},"PeriodicalIF":19.1,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144328639","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}

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Organelle conversations drive ferroptosis 细胞器对话驱动铁下垂

IF 19.1 1区生物学

Nature Cell Biology Pub Date : 2025-06-19 DOI: 10.1038/s41556-025-01694-x

Ancély Ferreira dos Santos, José Pedro Friedmann Angeli

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