Pub Date : 2025-01-20DOI: 10.1016/j.cell.2024.12.021
Side Hu, Heesu Kim, Pan Yang, Zishuo Yu, Barbara Ludeke, Shawna Mobilia, Junhua Pan, Margaret Stratton, Yuemin Bian, Rachel Fearns, Jonathan Abraham
Nipah virus (NiV) is a bat-borne, zoonotic RNA virus that is highly pathogenic in humans. The NiV polymerase, which mediates viral genome replication and mRNA transcription, is a promising drug target. We determined the cryoelectron microscopy (cryo-EM) structure of the NiV polymerase complex, comprising the large protein (L) and phosphoprotein (P), and performed structural, biophysical, and in-depth functional analyses of the NiV polymerase. The L protein assembles with a long P tetrameric coiled-coil that is capped by a bundle of ⍺-helices that we show are likely dynamic in solution. Docking studies with a known L inhibitor clarify mechanisms of antiviral drug resistance. In addition, we identified L protein features that are required for both transcription and RNA replication and mutations that have a greater impact on RNA replication than on transcription. Our findings have the potential to aid in the rational development of drugs to combat NiV infection.
{"title":"Structural and functional analysis of the Nipah virus polymerase complex","authors":"Side Hu, Heesu Kim, Pan Yang, Zishuo Yu, Barbara Ludeke, Shawna Mobilia, Junhua Pan, Margaret Stratton, Yuemin Bian, Rachel Fearns, Jonathan Abraham","doi":"10.1016/j.cell.2024.12.021","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.021","url":null,"abstract":"Nipah virus (NiV) is a bat-borne, zoonotic RNA virus that is highly pathogenic in humans. The NiV polymerase, which mediates viral genome replication and mRNA transcription, is a promising drug target. We determined the cryoelectron microscopy (cryo-EM) structure of the NiV polymerase complex, comprising the large protein (L) and phosphoprotein (P), and performed structural, biophysical, and in-depth functional analyses of the NiV polymerase. The L protein assembles with a long P tetrameric coiled-coil that is capped by a bundle of ⍺-helices that we show are likely dynamic in solution. Docking studies with a known L inhibitor clarify mechanisms of antiviral drug resistance. In addition, we identified L protein features that are required for both transcription and RNA replication and mutations that have a greater impact on RNA replication than on transcription. Our findings have the potential to aid in the rational development of drugs to combat NiV infection.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"78 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990312","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}
Pub Date : 2025-01-20DOI: 10.1016/j.cell.2024.12.014
Qi Chen, Binbin Zhao, Ziyang Tan, Gustav Hedberg, Jun Wang, Laura Gonzalez, Constantin Habimana Mugabo, Anette Johnsson, Erika Negrini, Laura Piñero Páez, Lucie Rodriguez, Anna James, Yang Chen, Jaromír Mikeš, Anna Karin Bernhardsson, Stefan Markus Reitzner, Ferdinand von Walden, Olivia O’Neill, Hugo Barcenilla, Chunlin Wang, Petter Brodin
Cancer is the leading cause of death from disease in children. Survival depends not only on surgery, cytostatic drugs, and radiation but also on systemic immune responses. Factors influencing these immune responses in children of different ages and tumor types are unknown. Novel immunotherapies can enhance anti-tumor immune responses, but few children have benefited, and markers of effective responses are lacking. Here, we present a systems-level analysis of immune responses in 191 children within a population-based cohort with diverse tumors and reveal that age and tumor type shape immune responses differently. Systemic inflammation and cytotoxic T cell responses correlate with tumor mutation rates and immune cell infiltration. Clonally expanded T cell responses are rarely detected in blood or tumors at diagnosis but are sometimes elicited during treatment. Expanded T cells are similarly regulated in children and adults with more immunogenic cancers. This research aims to facilitate the development of precision immunotherapies for children with cancer.
