Nature Cell Biology最新文献

{"title":"RNA sequestration in P-bodies sustains myeloid leukaemia","authors":"Srikanth Kodali, Ludovica Proietti, Gemma Valcarcel, Anna V. López-Rubio, Patrizia Pessina, Thomas Eder, Junchao Shi, Annie Jen, Núria Lupión-Garcia, Anne C. Starner, Mason D. Bartels, Yingzhi Cui, Caroline M. Sands, Ainoa Planas-Riverola, Alba Martínez, Talia Velasco-Hernandez, Laureano Tomás-Daza, Bernhard Alber, Gabriele Manhart, Isabella Maria Mayer, Karoline Kollmann, Alessandro Fatica, Pablo Menendez, Evgenia Shishkova, Rachel E. Rau, Biola M. Javierre, Joshua Coon, Qi Chen, Eric L. Van Nostrand, Jose L. Sardina, Florian Grebien, Bruno Di Stefano","doi":"10.1038/s41556-024-01489-6","DOIUrl":"10.1038/s41556-024-01489-6","url":null,"abstract":"Post-transcriptional mechanisms are fundamental safeguards of progenitor cell identity and are often dysregulated in cancer. Here, we identified regulators of P-bodies as crucial vulnerabilities in acute myeloid leukaemia (AML) through genome-wide CRISPR screens in normal and malignant haematopoietic progenitors. We found that leukaemia cells harbour aberrantly elevated numbers of P-bodies and show that P-body assembly is crucial for initiation and maintenance of AML. Notably, P-body loss had little effect upon homoeostatic haematopoiesis but impacted regenerative haematopoiesis. Molecular characterization of P-bodies purified from human AML cells unveiled their critical role in sequestering messenger RNAs encoding potent tumour suppressors from the translational machinery. P-body dissolution promoted translation of these mRNAs, which in turn rewired gene expression and chromatin architecture in leukaemia cells. Collectively, our findings highlight the contrasting and unique roles of RNA sequestration in P-bodies during tissue homoeostasis and oncogenesis. These insights open potential avenues for understanding myeloid leukaemia and future therapeutic interventions. Kodali, Proietti et al. report that increased numbers of P-bodies in leukaemia cells account for sequestration and prevention of tumour-suppressive mRNAs from being translated, which could be targeted as a potential intervention in myeloid leukaemia.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142013807","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":"Retinoic acid induces human gastruloids with posterior embryo-like structures","authors":"Nobuhiko Hamazaki, Wei Yang, Connor A. Kubo, Chengxiang Qiu, Beth K. Martin, Riddhiman K. Garge, Samuel G. Regalado, Eva K. Nichols, Sriram Pendyala, Nicholas Bradley, Douglas M. Fowler, Choli Lee, Riza M. Daza, Sanjay Srivatsan, Jay Shendure","doi":"10.1038/s41556-024-01487-8","DOIUrl":"10.1038/s41556-024-01487-8","url":null,"abstract":"Gastruloids are a powerful in vitro model of early human development. However, although elongated and composed of all three germ layers, human gastruloids do not morphologically resemble post-implantation human embryos. Here we show that an early pulse of retinoic acid (RA), together with later Matrigel, robustly induces human gastruloids with posterior embryo-like morphological structures, including a neural tube flanked by segmented somites and diverse cell types, including neural crest, neural progenitors, renal progenitors and myocytes. Through in silico staging based on single-cell RNA sequencing, we find that human RA-gastruloids progress further than other human or mouse embryo models, aligning to E9.5 mouse and CS11 cynomolgus monkey embryos. We leverage chemical and genetic perturbations of RA-gastruloids to confirm that WNT and BMP signalling regulate somite formation and neural tube length in the human context, while transcription factors TBX6 and PAX3 underpin presomitic mesoderm and neural crest, respectively. Looking forward, RA-gastruloids are a robust, scalable model for decoding early human embryogenesis. Hamazaki, Yang et al. report that an early pulse of retinoic acid robustly induces human gastruloids with a neural tube, segmented somites and more advanced cell types than conventional gastruloids.