CellPub Date : 2024-09-17DOI: 10.1016/j.cell.2024.08.034
Giacomo G. Rossetti, Noëlle Dommann, Angeliki Karamichali, Vasilis S. Dionellis, Ainhoa Asensio Aldave, Tural Yarahmadov, Eddie Rodriguez-Carballo, Adrian Keogh, Daniel Candinas, Deborah Stroka, Thanos D. Halazonetis
{"title":"In vivo DNA replication dynamics unveil aging-dependent replication stress","authors":"Giacomo G. Rossetti, Noëlle Dommann, Angeliki Karamichali, Vasilis S. Dionellis, Ainhoa Asensio Aldave, Tural Yarahmadov, Eddie Rodriguez-Carballo, Adrian Keogh, Daniel Candinas, Deborah Stroka, Thanos D. Halazonetis","doi":"10.1016/j.cell.2024.08.034","DOIUrl":"https://doi.org/10.1016/j.cell.2024.08.034","url":null,"abstract":"<p>The genome duplication program is affected by multiple factors <em>in vivo</em>, including developmental cues, genotoxic stress, and aging. Here, we monitored DNA replication initiation dynamics in regenerating livers of young and old mice after partial hepatectomy to investigate the impact of aging. In young mice, the origin firing sites were well defined; the majority were located 10–50 kb upstream or downstream of expressed genes, and their position on the genome was conserved in human cells. Old mice displayed the same replication initiation sites, but origin firing was inefficient and accompanied by a replication stress response. Inhibitors of the ATR checkpoint kinase fully restored origin firing efficiency in the old mice but at the expense of an inflammatory response and without significantly enhancing the fraction of hepatocytes entering the cell cycle. These findings unveil aging-dependent replication stress and a crucial role of ATR in mitigating the stress-associated inflammation, a hallmark of aging.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142235431","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 : 2024-09-17DOI: 10.1016/j.cell.2024.08.033
{"title":"Fine-grained descending control of steering in walking Drosophila","authors":"","doi":"10.1016/j.cell.2024.08.033","DOIUrl":"https://doi.org/10.1016/j.cell.2024.08.033","url":null,"abstract":"Locomotion involves rhythmic limb movement patterns that originate in circuits outside the brain. Purposeful locomotion requires descending commands f…","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142235430","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 : 2024-09-17DOI: 10.1016/j.cell.2024.08.044
Reika Watanabe, Dawid Zyla, Diptiben Parekh, Connor Hong, Ying Jones, Sharon L. Schendel, William Wan, Guillaume Castillon, Erica Ollmann Saphire
{"title":"Intracellular Ebola virus nucleocapsid assembly revealed by in situ cryo-electron tomography","authors":"Reika Watanabe, Dawid Zyla, Diptiben Parekh, Connor Hong, Ying Jones, Sharon L. Schendel, William Wan, Guillaume Castillon, Erica Ollmann Saphire","doi":"10.1016/j.cell.2024.08.044","DOIUrl":"https://doi.org/10.1016/j.cell.2024.08.044","url":null,"abstract":"<p>Filoviruses, including the Ebola and Marburg viruses, cause hemorrhagic fevers with up to 90% lethality. The viral nucleocapsid is assembled by polymerization of the nucleoprotein (NP) along the viral genome, together with the viral proteins VP24 and VP35. We employed cryo-electron tomography of cells transfected with viral proteins and infected with model Ebola virus to illuminate assembly intermediates, as well as a 9 Å map of the complete intracellular assembly. This structure reveals a previously unresolved third and outer layer of NP complexed with VP35. The intrinsically disordered region, together with the C-terminal domain of this outer layer of NP, provides the constant width between intracellular nucleocapsid bundles and likely functions as a flexible tether to the viral matrix protein in the virion. A comparison of intracellular nucleocapsids with prior in-virion nucleocapsid structures reveals that the nucleocapsid further condenses vertically in the virion. The interfaces responsible for nucleocapsid assembly are highly conserved and offer targets for broadly effective antivirals.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142235433","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 : 2024-09-16DOI: 10.1016/j.cell.2024.08.036
Mingliang Jin, Robert I. Seed, Guoqing Cai, Tiffany Shing, Li Wang, Saburo Ito, Anthony Cormier, Stephanie A. Wankowicz, Jillian M. Jespersen, Jody L. Baron, Nicholas D. Carey, Melody G. Campbell, Zanlin Yu, Phu K. Tang, Pilar Cossio, Weihua Wen, Jianlong Lou, James Marks, Stephen L. Nishimura, Yifan Cheng