{"title":"Systems-level immunomonitoring in children with solid tumors to enable precision medicine","authors":"Qi Chen, Binbin Zhao, Ziyang Tan, Gustav Hedberg, Jun Wang, Laura Gonzalez, Constantin Habimana Mugabo, Anette Johnsson, Erika Negrini, Laura Piñero Páez, Lucie Rodriguez, Anna James, Yang Chen, Jaromír Mikeš, Anna Karin Bernhardsson, Stefan Markus Reitzner, Ferdinand von Walden, Olivia O’Neill, Hugo Barcenilla, Chunlin Wang, Petter Brodin","doi":"10.1016/j.cell.2024.12.014","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.014","url":null,"abstract":"Cancer is the leading cause of death from disease in children. Survival depends not only on surgery, cytostatic drugs, and radiation but also on systemic immune responses. Factors influencing these immune responses in children of different ages and tumor types are unknown. Novel immunotherapies can enhance anti-tumor immune responses, but few children have benefited, and markers of effective responses are lacking. Here, we present a systems-level analysis of immune responses in 191 children within a population-based cohort with diverse tumors and reveal that age and tumor type shape immune responses differently. Systemic inflammation and cytotoxic T cell responses correlate with tumor mutation rates and immune cell infiltration. Clonally expanded T cell responses are rarely detected in blood or tumors at diagnosis but are sometimes elicited during treatment. Expanded T cells are similarly regulated in children and adults with more immunogenic cancers. This research aims to facilitate the development of precision immunotherapies for children with cancer.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"56 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990311","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}
Pub Date : 2025-01-20DOI: 10.1016/j.cell.2024.12.016
Rafael Valdés-Mas, Avner Leshem, Danping Zheng, Yotam Cohen, Lara Kern, Niv Zmora, Yiming He, Corine Katina, Shimrit Eliyahu-Miller, Tal Yosef-Hevroni, Liron Richman, Barbara Raykhel, Shira Allswang, Reut Better, Merav Shmueli, Aurelia Saftien, Nyssa Cullin, Fernando Slamovitz, Dragos Ciocan, Kyanna S. Ouyang, Eran Elinav
Host-microbiome-dietary interactions play crucial roles in regulating human health, yet their direct functional assessment remains challenging. We adopted metagenome-informed metaproteomics (MIM), in mice and humans, to non-invasively explore species-level microbiome-host interactions during commensal and pathogen colonization, nutritional modification, and antibiotic-induced perturbation. Simultaneously, fecal MIM accurately characterized the nutritional exposure landscape in multiple clinical and dietary contexts. Implementation of MIM in murine auto-inflammation and in human inflammatory bowel disease (IBD) characterized a “compositional dysbiosis” and a concomitant species-specific “functional dysbiosis” driven by suppressed commensal responses to inflammatory host signals. Microbiome transfers unraveled early-onset kinetics of these host-commensal cross-responsive patterns, while predictive analyses identified candidate fecal host-microbiome IBD biomarker protein pairs outperforming S100A8/S100A9 (calprotectin). Importantly, a simultaneous fecal nutritional MIM assessment enabled the determination of IBD-related consumption patterns, dietary treatment compliance, and small intestinal digestive aberrations. Collectively, a parallelized dietary-bacterial-host MIM assessment functionally uncovers trans-kingdom interactomes shaping gastrointestinal ecology while offering personalized diagnostic and therapeutic insights into microbiome-associated disease.
{"title":"Metagenome-informed metaproteomics of the human gut microbiome, host, and dietary exposome uncovers signatures of health and inflammatory bowel disease","authors":"Rafael Valdés-Mas, Avner Leshem, Danping Zheng, Yotam Cohen, Lara Kern, Niv Zmora, Yiming He, Corine Katina, Shimrit Eliyahu-Miller, Tal Yosef-Hevroni, Liron Richman, Barbara Raykhel, Shira Allswang, Reut Better, Merav Shmueli, Aurelia Saftien, Nyssa Cullin, Fernando Slamovitz, Dragos Ciocan, Kyanna S. Ouyang, Eran Elinav","doi":"10.1016/j.cell.2024.12.016","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.016","url":null,"abstract":"Host-microbiome-dietary interactions play crucial roles in regulating human health, yet their direct functional assessment remains challenging. We adopted metagenome-informed metaproteomics (MIM), in mice and humans, to non-invasively explore species-level microbiome-host interactions during commensal and pathogen colonization, nutritional modification, and antibiotic-induced perturbation. Simultaneously, fecal MIM accurately characterized the nutritional exposure landscape in multiple clinical and dietary contexts. Implementation of MIM in murine auto-inflammation and in human inflammatory bowel disease (IBD) characterized a “compositional dysbiosis” and a concomitant species-specific “functional dysbiosis” driven by suppressed commensal responses to inflammatory host signals. Microbiome transfers unraveled early-onset kinetics of these host-commensal cross-responsive patterns, while predictive analyses identified candidate fecal host-microbiome IBD biomarker protein pairs outperforming S100A8/S100A9 (calprotectin). Importantly, a simultaneous fecal nutritional MIM assessment enabled the determination of IBD-related consumption patterns, dietary treatment compliance, and small intestinal digestive aberrations. Collectively, a parallelized dietary-bacterial-host MIM assessment functionally uncovers trans-kingdom interactomes shaping gastrointestinal ecology while offering personalized diagnostic and therapeutic insights into microbiome-associated disease.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"26 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989764","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}