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01487-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007482","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":"Compression-dependent microtubule reinforcement enables cells to navigate confined environments","authors":"Robert J. Ju, Alistair D. Falconer, Christanny J. Schmidt, Marco A. Enriquez Martinez, Kevin M. Dean, Reto P. Fiolka, David P. Sester, Max Nobis, Paul Timpson, Alexis J. Lomakin, Gaudenz Danuser, Melanie D. White, Nikolas K. Haass, Dietmar B. Oelz, Samantha J. Stehbens","doi":"10.1038/s41556-024-01476-x","DOIUrl":"10.1038/s41556-024-01476-x","url":null,"abstract":"Cells migrating through complex three-dimensional environments experience considerable physical challenges, including tensile stress and compression. To move, cells need to resist these forces while also squeezing the large nucleus through confined spaces. This requires highly coordinated cortical contractility. Microtubules can both resist compressive forces and sequester key actomyosin regulators to ensure appropriate activation of contractile forces. Yet, how these two roles are integrated to achieve nuclear transmigration in three dimensions is largely unknown. Here, we demonstrate that compression triggers reinforcement of a dedicated microtubule structure at the rear of the nucleus by the mechanoresponsive recruitment of cytoplasmic linker-associated proteins, which dynamically strengthens and repairs the lattice. These reinforced microtubules form the mechanostat: an adaptive feedback mechanism that allows the cell to both withstand compressive force and spatiotemporally organize contractility signalling pathways. The microtubule mechanostat facilitates nuclear positioning and coordinates force production to enable the cell to pass through constrictions. Disruption of the mechanostat imbalances cortical contractility, stalling migration and ultimately resulting in catastrophic cell rupture. Our findings reveal a role for microtubules as cellular sensors that detect and respond to compressive forces, enabling movement and ensuring survival in mechanically demanding environments. Ju et al. show that during three-dimensional cell migration, compression recruits cytoplasmic linker-associated proteins to microtubules; these stabilized microtubules then coordinate nuclear positioning and contractility in confined migration.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142002726","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":"Lymphotoxin-β promotes breast cancer bone metastasis colonization and osteolytic outgrowth","authors":"Xuxiang Wang, Tengjiang Zhang, Bingxin Zheng, Youxue Lu, Yong Liang, Guoyuan Xu, Luyang Zhao, Yuwei Tao, Qianhui Song, Huiwen You, Haitian Hu, Xuan Li, Keyong Sun, Tianqi Li, Zian Zhang, Jianbin Wang, Xun Lan, Deng Pan, Yang-Xin Fu, Bin Yue, Hanqiu Zheng","doi":"10.1038/s41556-024-01478-9","DOIUrl":"10.1038/s41556-024-01478-9","url":null,"abstract":"Bone metastasis is a lethal consequence of breast cancer. Here we used single-cell transcriptomics to investigate the molecular mechanisms underlying bone metastasis colonization—the rate-limiting step in the metastatic cascade. We identified that lymphotoxin-β (LTβ) is highly expressed in tumour cells within the bone microenvironment and this expression is associated with poor bone metastasis-free survival. LTβ promotes tumour cell colonization and outgrowth in multiple breast cancer models. Mechanistically, tumour-derived LTβ activates osteoblasts through nuclear factor-κB2 signalling to secrete CCL2/5, which facilitates tumour cell adhesion to osteoblasts and accelerates osteoclastogenesis, leading to bone metastasis progression. Blocking LTβ signalling with a decoy receptor significantly suppressed bone metastasis in vivo, whereas clinical sample analysis revealed significantly higher LTβ expression in bone metastases than in primary tumours. Our findings highlight LTβ as a bone niche-induced factor that promotes tumour cell colonization and osteolytic outgrowth and underscore its potential as a therapeutic target for patients with bone metastatic disease. Wang, Zhang, Zheng et al. demonstrate that tumour cell-derived lymphotoxin-β activates NF-κB2 signalling and CCL2/5 secretion in osteoblasts to promote bone metastasis in breast cancer, which may potentially be targeted with a decoy receptor in vivo.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141986311","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":"Docking a flexible basket onto the core of the nuclear pore complex","authors":"Edvinas Stankunas, Alwin Köhler","doi":"10.1038/s41556-024-01484-x","DOIUrl":"10.1038/s41556-024-01484-x","url":null,"abstract":"The nuclear basket attaches to the nucleoplasmic side of the nuclear pore complex (NPC), coupling transcription to mRNA quality control and export. The basket expands the functional repertoire of a subset of NPCs in Saccharomyces cerevisiae by drawing a unique RNA/protein interactome. Yet, how the basket docks onto the NPC core remains unknown. By integrating AlphaFold-based interaction screens, electron microscopy and membrane-templated reconstitution, we uncovered a membrane-anchored tripartite junction between basket and NPC core. The basket subunit Nup60 harbours three adjacent short linear motifs, which connect Mlp1, a parallel homodimer consisting of coiled-coil segments interrupted by flexible hinges, and the Nup85 subunit of the Y-complex. We reconstituted the Y-complex•Nup60•Mlp1 assembly on a synthetic membrane and validated the protein interfaces in vivo. Here we explain how a short linear motif-based protein junction can substantially reshape NPC structure and function, advancing our understanding of compositional and conformational NPC heterogeneity. Stankunas and Köhler define how the nucleoplasmic portion of the nuclear pore complex (NPC), the basket, docks onto the NPC core by integrating AlphaFold-based interaction screens, electron microscopy, and membrane-templated reconstitutions.