{"title":"Dynamic allostery drives autocrine and paracrine TGF-β signaling","authors":"Mingliang Jin, Robert I. Seed, Guoqing Cai, Tiffany Shing, Li Wang, Saburo Ito, Anthony Cormier, Stephanie A. Wankowicz, Jillian M. Jespersen, Jody L. Baron, Nicholas D. Carey, Melody G. Campbell, Zanlin Yu, Phu K. Tang, Pilar Cossio, Weihua Wen, Jianlong Lou, James Marks, Stephen L. Nishimura, Yifan Cheng","doi":"10.1016/j.cell.2024.08.036","DOIUrl":"https://doi.org/10.1016/j.cell.2024.08.036","url":null,"abstract":"<p>TGF-β, essential for development and immunity, is expressed as a latent complex (L-TGF-β) non-covalently associated with its prodomain and presented on immune cell surfaces by covalent association with GARP. Binding to integrin αvβ8 activates L-TGF-β1/GARP. The dogma is that mature TGF-β must physically dissociate from L-TGF-β1 for signaling to occur. Our previous studies discovered that αvβ8-mediated TGF-β autocrine signaling can occur without TGF-β1 release from its latent form. Here, we show that mice engineered to express TGF-β1 that cannot release from L-TGF-β1 survive without early lethal tissue inflammation, unlike those with TGF-β1 deficiency. Combining cryogenic electron microscopy with cell-based assays, we reveal a dynamic allosteric mechanism of autocrine TGF-β1 signaling without release where αvβ8 binding redistributes the intrinsic flexibility of L-TGF-β1 to expose TGF-β1 to its receptors. Dynamic allostery explains the TGF-β3 latency/activation mechanism and why TGF-β3 functions distinctly from TGF-β1, suggesting that it broadly applies to other flexible cell surface receptor/ligand systems.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234056","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 : 2024-09-13DOI: 10.1016/j.cell.2024.08.026
Yuanlong Zhang, Mingrui Wang, Qiyu Zhu, Yuduo Guo, Bo Liu, Jiamin Li, Xiao Yao, Chui Kong, Yi Zhang, Yuchao Huang, Hai Qi, Jiamin Wu, Zengcai V. Guo, Qionghai Dai
{"title":"Long-term mesoscale imaging of 3D intercellular dynamics across a mammalian organ","authors":"Yuanlong Zhang, Mingrui Wang, Qiyu Zhu, Yuduo Guo, Bo Liu, Jiamin Li, Xiao Yao, Chui Kong, Yi Zhang, Yuchao Huang, Hai Qi, Jiamin Wu, Zengcai V. Guo, Qionghai Dai","doi":"10.1016/j.cell.2024.08.026","DOIUrl":"https://doi.org/10.1016/j.cell.2024.08.026","url":null,"abstract":"<p>A comprehensive understanding of physio-pathological processes necessitates non-invasive intravital three-dimensional (3D) imaging over varying spatial and temporal scales. However, huge data throughput, optical heterogeneity, surface irregularity, and phototoxicity pose great challenges, leading to an inevitable trade-off between volume size, resolution, speed, sample health, and system complexity. Here, we introduce a compact real-time, ultra-large-scale, high-resolution 3D mesoscope (RUSH3D), achieving uniform resolutions of 2.6 × 2.6 × 6 μm<sup>3</sup> across a volume of 8,000 × 6,000 × 400 μm<sup>3</sup> at 20 Hz with low phototoxicity. Through the integration of multiple computational imaging techniques, RUSH3D facilitates a 13-fold improvement in data throughput and an orders-of-magnitude reduction in system size and cost. With these advantages, we observed premovement neural activity and cross-day visual representational drift across the mouse cortex, the formation and progression of multiple germinal centers in mouse inguinal lymph nodes, and heterogeneous immune responses following traumatic brain injury—all at single-cell resolution, opening up a horizon for intravital mesoscale study of large-scale intercellular interactions at the organ level.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142205066","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":"Neoself-antigens are the primary target for autoreactive T cells in human lupus","authors":"Shunsuke Mori, Masako Kohyama, Yoshiaki Yasumizu, Asa Tada, Kaito Tanzawa, Tatsuya Shishido, Kazuki Kishida, Hui Jin, Masayuki Nishide, Shoji Kawada, Daisuke Motooka, Daisuke Okuzaki, Ryota Naito, Wataru Nakai, Teru Kanda, Takayuki Murata, Chikashi Terao, Koichiro Ohmura, Noriko Arase, Tomohiro Kurosaki, Hisashi Arase","doi":"10.1016/j.cell.2024.08.025","DOIUrl":"https://doi.org/10.1016/j.cell.2024.08.025","url":null,"abstract":"<p>Major histocompatibility complex class II (MHC-II) is the most significant genetic risk