Nature Cell Biology最新文献

Sphingosine-1-phosphate signalling activates E-Syt1 to facilitate HDL-derived cholesterol transport 鞘氨醇-1-磷酸信号激活E-Syt1促进高密度脂蛋白来源的胆固醇运输

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-05-28 DOI: 10.1038/s41556-025-01665-2

Zizhen Xu, Ying Meng, Jonathan St-Germain, Arezoo Afshari, Charneal L. Dixon, Saskia Heybrock, Qiang Zhao, Xialian Weng, Jishun Chen, Richard Collins, Hu Hu, Quan Zhou, Qiming Sun, Pinglong Xu, Wei Liu, Paul Saftig, Brian Raught, Gregory D. Fairn, Dante Neculai

{"title":"Sphingosine-1-phosphate signalling activates E-Syt1 to facilitate HDL-derived cholesterol transport","authors":"Zizhen Xu, Ying Meng, Jonathan St-Germain, Arezoo Afshari, Charneal L. Dixon, Saskia Heybrock, Qiang Zhao, Xialian Weng, Jishun Chen, Richard Collins, Hu Hu, Quan Zhou, Qiming Sun, Pinglong Xu, Wei Liu, Paul Saftig, Brian Raught, Gregory D. Fairn, Dante Neculai","doi":"10.1038/s41556-025-01665-2","DOIUrl":"https://doi.org/10.1038/s41556-025-01665-2","url":null,"abstract":"Cholesterol derived from high-density lipoprotein (HDL) is rapidly redistributed to intracellular compartments in steroidogenic and bile-producing cells, but the molecular mechanisms governing this essential transport process remain poorly understood. Here we uncover a signalling cascade coordinating HDL-derived cholesterol transport through membrane contact sites between the endoplasmic reticulum (ER) and plasma membrane (PM). We find that HDL-resident sphingosine-1-phosphate (S1P) activates S1P receptor 3 and its associated G protein αq, leading to phospholipase-C-β3-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate and an elevation in cytosolic calcium. This calcium signal triggers the rapid recruitment of Extended-Synaptotagmin 1 to ER–PM membrane contact sites. Genetic or pharmacological disruption of this pathway impairs the non-vesicular transfer of HDL-derived cholesterol to intracellular compartments. Our findings reveal how HDL binding to the cell surface alters ER–PM membrane contact site dynamics through S1P signalling. This ensures efficient offloading and redistribution of HDL cholesterol to support steroid and bile acid synthesis.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"30 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153385","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

Psychological stress-induced ALKBH5 deficiency promotes tumour innervation and pancreatic cancer via extracellular vesicle transfer of RNA 心理应激诱导的ALKBH5缺乏通过RNA的细胞外囊泡转移促进肿瘤神经支配和胰腺癌

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-05-26 DOI: 10.1038/s41556-025-01667-0

Ziming Chen, Yifan Zhou, Chunling Xue, Lingxing Zeng, Shuang Deng, Zilan Xu, Mei Li, Hongzhe Zhao, Xiaowei He, Shaoqiu Liu, Ji Liu, Shuang Liu, Sihan Zhao, Shaoping Zhang, Xinyi Peng, Xiaoyu Wu, Ruihong Bai, Lisha Zhuang, Shaojia Wu, Jialiang Zhang, Dongxin Lin, Xudong Huang, Jian Zheng

{"title":"Psychological stress-induced ALKBH5 deficiency promotes tumour innervation and pancreatic cancer via extracellular vesicle transfer of RNA","authors":"Ziming Chen, Yifan Zhou, Chunling Xue, Lingxing Zeng, Shuang Deng, Zilan Xu, Mei Li, Hongzhe Zhao, Xiaowei He, Shaoqiu Liu, Ji Liu, Shuang Liu, Sihan Zhao, Shaoping Zhang, Xinyi Peng, Xiaoyu Wu, Ruihong Bai, Lisha Zhuang, Shaojia Wu, Jialiang Zhang, Dongxin Lin, Xudong Huang, Jian Zheng","doi":"10.1038/s41556-025-01667-0","DOIUrl":"https://doi.org/10.1038/s41556-025-01667-0","url":null,"abstract":"The pathological role and mechanism of psychological stress in cancer progression are little known. Here we show in a mouse model that psychological stress drives pancreatic ductal adenocarcinoma (PDAC) progression by stimulating tumour nerve innervation. We demonstrate that nociception and other stressors activate sympathetic nerves to release noradrenaline, downregulating RNA demethylase alkB homologue 5 (Alkbh5) in tumour cells. Alkbh5 deficiency in these cancer cells causes aberrant N6-methyladenosine (m6A) modification of RNAs, which are packed into extracellular vesicles and delivered to nerves in the tumour microenvironment, enhancing hyperinnervation and PDAC progression. ALKBH5 levels are inversely correlated with tumour innervation and survival time in patients with PDAC. Animal experiments identify a natural flavonoid, fisetin, that prevents neurons from taking in extracellular vesicles containing m6A-modified RNAs, thus suppressing the excessive innervation and progression of PDAC tumours. Our study sheds light on a molecular mechanism by which crosstalk between the neuroendocrine system and cancer cells links psychological stress and cancer progression and raises a potential strategy for PDAC therapy.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"47 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144137163","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

Dynamic regulation of integrin β1 phosphorylation supports invasion of breast cancer cells 整合素β1磷酸化的动态调控支持乳腺癌细胞的侵袭

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-05-26 DOI: 10.1038/s41556-025-01663-4

James R. W. Conway, Omkar Joshi, Jasmin Kaivola, Gautier Follain, Michalis Gounis, David Kühl, Johanna Ivaska