Pub Date : 2025-01-20DOI: 10.1016/j.cell.2024.12.013
Marlies E. Oomen, Diego Rodriguez-Terrones, Mayuko Kurome, Valeri Zakhartchenko, Lorenza Mottes, Kilian Simmet, Camille Noll, Tsunetoshi Nakatani, Carlos Michel Mourra-Diaz, Irene Aksoy, Pierre Savatier, Jonathan Göke, Eckhard Wolf, Henrik Kaessmann, Maria-Elena Torres-Padilla
Transcriptional activation of the embryonic genome (EGA) is a major developmental landmark enabling the embryo to become independent from maternal control. The magnitude and control of transcriptional reprogramming during this event across mammals remains poorly understood. Here, we developed Smart-seq+5′ for high sensitivity, full-length transcript coverage and simultaneous capture of 5′ transcript information from single cells and single embryos. Using Smart-seq+5′, we profiled 34 developmental stages in 5 mammalian species and provide an extensive characterization of the transcriptional repertoire of early development before, during, and after EGA. We demonstrate widespread transposable element (TE)-driven transcription across species, including, remarkably, of DNA transposons. We identify 19,657 TE-driven genic transcripts, suggesting extensive TE co-option in early development over evolutionary timescales. TEs display similar expression dynamics across species and species-specific patterns, suggesting shared and divergent regulation. Our work provides a powerful resource for understanding transcriptional regulation of mammalian development.
{"title":"An atlas of transcription initiation reveals regulatory principles of gene and transposable element expression in early mammalian development","authors":"Marlies E. Oomen, Diego Rodriguez-Terrones, Mayuko Kurome, Valeri Zakhartchenko, Lorenza Mottes, Kilian Simmet, Camille Noll, Tsunetoshi Nakatani, Carlos Michel Mourra-Diaz, Irene Aksoy, Pierre Savatier, Jonathan Göke, Eckhard Wolf, Henrik Kaessmann, Maria-Elena Torres-Padilla","doi":"10.1016/j.cell.2024.12.013","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.013","url":null,"abstract":"Transcriptional activation of the embryonic genome (EGA) is a major developmental landmark enabling the embryo to become independent from maternal control. The magnitude and control of transcriptional reprogramming during this event across mammals remains poorly understood. Here, we developed Smart-seq+5′ for high sensitivity, full-length transcript coverage and simultaneous capture of 5′ transcript information from single cells and single embryos. Using Smart-seq+5′, we profiled 34 developmental stages in 5 mammalian species and provide an extensive characterization of the transcriptional repertoire of early development before, during, and after EGA. We demonstrate widespread transposable element (TE)-driven transcription across species, including, remarkably, of DNA transposons. We identify 19,657 TE-driven genic transcripts, suggesting extensive TE co-option in early development over evolutionary timescales. TEs display similar expression dynamics across species and species-specific patterns, suggesting shared and divergent regulation. Our work provides a powerful resource for understanding transcriptional regulation of mammalian development.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"77 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989765","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}
Recently, oncolytic virus (OV) therapy has shown great promise in treating malignancies. However, intravenous safety and inherent lack of immunity are two significant limitations in clinical practice. Herein, we successfully developed a recombinant Newcastle disease virus with porcine α1,3GT gene (NDV-GT) triggering hyperacute rejection. We demonstrated its feasibility in preclinical studies. The intravenous NDV-GT showed superior ability to eradicate tumor cells in our innovative CRISPR-mediated primary hepatocellular carcinoma monkeys. Importantly, the interventional clinical trial treating 20 patients with relapsed/refractory metastatic cancer (Chinese Clinical Trial Registry of WHO, ChiCTR2000031980) showed a high rate (90.00%) of disease control and durable responses, without serious adverse events and clinically functional neutralizing antibodies, further suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of NDV-GT for immunovirotherapy. Collectively, our results demonstrate the high safety and efficacy of intravenous NDV-GT, thus providing an innovative technology for OV therapy in oncological therapeutics and beyond.