factor for systemic lupus erythematosus (SLE), but the nature of the self-antigens that trigger autoimmunity remains unclear. Unusual self-antigens, termed neoself-antigens, are presented on MHC-II in the absence of the invariant chain essential for peptide presentation. Here, we demonstrate that neoself-antigens are the primary target for autoreactive T cells clonally expanded in SLE. When neoself-antigen presentation was induced by deleting the invariant chain in adult mice, neoself-reactive T cells were clonally expanded, leading to the development of lupus-like disease. Furthermore, we found that neoself-reactive CD4<sup>+</sup> T cells were significantly expanded in SLE patients. A high frequency of Epstein-Barr virus reactivation is a risk factor for SLE. Neoself-reactive lupus T cells were activated by Epstein-Barr-virus-reactivated cells through downregulation of the invariant chain. Together, our findings imply that neoself-antigen presentation by MHC-II plays a crucial role in the pathogenesis of SLE.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142205064","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 : 2024-09-13DOI: 10.1016/j.cell.2024.08.029
Jeremy G. Baldwin, Christoph Heuser-Loy, Tanmoy Saha, Roland C. Schelker, Dragana Slavkovic-Lukic, Nicholas Strieder, Inmaculada Hernandez-Lopez, Nisha Rana, Markus Barden, Fabio Mastrogiovanni, Azucena Martín-Santos, Andrea Raimondi, Philip Brohawn, Brandon W. Higgs, Claudia Gebhard, Veena Kapoor, William G. Telford, Sanjivan Gautam, Maria Xydia, Philipp Beckhove, Luca Gattinoni
{"title":"Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy","authors":"Jeremy G. Baldwin, Christoph Heuser-Loy, Tanmoy Saha, Roland C. Schelker, Dragana Slavkovic-Lukic, Nicholas Strieder, Inmaculada Hernandez-Lopez, Nisha Rana, Markus Barden, Fabio Mastrogiovanni, Azucena Martín-Santos, Andrea Raimondi, Philip Brohawn, Brandon W. Higgs, Claudia Gebhard, Veena Kapoor, William G. Telford, Sanjivan Gautam, Maria Xydia, Philipp Beckhove, Luca Gattinoni","doi":"10.1016/j.cell.2024.08.029","DOIUrl":"https://doi.org/10.1016/j.cell.2024.08.029","url":null,"abstract":"<p>Mitochondrial loss and dysfunction drive T cell exhaustion, representing major barriers to successful T cell-based immunotherapies. Here, we describe an innovative platform to supply exogenous mitochondria to T cells, overcoming these limitations. We found that bone marrow stromal cells establish nanotubular connections with T cells and leverage these intercellular highways to transplant stromal cell mitochondria into CD8<sup>+</sup> T cells. Optimal mitochondrial transfer required Talin 2 on both donor and recipient cells. CD8<sup>+</sup> T cells with donated mitochondria displayed enhanced mitochondrial respiration and spare respiratory capacity. When transferred into tumor-bearing hosts, these supercharged T cells expanded more robustly, infiltrated the tumor more efficiently, and exhibited fewer signs of exhaustion compared with T cells that did not take up mitochondria. As a result, mitochondria-boosted CD8<sup>+</sup> T cells mediated superior antitumor responses, prolonging animal survival. These findings establish intercellular mitochondrial transfer as a prototype of organelle medicine, opening avenues to next-generation cell therapies.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142205334","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 : 2024-09-13DOI: 10.1016/j.cell.2024.08.027
Niraj Mehta, Yifan Meng, Richard Zare, Rina Kamenetsky-Goldstein, Elizabeth Sattely
{"title":"A developmental gradient reveals biosynthetic pathways to eukaryotic toxins in monocot geophytes","authors":"Niraj Mehta, Yifan Meng, Richard Zare, Rina Kamenetsky-Goldstein, Elizabeth Sattely","doi":"10.1016/j.cell.2024.08.027","DOIUrl":"https://doi.org/10.1016/j.cell.2024.08.027","url":null,"abstract":"<p>Numerous eukaryotic toxins that accumulate in geophytic plants are valuable in the clinic, yet their biosynthetic pathways have remained elusive. A notable example is the >150 Amaryllidaceae alkaloids (AmAs), including galantamine, an FDA-approved treatment for Alzheimer’s disease. We show that while AmAs accumulate to high levels in many daffodil tissues, biosynthesis is localized to nascent, growing tissue at the leaf base. A similar trend is found in the production of steroidal alkaloids (e.g., cyclopamine) in corn lily. This model of active biosynthesis enabled the elucidation of a complete set of biosynthetic genes that can be used to produce AmAs. Taken together, our work sheds light on the developmental and enzymatic logic of diverse alkaloid biosynthesis in daffodils. More broadly, it suggests a paradigm for biosynthesis regulation in monocot geophytes, where plants are protected from herbivory through active charging of newly formed cells with eukaryotic toxins that persist as above-ground tissue develops.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142205336","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 : 2024-09-13DOI: 10.1016/j.cell.2024.08.024
