CellPub Date : 2025-03-31DOI: 10.1016/j.cell.2025.02.032
Frank Bürmann, Bryony Clifton, Sophie Koekemoer, Oliver J. Wilkinson, Dari Kimanius, Mark S. Dillingham, Jan Löwe
{"title":"Mechanism of DNA capture by the MukBEF SMC complex and its inhibition by a viral DNA mimic","authors":"Frank Bürmann, Bryony Clifton, Sophie Koekemoer, Oliver J. Wilkinson, Dari Kimanius, Mark S. Dillingham, Jan Löwe","doi":"10.1016/j.cell.2025.02.032","DOIUrl":"https://doi.org/10.1016/j.cell.2025.02.032","url":null,"abstract":"Ring-like structural maintenance of chromosome (SMC) complexes are crucial for genome organization and operate through mechanisms of DNA entrapment and loop extrusion. Here, we explore the DNA loading process of the bacterial SMC complex MukBEF. Using cryoelectron microscopy (cryo-EM), we demonstrate that ATP binding opens one of MukBEF’s three potential DNA entry gates, exposing a DNA capture site that positions DNA at the open neck gate. We discover that the gp5.9 protein of bacteriophage T7 blocks this capture site by DNA mimicry, thereby preventing DNA loading and inactivating MukBEF. We propose a comprehensive and unidirectional loading mechanism in which DNA is first captured at the complex’s periphery and then ingested through the DNA entry gate, powered by a single cycle of ATP hydrolysis. These findings illuminate a fundamental aspect of how ubiquitous DNA organizers are primed for genome maintenance and demonstrate how this process can be disrupted by viruses.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"10 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737143","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":"Optimizing stem cell infusion timing in the prevention of acute graft-versus-host disease","authors":"Yiwen Hou, Yue Wu, Yang Cao, Xiaoxia Hu, Yuqian Sun, Hongmei Wang, Liang Wang, Jialin Zhou, Zhonglin Zhang, Zhiwei Liu, Baolin Tang, Kaidi Song, Guangyu Sun, Wen Gao, Tianqi Zheng, Ping Wu, Weiwei Wu, Dapeng Ju, Xiaoyu Zhu, Cheng Zhan","doi":"10.1016/j.cell.2025.03.022","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.022","url":null,"abstract":"Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a cornerstone treatment for a broad spectrum of malignant and nonmalignant hematological disorders. However, the success of allo-HSCT is often overshadowed by acute graft-versus-host disease (aGVHD), a life-threatening complication. Here, we show in patients and murine models that the circadian timing of stem cell infusion dictates the development of aGVHD. Early-infused patients exhibit a significantly lower incidence and severity of aGVHD, as well as improved survival. We observed time-of-day variations in the levels of cytokines, especially IL-1α, which controls donor T cell responses after transplantation. The levels of IL-1α in patients were strongly associated with the development of aGVHD. Furthermore, preclinical results showed that the administration of IL-1α neutralizing antibodies markedly alleviated aGVHD and increased survival. Our study suggests that scheduling stem cell infusions early in the day could be a simple yet transformative intervention for preventing aGVHD.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"21 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736970","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}
CellPub Date : 2025-03-31DOI: 10.1016/j.cell.2025.03.002
Pierre Sabatier, Maico Lechner, Ulises H. Guzmán, Christian M. Beusch, Xinlei Zeng, Longteng Wang, Fabiana Izaguirre, Anjali Seth, Olga Gritsenko, Sergey Rodin, Karl-Henrik Grinnemo, Zilu Ye, Jesper V. Olsen
{"title":"Global analysis of protein turnover dynamics in single cells","authors":"Pierre Sabatier, Maico Lechner, Ulises H. Guzmán, Christian M. Beusch, Xinlei Zeng, Longteng Wang, Fabiana Izaguirre, Anjali Seth, Olga Gritsenko, Sergey Rodin, Karl-Henrik Grinnemo, Zilu Ye, Jesper V. Olsen","doi":"10.1016/j.cell.2025.03.002","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.002","url":null,"abstract":"Single-cell proteomics (SCPs) has advanced significantly, yet it remains largely unidimensional, focusing primarily on protein abundances. In this study, we employed a pulsed stable isotope labeling by amino acids in cell culture (pSILAC) approach to simultaneously analyze protein abundance and turnover in single cells (SC-pSILAC). Using a state-of-the-art SCP workflow, we demonstrated that two SILAC labels are