{"title":"Hyperacute rejection-engineered oncolytic virus for interventional clinical trial in refractory cancer patients","authors":"Liping Zhong, Lu Gan, Bing Wang, Tao Wu, Fei Yao, Wenlin Gong, Hongmei Peng, Zhiming Deng, Guoyou Xiao, Xiyu Liu, Jintong Na, Desong Xia, Xianjun Yu, Zhikun Zhang, Bangde Xiang, Yu Huo, Dan Yan, Zhixin Dong, Fang Fang, Yun Ma, Yongxiang Zhao","doi":"10.1016/j.cell.2024.12.010","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.010","url":null,"abstract":"Recently, oncolytic virus (OV) therapy has shown great promise in treating malignancies. However, intravenous safety and inherent lack of immunity are two significant limitations in clinical practice. Herein, we successfully developed a recombinant Newcastle disease virus with porcine <em>α1,3GT</em> gene (NDV-GT) triggering hyperacute rejection. We demonstrated its feasibility in preclinical studies. The intravenous NDV-GT showed superior ability to eradicate tumor cells in our innovative CRISPR-mediated primary hepatocellular carcinoma monkeys. Importantly, the interventional clinical trial treating 20 patients with relapsed/refractory metastatic cancer (Chinese Clinical Trial Registry of WHO, ChiCTR2000031980) showed a high rate (90.00%) of disease control and durable responses, without serious adverse events and clinically functional neutralizing antibodies, further suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of NDV-GT for immunovirotherapy. Collectively, our results demonstrate the high safety and efficacy of intravenous NDV-GT, thus providing an innovative technology for OV therapy in oncological therapeutics and beyond.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"30 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987537","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}
Pub Date : 2025-01-17DOI: 10.1016/j.cell.2024.12.009
Giuseppe Quarto, Andrea Li Greci, Martin Bizet, Audrey Penning, Irina Primac, Frédéric Murisier, Liliana Garcia-Martinez, Rodrigo L. Borges, Qingzeng Gao, Pradeep K.R. Cingaram, Emilie Calonne, Bouchra Hassabi, Céline Hubert, Adèle Herpoel, Pascale Putmans, Frédérique Mies, Jérôme Martin, Louis Van der Linden, Gaurav Dube, Pankaj Kumar, François Fuks
The marking of DNA, histones, and RNA is central to gene expression regulation in development and disease. Recent evidence links N6-methyladenosine (m6A), installed on RNA by the METTL3-METTL14 methyltransferase complex, to histone modifications, but the link between m6A and DNA methylation remains scarcely explored. This study shows that METTL3-METTL14 recruits the DNA methyltransferase DNMT1 to chromatin for gene-body methylation. We identify a set of genes whose expression is fine-tuned by both gene-body 5mC, which promotes transcription, and m6A, which destabilizes transcripts. We demonstrate that METTL3-METTL14-dependent 5mC and m6A are both essential for the differentiation of embryonic stem cells into embryoid bodies and that the upregulation of key differentiation genes during early differentiation depends on the dynamic balance between increased 5mC and decreased m6A. Our findings add a surprising dimension to our understanding of how epigenetics and epitranscriptomics combine to regulate gene expression and impact development and likely other biological processes.