Lauren V.C. Miller, Guido Papa, Marina Vaysburd, Shi Cheng, Paul W. Sweeney, Annabel Smith, Catarina Franco, Taxiarchis Katsinelos, Melissa Huang, Sophie A.I. Sanford, Jonathan Benn, Jasmine Farnsworth, Katie Higginson, Holly Joyner, William A. McEwan, Leo C. James
{"title":"Co-opting templated aggregation to degrade pathogenic tau assemblies and improve motor function","authors":"Lauren V.C. Miller, Guido Papa, Marina Vaysburd, Shi Cheng, Paul W. Sweeney, Annabel Smith, Catarina Franco, Taxiarchis Katsinelos, Melissa Huang, Sophie A.I. Sanford, Jonathan Benn, Jasmine Farnsworth, Katie Higginson, Holly Joyner, William A. McEwan, Leo C. James","doi":"10.1016/j.cell.2024.08.024","DOIUrl":"https://doi.org/10.1016/j.cell.2024.08.024","url":null,"abstract":"<p>Protein aggregation causes a wide range of neurodegenerative diseases. Targeting and removing aggregates, but not the functional protein, is a considerable therapeutic challenge. Here, we describe a therapeutic strategy called “RING-Bait,” which employs an aggregating protein sequence combined with an E3 ubiquitin ligase. RING-Bait is recruited into aggregates, whereupon clustering dimerizes the RING domain and activates its E3 function, resulting in the degradation of the aggregate complex. We exemplify this concept by demonstrating the specific degradation of tau aggregates while sparing soluble tau. Unlike immunotherapy, RING-Bait is effective against both seeded and cell-autonomous aggregation. RING-Bait removed tau aggregates seeded from Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP) brain extracts and was also effective in primary neurons. We used a brain-penetrant adeno-associated virus (AAV) to treat P301S tau transgenic mice, reducing tau pathology and improving motor function. A RING-Bait strategy could be applied to other neurodegenerative proteinopathies by replacing the Bait sequence to match the target aggregate.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142205065","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":"Metformin decelerates aging clock in male monkeys","authors":"Yuanhan Yang, Xiaoyong Lu, Ning Liu, Shuai Ma, Hui Zhang, Zhiyi Zhang, Kuan Yang, Mengmeng Jiang, Zikai Zheng, Yicheng Qiao, Qinchao Hu, Ying Huang, Yiyuan Zhang, Muzhao Xiong, Lixiao Liu, Xiaoyu Jiang, Pradeep Reddy, Xueda Dong, Fanshu Xu, Qiaoran Wang, Guang-Hui Liu","doi":"10.1016/j.cell.2024.08.021","DOIUrl":"https://doi.org/10.1016/j.cell.2024.08.021","url":null,"abstract":"<p>In a rigorous 40-month study, we evaluated the geroprotective effects of metformin on adult male cynomolgus monkeys, addressing a gap in primate aging research. The study encompassed a comprehensive suite of physiological, imaging, histological, and molecular evaluations, substantiating metformin’s influence on delaying age-related phenotypes at the organismal level. Specifically, we leveraged pan-tissue transcriptomics, DNA methylomics, plasma proteomics, and metabolomics to develop innovative monkey aging clocks and applied these to gauge metformin’s effects on aging. The results highlighted a significant slowing of aging indicators, notably a roughly 6-year regression in brain aging. Metformin exerts a substantial neuroprotective effect, preserving brain structure and enhancing cognitive ability. The geroprotective effects on primate neurons were partially mediated by the activation of Nrf2, a transcription factor with anti-oxidative capabilities. Our research pioneers the systemic reduction of multi-dimensional biological age in primates through metformin, paving the way for advancing pharmaceutical strategies against human aging.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171415","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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