detectable from ∼4,000 proteins in single HeLa cells recapitulating known biology. We performed a large-scale time-series SC-pSILAC analysis of undirected differentiation of human induced pluripotent stem cells (iPSCs) encompassing 6 sampling times over 2 months and analyzed >1,000 cells. Protein turnover dynamics highlighted differentiation-specific co-regulation of protein complexes with core histone turnover, discriminating dividing and non-dividing cells. Lastly, correlating cell diameter with the abundance of individual proteins showed that histones and some cell-cycle proteins do not scale with cell size. The SC-pSILAC method provides a multidimensional view of protein dynamics in single-cell biology.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"34 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736971","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":"A single-cell atlas reveals immune heterogeneity in anti-PD-1-treated non-small cell lung cancer","authors":"Zedao Liu, Zhenlin Yang, Junqi Wu, Wenjie Zhang, Yuxuan Sun, Chao Zhang, Guangyu Bai, Li Yang, Hongtao Fan, Yawen Chen, Lei Zhang, Benyuan Jiang, Xiaoyan Liu, Xiaoshi Ma, Wei Tang, Chang Liu, Yang Qu, Lixu Yan, Deping Zhao, Yilong Wu, Zemin Zhang","doi":"10.1016/j.cell.2025.03.018","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.018","url":null,"abstract":"Anti-PD-(L)1 treatment is standard for non-small cell lung cancer (NSCLC), but patients show variable responses to the same regimen. The tumor immune microenvironment (TIME) is associated with immunotherapy response, yet the heterogeneous underlying therapeutic outcomes remain underexplored. We applied single-cell RNA and TCR sequencing (scRNA/TCR-seq) to analyze surgical tumor samples from 234 NSCLC patients post-neoadjuvant chemo-immunotherapy. Analyses revealed five distinct TIME subtypes with varying major pathological response (MPR) rates. MPR patients had elevated levels of <em>FGFBP2</em><sup>+</sup> NK/NK-like T cells, memory B cells, or effector T cells, while non-MPR patients showed higher <em>CCR8</em><sup>+</sup> Tregs. T cell clonal expansion analyses unveiled heterogeneity in non-MPR patients, marked by varying expansions of Tex-relevant cells and <em>CCR8</em><sup>+</sup> Tregs. Precursor exhausted T cells (Texp cells) correlated with recurrence-free survival, identifying a patient subgroup with reduced recurrence risk despite lack of MPR. Our study dissects TIME heterogeneity in response to chemoimmunotherapy, offering insights for NSCLC management.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"2 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703201","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":"Large language models deconstruct the clinical intuition behind diagnosing autism","authors":"Jack Stanley, Emmett Rabot, Siva Reddy, Eugene Belilovsky, Laurent Mottron, Danilo Bzdok","doi":"10.1016/j.cell.2025.02.025","DOIUrl":"https://doi.org/10.1016/j.cell.2025.02.025","url":null,"abstract":"Efforts to use genome-wide assays or brain scans to diagnose autism have seen diminishing returns. Yet the clinical intuition of healthcare professionals, based on longstanding first-hand experience, remains the gold standard for diagnosis of autism. We leveraged deep learning to deconstruct and interrogate the logic of expert clinician intuition from clinical reports to inform our understanding of autism. After pre-training on hundreds of millions of general sentences, we finessed large language models (LLMs) on >4,000 free-form health records from healthcare professionals to distinguish confirmed versus suspected autism cases. By introducing an explainability strategy, our extended language model architecture could pin down the most salient single sentences in what drives clinical thinking toward correct diagnoses. Our framework flagged the most autism-critical DSM-5 criteria to be stereotyped repetitive behaviors, special interests, and perception-based behaviors, which challenges today’s focus on deficits in social interplay, suggesting necessary revision of long-trusted diagnostic criteria in gold-standard instruments.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703242","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}
CellPub Date : 2025-03-24DOI: 10.1016/j.cell.2025.02.030
Brendan B. Larsen, Teagan McMahon, Jack T. Brown, Zhaoqian Wang, Caelan E. Radford, James E. Crowe, David Veesler, Jesse D. Bloom