{"title":"Fine-tuning of gene expression through the Mettl3-Mettl14-Dnmt1 axis controls ESC differentiation","authors":"Giuseppe Quarto, Andrea Li Greci, Martin Bizet, Audrey Penning, Irina Primac, Frédéric Murisier, Liliana Garcia-Martinez, Rodrigo L. Borges, Qingzeng Gao, Pradeep K.R. Cingaram, Emilie Calonne, Bouchra Hassabi, Céline Hubert, Adèle Herpoel, Pascale Putmans, Frédérique Mies, Jérôme Martin, Louis Van der Linden, Gaurav Dube, Pankaj Kumar, François Fuks","doi":"10.1016/j.cell.2024.12.009","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.009","url":null,"abstract":"The marking of DNA, histones, and RNA is central to gene expression regulation in development and disease. Recent evidence links N6-methyladenosine (m<sup>6</sup>A), installed on RNA by the METTL3-METTL14 methyltransferase complex, to histone modifications, but the link between m<sup>6</sup>A and DNA methylation remains scarcely explored. This study shows that METTL3-METTL14 recruits the DNA methyltransferase DNMT1 to chromatin for gene-body methylation. We identify a set of genes whose expression is fine-tuned by both gene-body 5mC, which promotes transcription, and m<sup>6</sup>A, which destabilizes transcripts. We demonstrate that METTL3-METTL14-dependent 5mC and m<sup>6</sup>A are both essential for the differentiation of embryonic stem cells into embryoid bodies and that the upregulation of key differentiation genes during early differentiation depends on the dynamic balance between increased 5mC and decreased m<sup>6</sup>A. Our findings add a surprising dimension to our understanding of how epigenetics and epitranscriptomics combine to regulate gene expression and impact development and likely other biological processes.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"83 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987695","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}
Pub Date : 2025-01-17DOI: 10.1016/j.cell.2024.12.008
Jan Philipp Kreysing, Maziar Heidari, Vojtech Zila, Sergio Cruz-León, Agnieszka Obarska-Kosinska, Vibor Laketa, Lara Rohleder, Sonja Welsch, Jürgen Köfinger, Beata Turoňová, Gerhard Hummer, Hans-Georg Kräusslich, Martin Beck
Upon infection, human immunodeficiency virus type 1 (HIV-1) releases its cone-shaped capsid into the cytoplasm of infected T cells and macrophages. The capsid enters the nuclear pore complex (NPC), driven by interactions with numerous phenylalanine-glycine (FG)-repeat nucleoporins (FG-Nups). Whether NPCs structurally adapt to capsid passage and whether capsids are modified during passage remains unknown, however. Here, we combined super-resolution and correlative microscopy with cryoelectron tomography and molecular simulations to study the nuclear entry of HIV-1 capsids in primary human macrophages. Our data indicate that cytosolically bound cyclophilin A is stripped off capsids entering the NPC, and the capsid hexagonal lattice remains largely intact inside and beyond the central channel. Strikingly, the NPC scaffold rings frequently crack during capsid passage, consistent with computer simulations indicating the need for NPC widening. The unique cone shape of the HIV-1 capsid facilitates its entry into NPCs and helps to crack their rings.
{"title":"Passage of the HIV capsid cracks the nuclear pore","authors":"Jan Philipp Kreysing, Maziar Heidari, Vojtech Zila, Sergio Cruz-León, Agnieszka Obarska-Kosinska, Vibor Laketa, Lara Rohleder, Sonja Welsch, Jürgen Köfinger, Beata Turoňová, Gerhard Hummer, Hans-Georg Kräusslich, Martin Beck","doi":"10.1016/j.cell.2024.12.008","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.008","url":null,"abstract":"Upon infection, human immunodeficiency virus type 1 (HIV-1) releases its cone-shaped capsid into the cytoplasm of infected T cells and macrophages. The capsid enters the nuclear pore complex (NPC), driven by interactions with numerous phenylalanine-glycine (FG)-repeat nucleoporins (FG-Nups). Whether NPCs structurally adapt to capsid passage and whether capsids are modified during passage remains unknown, however. Here, we combined super-resolution and correlative microscopy with cryoelectron tomography and molecular simulations to study the nuclear entry of HIV-1 capsids in primary human macrophages. Our data indicate that cytosolically bound cyclophilin A is stripped off capsids entering the NPC, and the capsid hexagonal lattice remains largely intact inside and beyond the central channel. Strikingly, the NPC scaffold rings frequently crack during capsid passage, consistent with computer simulations indicating the need for NPC widening. The unique cone shape of the HIV-1 capsid facilitates its entry into NPCs and helps to crack their rings.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"2 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987694","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}
Pub Date : 2025-01-16DOI: 10.1016/j.cell.2024.12.004
Mingrui Ding, Danni Wang, Hui Chen, Barry Kesner, Niklas-Benedikt Grimm, Uri Weissbein, Anna Lappala, Jiying Jiang, Carlos Rivera, Jizhong Lou, Pilong Li, Jeannie T. Lee
Xist RNA initiates X inactivation as it spreads in cis across the chromosome. Here, we reveal a biophysical basis for its cis-limited diffusion. Xist RNA and HNRNPK together drive a liquid-liquid phase separation (LLPS) that encapsulates the chromosome. HNRNPK droplets pull on Xist and internalize the RNA. Once internalized, Xist induces a further phase transition and “softens” the HNRNPK droplet. Xist alters the condensate’s deformability, adhesiveness, and wetting properties in vitro. Other Xist-interacting proteins are internalized and entrapped within the droplet, resulting in a concentration of Xist and protein partners within the condensate. We attribute LLPS to HNRNPK’s RGG and Xist’s repeat B (RepB) motifs. Mutating these motifs causes Xist diffusion, disrupts polycomb recruitment, and precludes the required mixing of chromosomal compartments for Xist’s migration. Thus, we hypothesize that phase transitions in HNRNPK condensates allow Xist to locally concentrate silencing factors and to spread through internal channels of the HNRNPK-encapsulated chromosome.