{"title":"Dynamic regulation of integrin β1 phosphorylation supports invasion of breast cancer cells","authors":"James R. W. Conway, Omkar Joshi, Jasmin Kaivola, Gautier Follain, Michalis Gounis, David Kühl, Johanna Ivaska","doi":"10.1038/s41556-025-01663-4","DOIUrl":"https://doi.org/10.1038/s41556-025-01663-4","url":null,"abstract":"Integrins provide an essential bridge between cancer cells and the extracellular matrix, playing a central role in every stage of disease progression. Despite the recognized importance of integrin phosphorylation in several biological processes, the regulatory mechanisms and their relevance remained elusive. Here we engineer a fluorescence resonance energy transfer biosensor for integrin β1 phosphorylation, screening 96 protein tyrosine phosphatases and identifying Shp2 and PTP-PEST as negative regulators to address this gap. Mutation of the integrin NPxY(783/795) sites revealed the importance of integrin phosphorylation for efficient cancer cell invasion, further supported by inhibition of the identified integrin phosphorylation regulators Shp2 and Src kinase. Using proteomics approaches, we uncovered Cofilin as a component of the phosphorylated integrin-Dok1 complex and linked this axis to effective invadopodia formation, a process supporting breast cancer invasion. These data further implicate dynamic modulation of integrin β1 phosphorylation at NPxY sites at different stages of metastatic dissemination.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"57 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144137162","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

Neutrophils secrete exosome-associated DNA to resolve sterile acute inflammation 中性粒细胞分泌外泌体相关的DNA来解决无菌急性炎症

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-05-22 DOI: 10.1038/s41556-025-01671-4

Subhash B. Arya, Samuel P. Collie, Yang Xu, Martin Fernandez, Jonathan Z. Sexton, Shyamal Mosalaganti, Pierre A. Coulombe, Carole A. Parent

引用次数: 0

Author Correction: Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism 作者更正：线粒体NADPH为线粒体脂肪酸合成和脂酰化提供燃料，为氧化代谢提供动力

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-05-22 DOI: 10.1038/s41556-025-01695-w

Dohun Kim, Rushendhiran Kesavan, Kevin Ryu, Trishna Dey, Austin Marckx, Cameron Menezes, Prakash P. Praharaj, Stewart Morley, Bookyung Ko, Mona H. Soflaee, Harrison J. Tom, Harrison Brown, Hieu S. Vu, Shih-Chia Tso, Chad A. Brautigam, Andrew Lemoff, Marcel Mettlen, Prashant Mishra, Feng Cai, Doug K. Allen, Gerta Hoxhaj

引用次数: 0

Three-way regulation of transcription 转录的三向调控

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-05-15 DOI: 10.1038/s41556-025-01675-0

Sabrya Carim

引用次数: 0

Stem cells against Parkinson’s 干细胞对抗帕金森症

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-05-15 DOI: 10.1038/s41556-025-01676-z

Stylianos Lefkopoulos

引用次数: 0

Stem cells in the clinic 干细胞在临床中的应用

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-05-15 DOI: 10.1038/s41556-025-01677-y

Stylianos Lefkopoulos

引用次数: 0

ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression ALDH4A1作为MPC复合物的活性成分，维持线粒体丙酮酸的输入，用于TCA循环进入和肿瘤抑制

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-05-12 DOI: 10.1038/s41556-025-01651-8

Che-Chia Hsu, Chi-Yun Wang, Rajesh Kumar Manne, Zhen Cai, Vasudevarao Penugurti, Rajni Kant, Ling Bai, Bo-Syong Pan, Tingjin Chen, Yuan-Ru Chen, Hsin-En Wu, Yan Jin, Haiwei Gu, Chia-Yang Li, Hui-Kuan Lin

{"title":"ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression","authors":"Che-Chia Hsu, Chi-Yun Wang, Rajesh Kumar Manne, Zhen Cai, Vasudevarao Penugurti, Rajni Kant, Ling Bai, Bo-Syong Pan, Tingjin Chen, Yuan-Ru Chen, Hsin-En Wu, Yan Jin, Haiwei Gu, Chia-Yang Li, Hui-Kuan Lin","doi":"10.1038/s41556-025-01651-8","DOIUrl":"https://doi.org/10.1038/s41556-025-01651-8","url":null,"abstract":"MPC1 and MPC2 are two well-known components of the mitochondrial pyruvate carrier (MPC) complex maintaining MPC activity to transport pyruvate into mitochondria for tricarboxylic acid (TCA) cycle entry in mammalian cells. It is currently unknown whether there is an additional MPC component crucially maintaining MPC complex activity for pyruvate mitochondrial import. Here we show that ALDH4A1, a proline-metabolizing enzyme localized in mitochondria, serves as a previously unrecognized MPC component maintaining pyruvate mitochondrial import and the TCA cycle independently of its enzymatic activity. Loss of ALDH4A1 in mammalian cells impairs pyruvate entry to mitochondria, resulting in defective TCA cycle entry. ALDH4A1 forms an active trimeric complex with MPC1–MPC2 to maintain the integrity and oligomerization of MPC1–MPC2 and facilitates pyruvate transport in an in vitro system. ALDH4A1 displays tumour suppression by maintaining MPC complex activity. Our study identifies ALDH4A1 as an essential component of MPC for pyruvate mitochondrial import, TCA cycle entry and tumour suppression.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"20 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143933220","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

Import mechanism of peroxisomal proteins with an N-terminal signal sequence 具有n端信号序列的过氧化物酶体蛋白的进口机制

IF 21.3 1区生物学

Nature Cell Biology Pub Date : 2025-05-09 DOI: 10.1038/s41556-025-01662-5

Michael L. Skowyra, Tom A. Rapoport

引用次数: 0