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01484-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141973981","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 fatty acid switch drives ferroptosis in EMT","authors":"Alina M. Winkelkotte, Almut Schulze","doi":"10.1038/s41556-024-01483-y","DOIUrl":"10.1038/s41556-024-01483-y","url":null,"abstract":"Ferroptosis is mediated by toxic accumulation of lipid peroxides. A new study reports that the transcription factor ZEB1 drives ferroptosis sensitivity by regulating the synthesis of highly oxidizable poly-unsaturated fatty acids. This creates a selective vulnerability that can be exploited to eliminate aggressive mesenchymal cancer cells.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141973780","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":"Spermidine is essential for fasting-mediated autophagy and longevity","authors":"Sebastian J. Hofer, Ioanna Daskalaki, Martina Bergmann, Jasna Friščić, Andreas Zimmermann, Melanie I. Mueller, Mahmoud Abdellatif, Raffaele Nicastro, Sarah Masser, Sylvère Durand, Alexander Nartey, Mara Waltenstorfer, Sarah Enzenhofer, Isabella Faimann, Verena Gschiel, Thomas Bajaj, Christine Niemeyer, Ilias Gkikas, Lukas Pein, Giulia Cerrato, Hui Pan, YongTian Liang, Jelena Tadic, Andrea Jerkovic, Fanny Aprahamian, Christine E. Robbins, Nitharsshini Nirmalathasan, Hansjörg Habisch, Elisabeth Annerer, Frederik Dethloff, Michael Stumpe, Franziska Grundler, Françoise Wilhelmi de Toledo, Daniel E. Heinz, Daniela A. Koppold, Anika Rajput Khokhar, Andreas Michalsen, Norbert J. Tripolt, Harald Sourij, Thomas R. Pieber, Rafael de Cabo, Mark A. McCormick, Christoph Magnes, Oliver Kepp, Joern Dengjel, Stephan J. Sigrist, Nils C. Gassen, Simon Sedej, Tobias Madl, Claudio De Virgilio, Ulrich Stelzl, Markus H. Hoffmann, Tobias Eisenberg, Nektarios Tavernarakis, Guido Kroemer, Frank Madeo","doi":"10.1038/s41556-024-01468-x","DOIUrl":"10.1038/s41556-024-01468-x","url":null,"abstract":"Caloric restriction and intermittent fasting prolong the lifespan and healthspan of model organisms and improve human health. The natural polyamine spermidine has been similarly linked to autophagy enhancement, geroprotection and reduced incidence of cardiovascular and neurodegenerative diseases across species borders. Here, we asked whether the cellular and physiological consequences of caloric restriction and fasting depend on polyamine metabolism. We report that spermidine levels increased upon distinct regimens of fasting or caloric restriction in yeast, flies, mice and human volunteers. Genetic or pharmacological blockade of endogenous spermidine synthesis reduced fasting-induced autophagy in yeast, nematodes and human cells. Furthermore, perturbing the polyamine pathway in vivo abrogated the lifespan- and healthspan-extending effects, as well as the cardioprotective and anti-arthritic consequences of fasting. Mechanistically, spermidine mediated these effects via autophagy induction and hypusination of the translation regulator eIF5A. In summary, the polyamine–hypusination axis emerges as a phylogenetically conserved metabolic control hub for fasting-mediated autophagy enhancement and longevity. Hofer et al. show that fasting promotes the synthesis of spermidine, which stimulates eIF5A hypusination to induce autophagy and increase lifespan in various species in a conserved manner.