当它在染色体上顺式传播时，Xist RNA启动X的失活。在这里，我们揭示了其顺式有限扩散的生物物理基础。Xist RNA和HNRNPK一起驱动包裹染色体的液-液相分离（LLPS）。HNRNPK液滴拉住Xist并内化RNA。一旦内化，Xist诱导进一步的相变并“软化”HNRNPK液滴。Xist在体外改变冷凝物的变形性、黏附性和润湿性。其他与Xist相互作用的蛋白质被内化并被包裹在液滴中，从而在冷凝物中形成Xist和蛋白质伙伴的浓度。我们将LLPS归因于HNRNPK的RGG和Xist的repeat B （RepB）基序。这些基序的突变会导致Xist的扩散，破坏多梳的招募，并阻止Xist迁移所需的染色体区室混合。因此，我们假设HNRNPK凝聚体中的相变允许Xist局部集中沉默因子并通过HNRNPK包裹染色体的内部通道传播。
{"title":"A biophysical basis for the spreading behavior and limited diffusion of Xist","authors":"Mingrui Ding, Danni Wang, Hui Chen, Barry Kesner, Niklas-Benedikt Grimm, Uri Weissbein, Anna Lappala, Jiying Jiang, Carlos Rivera, Jizhong Lou, Pilong Li, Jeannie T. Lee","doi":"10.1016/j.cell.2024.12.004","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.004","url":null,"abstract":"Xist RNA initiates X inactivation as it spreads in <em>cis</em> across the chromosome. Here, we reveal a biophysical basis for its <em>cis</em>-limited diffusion. Xist RNA and HNRNPK together drive a liquid-liquid phase separation (LLPS) that encapsulates the chromosome. HNRNPK droplets pull on Xist and internalize the RNA. Once internalized, Xist induces a further phase transition and “softens” the HNRNPK droplet. Xist alters the condensate’s deformability, adhesiveness, and wetting properties <em>in vitro</em>. Other Xist-interacting proteins are internalized and entrapped within the droplet, resulting in a concentration of Xist and protein partners within the condensate. We attribute LLPS to HNRNPK’s RGG and Xist’s repeat B (RepB) motifs. Mutating these motifs causes Xist diffusion, disrupts polycomb recruitment, and precludes the required mixing of chromosomal compartments for Xist’s migration. Thus, we hypothesize that phase transitions in HNRNPK condensates allow Xist to locally concentrate silencing factors and to spread through internal channels of the HNRNPK-encapsulated chromosome.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"7 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987030","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}
Pub Date : 2025-01-16DOI: 10.1016/j.cell.2024.11.038
Robert E. Handsaker, Seva Kashin, Nora M. Reed, Steven Tan, Won-Seok Lee, Tara M. McDonald, Kiely Morris, Nolan Kamitaki, Christopher D. Mullally, Neda R. Morakabati, Melissa Goldman, Gabriel Lind, Rhea Kohli, Elisabeth Lawton, Marina Hogan, Kiku Ichihara, Sabina Berretta, Steven A. McCarroll
In Huntington’s disease (HD), striatal projection neurons (SPNs) degenerate during midlife; the core biological question involves how the disease-causing DNA repeat (CAG)n in the huntingtin (HTT) gene leads to neurodegeneration after decades of biological latency. We developed a single-cell method for measuring this repeat’s length alongside genome-wide RNA expression. We found that the HTT CAG repeat expands somatically from 40–45 to 100–500+ CAGs in SPNs. Somatic expansion from 40 to 150 CAGs had no apparent cell-autonomous effect, but SPNs with 150–500+ CAGs lost positive and then negative features of neuronal identity, de-repressed senescence/apoptosis genes, and were lost. Our results suggest that somatic repeat expansion beyond 150 CAGs causes SPNs to degenerate quickly and asynchronously. We conclude that in HD, at any one time, most neurons have an innocuous but unstable HTT gene and that HD pathogenesis is a DNA process for almost all of a neuron’s life.