{"title":"Functional and antigenic landscape of the Nipah virus receptor-binding protein","authors":"Brendan B. Larsen, Teagan McMahon, Jack T. Brown, Zhaoqian Wang, Caelan E. Radford, James E. Crowe, David Veesler, Jesse D. Bloom","doi":"10.1016/j.cell.2025.02.030","DOIUrl":"https://doi.org/10.1016/j.cell.2025.02.030","url":null,"abstract":"Nipah virus recurrently spills over to humans, causing fatal infections. The viral receptor-binding protein (RBP or G) attaches to host receptors and is a major target of neutralizing antibodies. Here, we use deep mutational scanning to measure how all amino-acid mutations to the RBP affect cell entry, receptor binding, and escape from neutralizing antibodies. We identify functionally constrained regions of the RBP, including sites involved in oligomerization, along with mutations that differentially modulate RBP binding to its two ephrin receptors. We map escape mutations for six anti-RBP antibodies and find that few antigenic mutations are present in natural Nipah strains. Our findings offer insights into the potential for functional and antigenic evolution of the RBP that can inform the development of antibody therapies and vaccines.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"71 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677864","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}
CellPub Date : 2025-03-24DOI: 10.1016/j.cell.2025.02.028
Kai Sandvold Beckwith, Andreas Brunner, Natalia Rosalia Morero, Ralf Jungmann, Jan Ellenberg
{"title":"Nanoscale DNA tracing reveals the self-organization mechanism of mitotic chromosomes","authors":"Kai Sandvold Beckwith, Andreas Brunner, Natalia Rosalia Morero, Ralf Jungmann, Jan Ellenberg","doi":"10.1016/j.cell.2025.02.028","DOIUrl":"https://doi.org/10.1016/j.cell.2025.02.028","url":null,"abstract":"How genomic DNA is folded during cell division to form the characteristic rod-shaped mitotic chromosomes essential for faithful genome inheritance is a long-standing open question in biology. Here, we use nanoscale DNA tracing in single dividing cells to directly visualize how the 3D fold of genomic DNA changes during mitosis at scales from single loops to entire chromosomes. Our structural analysis reveals a characteristic genome scaling minimum of 6–8 megabases in mitosis. Combined with data-driven modeling and molecular perturbations, we can show that very large and strongly overlapping loops formed by condensins are the fundamental structuring principle of mitotic chromosomes. These loops compact chromosomes locally and globally to the limit set by chromatin self-repulsion. The characteristic length, density, and increasingly overlapping structure of mitotic loops we observe in 3D fully explain how the rod-shaped mitotic chromosome structure emerges by self-organization during cell division.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"183 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677863","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":"Enteric neuronal Piezo1 maintains mechanical and immunological homeostasis by sensing force","authors":"Zili Xie, Lillian Rose, Jing Feng, Yonghui Zhao, Yisi Lu, Harry Kane, Timothy J. Hibberd, Xueming Hu, Zhen Wang, Kaikai Zang, Xingliang Yang, Quentin Richardson, Rahmeh Othman, Olivia Venezia, Ademi Zhakyp, Fang Gao, Nobuya Abe, Keren Vigeland, Hongshen Wang, Camren Branch, Ruaidhrí Jackson","doi":"10.1016/j.cell.2025.02.031","DOIUrl":"https://doi.org/10.1016/j.cell.2025.02.031","url":null,"abstract":"The gastrointestinal (GI) tract experiences a myriad of mechanical forces while orchestrating digestion and barrier immunity. A central conductor of these processes, the enteric nervous system (ENS), detects luminal pressure to regulate peristalsis independently of extrinsic input from the central and peripheral nervous systems. However, how the ∼500 million enteric neurons that reside in the GI tract sense and respond to force remains unknown. Herein, we establish that the mechanosensor <em>Piezo1</em> is functionally expressed in cholinergic enteric neurons. Optogenetic stimulation of Piezo1<sup>+</sup> cholinergic enteric neurons drives colonic motility, while Piezo1 deficiency reduces cholinergic neuronal activity and slows peristalsis. Additionally, Piezo1 deficiency in cholinergic enteric neurons abolishes exercise-induced acceleration of GI motility. Finally, we uncover that enteric neuronal Piezo1 function is required for motility alterations in colitis and acts to prevent aberrant inflammation and tissue damage. This work uncovers how the ENS senses and responds to mechanical force.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"57 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677862","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}