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01468-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904173","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":"TorsinA is essential for neuronal nuclear pore complex localization and maturation","authors":"Sumin Kim, Sébastien Phan, Hung Tri Tran, Thomas R. Shaw, Sarah H. Shahmoradian, Mark H. Ellisman, Sarah L. Veatch, Sami J. Barmada, Samuel S. Pappas, William T. Dauer","doi":"10.1038/s41556-024-01480-1","DOIUrl":"10.1038/s41556-024-01480-1","url":null,"abstract":"As lifelong interphase cells, neurons face an array of unique challenges. A key challenge is regulating nuclear pore complex (NPC) biogenesis and localization, the mechanisms of which are largely unknown. Here we identify neuronal maturation as a period of strongly upregulated NPC biogenesis. We demonstrate that the AAA+ protein torsinA, whose dysfunction causes the neurodevelopmental movement disorder DYT-TOR1A dystonia and co-ordinates NPC spatial organization without impacting total NPC density. We generated an endogenous Nup107-HaloTag mouse line to directly visualize NPC organization in developing neurons and find that torsinA is essential for proper NPC localization. In the absence of torsinA, the inner nuclear membrane buds excessively at sites of mislocalized nascent NPCs, and the formation of complete NPCs is delayed. Our work demonstrates that NPC spatial organization and number are independently determined and identifies NPC biogenesis as a process vulnerable to neurodevelopmental disease insults. Kim et al. show that nuclear pore complex (NPC) formation is strongly upregulated during a specific neurodevelopmental window. In neurons, torsinA is required for the maturation and normal localization of nascent NPCs, but not their density.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904174","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":"Spindle architecture constrains karyotype evolution","authors":"Jana Helsen, Md Hashim Reza, Ricardo Carvalho, Gavin Sherlock, Gautam Dey","doi":"10.1038/s41556-024-01485-w","DOIUrl":"10.1038/s41556-024-01485-w","url":null,"abstract":"The eukaryotic cell division machinery must rapidly and reproducibly duplicate and partition the cell’s chromosomes in a carefully coordinated process. However, chromosome numbers vary dramatically between genomes, even on short evolutionary timescales. We sought to understand how the mitotic machinery senses and responds to karyotypic changes by using a series of budding yeast strains in which the native chromosomes have been successively fused. Using a combination of cell biological profiling, genetic engineering and experimental evolution, we show that chromosome fusions are well tolerated up until a critical point. Cells with fewer than five centromeres lack the necessary number of kinetochore-microtubule attachments needed to counter outward forces in the metaphase spindle, triggering the spindle assembly checkpoint and prolonging metaphase. Our findings demonstrate that spindle architecture is a constraining factor for karyotype evolution. Helsen et al. use experimental evolution and chromosome engineering to probe the link between karyotype changes and the cell division machinery. They conclude that spindle organization dictates the available trajectories for karyotype evolution.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01485-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904175","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":"p16-dependent increase of PD-L1 stability regulates immunosurveillance of senescent cells","authors":"Julia Majewska, Amit Agrawal, Avi Mayo, Lior Roitman, Rishita Chatterjee, Jarmila Sekeresova Kralova, Tomer Landsberger, Yonatan Katzenelenbogen, Tomer Meir-Salame, Efrat Hagai, Ilanit Sopher, Juan-Felipe Perez-Correa, Wolfgang Wagner, Avi Maimon, Ido Amit, Uri Alon, Valery Krizhanovsky","doi":"10.1038/s41556-024-01465-0","DOIUrl":"10.1038/s41556-024-01465-0","url":null,"abstract":"The accumulation of senescent cells promotes ageing and age-related diseases, but molecular mechanisms that senescent cells use to evade immune clearance and accumulate in tissues remain to be elucidated. Here we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in ageing and chronic inflammation. We show that p16-mediated inhibition of cell cycle kinases CDK4/6 induces PD-L1 stability in senescent cells via downregulation of its ubiquitin-dependent degradation. p16-expressing senescent alveolar macrophages elevate PD-L1 to promote an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with activating anti-PD-L1 antibodies engaging Fcγ receptors on effector cells leads to the elimination of PD-L1 and p16-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of targeting PD-L1 to improve immunosurveillance of senescent cells and ameliorate senescence-associated inflammation. Majewska et al. show that p16-expressing senescent cells enhance the stability of the immune checkpoint PD-L1 by downregulating its proteasome-mediated ubiquitin-dependent degradation, leading to their accumulation in ageing and chronic inflammation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01465-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893820","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}