{"title":"Long somatic DNA-repeat expansion drives neurodegeneration in Huntington’s disease","authors":"Robert E. Handsaker, Seva Kashin, Nora M. Reed, Steven Tan, Won-Seok Lee, Tara M. McDonald, Kiely Morris, Nolan Kamitaki, Christopher D. Mullally, Neda R. Morakabati, Melissa Goldman, Gabriel Lind, Rhea Kohli, Elisabeth Lawton, Marina Hogan, Kiku Ichihara, Sabina Berretta, Steven A. McCarroll","doi":"10.1016/j.cell.2024.11.038","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.038","url":null,"abstract":"In Huntington’s disease (HD), striatal projection neurons (SPNs) degenerate during midlife; the core biological question involves how the disease-causing DNA repeat (CAG)<sub>n</sub> in the <em>huntingtin</em> (<em>HTT</em>) gene leads to neurodegeneration after decades of biological latency. We developed a single-cell method for measuring this repeat’s length alongside genome-wide RNA expression. We found that the <em>HTT</em> CAG repeat expands somatically from 40–45 to 100–500+ CAGs in SPNs. Somatic expansion from 40 to 150 CAGs had no apparent cell-autonomous effect, but SPNs with 150–500+ CAGs lost positive and then negative features of neuronal identity, de-repressed senescence/apoptosis genes, and were lost. Our results suggest that somatic repeat expansion beyond 150 CAGs causes SPNs to degenerate quickly and asynchronously. We conclude that in HD, at any one time, most neurons have an innocuous but unstable <em>HTT</em> gene and that HD pathogenesis is a DNA process for almost all of a neuron’s life.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"8 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987033","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}
Pub Date : 2025-01-16DOI: 10.1016/j.cell.2024.12.020
Roman Barth, Iain F. Davidson, Jaco van der Torre, Michael Taschner, Stephan Gruber, Jan-Michael Peters, Cees Dekker
Structural maintenance of chromosomes (SMC) complexes organize the genome via DNA loop extrusion. Although some SMCs were reported to do so symmetrically, reeling DNA from both sides into the extruded DNA loop simultaneously, others perform loop extrusion asymmetrically toward one direction only. The mechanism underlying this variability remains unclear. Here, we examine the directionality of DNA loop extrusion by SMCs using in vitro single-molecule experiments. We find that cohesin and SMC5/6 do not reel in DNA from both sides, as reported before, but instead extrude DNA asymmetrically, although the direction can switch over time. Asymmetric DNA loop extrusion thus is the shared mechanism across all eukaryotic SMC complexes. For cohesin, direction switches strongly correlate with the turnover of the subunit NIPBL, during which DNA strand switching may occur. Apart from expanding by extrusion, loops frequently diffuse and shrink. The findings reveal that SMCs, surprisingly, can switch directions.
{"title":"SMC motor proteins extrude DNA asymmetrically and can switch directions","authors":"Roman Barth, Iain F. Davidson, Jaco van der Torre, Michael Taschner, Stephan Gruber, Jan-Michael Peters, Cees Dekker","doi":"10.1016/j.cell.2024.12.020","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.020","url":null,"abstract":"Structural maintenance of chromosomes (SMC) complexes organize the genome via DNA loop extrusion. Although some SMCs were reported to do so symmetrically, reeling DNA from both sides into the extruded DNA loop simultaneously, others perform loop extrusion asymmetrically toward one direction only. The mechanism underlying this variability remains unclear. Here, we examine the directionality of DNA loop extrusion by SMCs using <em>in vitro</em> single-molecule experiments. We find that cohesin and SMC5/6 do not reel in DNA from both sides, as reported before, but instead extrude DNA asymmetrically, although the direction can switch over time. Asymmetric DNA loop extrusion thus is the shared mechanism across all eukaryotic SMC complexes. For cohesin, direction switches strongly correlate with the turnover of the subunit NIPBL, during which DNA strand switching may occur. Apart from expanding by extrusion, loops frequently diffuse and shrink. The findings reveal that SMCs, surprisingly, can switch directions.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"49 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987031","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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