CellPub Date : 2025-03-21DOI: 10.1016/j.cell.2025.02.022
Kyungdeok Kim, Daviti Abramishvili, Siling Du, Zachary Papadopoulos, Jay Cao, Jasmin Herz, Igor Smirnov, Jean-Leon Thomas, Marco Colonna, Jonathan Kipnis
{"title":"Meningeal lymphatics-microglia axis regulates synaptic physiology","authors":"Kyungdeok Kim, Daviti Abramishvili, Siling Du, Zachary Papadopoulos, Jay Cao, Jasmin Herz, Igor Smirnov, Jean-Leon Thomas, Marco Colonna, Jonathan Kipnis","doi":"10.1016/j.cell.2025.02.022","DOIUrl":"https://doi.org/10.1016/j.cell.2025.02.022","url":null,"abstract":"Meningeal lymphatics serve as an outlet for cerebrospinal fluid, and their dysfunction is associated with various neurodegenerative conditions. Previous studies have demonstrated that dysfunctional meningeal lymphatics evoke behavioral changes, but the neural mechanisms underlying these changes have remained elusive. Here, we show that prolonged impairment of meningeal lymphatics alters the balance of cortical excitatory and inhibitory synaptic inputs, accompanied by deficits in memory tasks. These synaptic and behavioral alterations induced by lymphatic dysfunction are mediated by microglia, leading to increased expression of the interleukin 6 gene (<em>Il6</em>). IL-6 drives inhibitory synapse phenotypes via a combination of <em>trans</em>- and classical IL-6 signaling. Restoring meningeal lymphatic function in aged mice reverses age-associated synaptic and behavioral alterations. Our findings suggest that dysfunctional meningeal lymphatics adversely impact cortical circuitry through an IL-6-dependent mechanism and identify a potential target for treating aging-associated cognitive decline.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"26 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666289","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}
CellPub Date : 2025-03-21DOI: 10.1016/j.cell.2025.02.027
Florian Wollweber, Jingwei Xu, Rafael I. Ponce-Toledo, Florina Marxer, Thiago Rodrigues-Oliveira, Anja Pössnecker, Zhen-Hao Luo, Jessie James Limlingan Malit, Anastasiia Kokhanovska, Michal Wieczorek, Christa Schleper, Martin Pilhofer
{"title":"Microtubules in Asgard archaea","authors":"Florian Wollweber, Jingwei Xu, Rafael I. Ponce-Toledo, Florina Marxer, Thiago Rodrigues-Oliveira, Anja Pössnecker, Zhen-Hao Luo, Jessie James Limlingan Malit, Anastasiia Kokhanovska, Michal Wieczorek, Christa Schleper, Martin Pilhofer","doi":"10.1016/j.cell.2025.02.027","DOIUrl":"https://doi.org/10.1016/j.cell.2025.02.027","url":null,"abstract":"Microtubules are a hallmark of eukaryotes. Archaeal and bacterial homologs of tubulins typically form homopolymers and non-tubular superstructures. The origin of heterodimeric tubulins assembling into microtubules remains unclear.Here, we report the discovery of microtubule-forming tubulins in Asgard archaea, the closest known relatives of eukaryotes. These Asgard tubulins (AtubA/B) are closely related to eukaryotic α/β-tubulins and the enigmatic bacterial tubulins BtubA/B. Proteomics of <em>Candidatus</em> Lokiarchaeum ossiferum showed that AtubA/B were highly expressed. Cryoelectron microscopy structures demonstrate that AtubA/B form eukaryote-like heterodimers, which assembled into 5-protofilament bona fide microtubules <em>in vitro</em>. The additional paralog AtubB2 lacks a nucleotide-binding site and competitively displaced AtubB. These AtubA/B2 heterodimers polymerized into 7-protofilament non-canonical microtubules. In a sub-population of <em>Ca.</em> Lokiarchaeum ossiferum cells, cryo-tomography revealed tubular structures, while expansion microscopy identified AtubA/B cytoskeletal assemblies.Our findings suggest a pre-eukaryotic origin of microtubules and provide a framework for understanding the fundamental principles of microtubule assembly.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"93 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666288","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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