Pub Date : 2025-02-14DOI: 10.1016/j.cell.2025.01.028
Dan Corral, Eduard Ansaldo, Jérémie Delaleu, Andrea C. Pichler, Juraj Kabat, Cihan Oguz, Ana Teijeiro, Daniel Yong, Mahnoor Abid, Claudia A. Rivera, Verena M. Link, Katharine Yang, Liang Chi, Jia Nie, Olena Kamenyeva, Yiping Fan, Jerry Kok Yen Chan, Florent Ginhoux, Rémy Bosselut, Yasmine Belkaid
Breastfeeding is an obligatory requirement of mammalian survival. This fundamental process is associated with the adaptation of maternal physiology, including the transformation of the mammary gland into a milk-secreting organ. How maternal immunity contributes to mammary gland remodeling and function remains largely unknown. Here, we show that maternal adaptive immunity plays a critical role in shaping lactogenesis. Specifically, physiological adaptation during pregnancy is associated with thymic involution and a paradoxical enrichment in intraepithelial lymphocyte (IEL) precursors that no longer migrate to the gut but instead preferentially accumulate within the mammary gland. IEL precursors differentiate into T-bet-expressing unconventional CD8αα lymphocytes in an IL-15-dependent manner. Mammary IELs control milk production by favoring the differentiation and maturation of contractile and milk-secreting cells, thereby promoting offspring fitness. Altogether, this work uncovers a contribution of the maternal adaptive immune system in organismal remodeling during pregnancy that is associated with mammary gland development and function.
{"title":"Mammary intraepithelial lymphocytes promote lactogenesis and offspring fitness","authors":"Dan Corral, Eduard Ansaldo, Jérémie Delaleu, Andrea C. Pichler, Juraj Kabat, Cihan Oguz, Ana Teijeiro, Daniel Yong, Mahnoor Abid, Claudia A. Rivera, Verena M. Link, Katharine Yang, Liang Chi, Jia Nie, Olena Kamenyeva, Yiping Fan, Jerry Kok Yen Chan, Florent Ginhoux, Rémy Bosselut, Yasmine Belkaid","doi":"10.1016/j.cell.2025.01.028","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.028","url":null,"abstract":"Breastfeeding is an obligatory requirement of mammalian survival. This fundamental process is associated with the adaptation of maternal physiology, including the transformation of the mammary gland into a milk-secreting organ. How maternal immunity contributes to mammary gland remodeling and function remains largely unknown. Here, we show that maternal adaptive immunity plays a critical role in shaping lactogenesis. Specifically, physiological adaptation during pregnancy is associated with thymic involution and a paradoxical enrichment in intraepithelial lymphocyte (IEL) precursors that no longer migrate to the gut but instead preferentially accumulate within the mammary gland. IEL precursors differentiate into T-bet-expressing unconventional CD8αα lymphocytes in an IL-15-dependent manner. Mammary IELs control milk production by favoring the differentiation and maturation of contractile and milk-secreting cells, thereby promoting offspring fitness. Altogether, this work uncovers a contribution of the maternal adaptive immune system in organismal remodeling during pregnancy that is associated with mammary gland development and function.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"11 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417807","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}
Coenzyme Q (CoQ) is essential for energy production by mitochondrial respiration, and it is a supplement most often used to promote cardiovascular health. Humans make CoQ10, but cereals and some vegetable/fruit crops synthesize CoQ9 with a side chain of nine isoprene units. Engineering CoQ10 production in crops would benefit human health, but this is hindered by the fact that the specific residues of the enzyme Coq1 that control chain length are unknown. Based on an extensive investigation of the distribution of CoQ9 and CoQ10 in land plants and the associated Coq1 sequence variation, we identified key amino acid changes at the base of the Coq1 catalytic pocket that occurred independently in multiple angiosperm lineages and repeatedly drove CoQ9 formation. Guided by this knowledge, we used gene editing to modify the native Coq1 genes of rice and wheat to produce CoQ10, paving the way for developing additional dietary sources of CoQ10.
{"title":"Design of CoQ10 crops based on evolutionary history","authors":"Jing-Jing Xu, Yuan Lei, Xiao-Fan Zhang, Jian-Xu Li, Qiupeng Lin, Xiang-Dong Wu, Yu-Guo Jiang, Wenyi Zhang, Runtong Qian, Shu-Yi Xiong, Kuo Tan, Yu Jia, Qiang Zhou, Yan Jiang, Hang Fan, Yan-Bo Huang, Ling-Jian Wang, Ji-Yun Liu, Yu Kong, Qing Zhao, Xiao-Ya Chen","doi":"10.1016/j.cell.2025.01.023","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.023","url":null,"abstract":"Coenzyme Q (CoQ) is essential for energy production by mitochondrial respiration, and it is a supplement most often used to promote cardiovascular health. Humans make CoQ<sub>10</sub>, but cereals and some vegetable/fruit crops synthesize CoQ<sub>9</sub> with a side chain of nine isoprene units. Engineering CoQ<sub>10</sub> production in crops would benefit human health, but this is hindered by the fact that the specific residues of the enzyme Coq1 that control chain length are unknown. Based on an extensive investigation of the distribution of CoQ<sub>9</sub> and CoQ<sub>10</sub> in land plants and the associated Coq1 sequence variation, we identified key amino acid changes at the base of the Coq1 catalytic pocket that occurred independently in multiple angiosperm lineages and repeatedly drove CoQ<sub>9</sub> formation. Guided by this knowledge, we used gene editing to modify the native <em>Coq1</em> genes of rice and wheat to produce CoQ<sub>10</sub>, paving the way for developing additional dietary sources of CoQ<sub>10</sub>.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"19 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401334","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}
Cancer cells acquire numerous mutations during tumorigenesis, including synonymous mutations that do not change the amino acid sequence of a protein. RNA N6-methyladenosine (m6A) is a post-transcriptional modification that plays critical roles in oncogenesis. Herein, we identified 12,849 mutations in the cancer genome with the potential to perturb m6A modification patterns, which we refer to as “m6A disruption mutations (m6A-DMs).” These are either synonymous m6A-DMs (sm6A-DMs) or missense m6A-DMs (mm6A-DMs) mutations, and the former is enriched within tumor suppressor genes, such as CDKN2A and BRCA2. Using epitranscriptomic editing, we demonstrate that manipulating m6A levels at specific sm6A-DM sites influences mRNA stability. Furthermore, introducing CDKN2A sm6A-DMs into cancer cells promotes tumor growth while BRCA2 sm6A-DMs sensitize tumors to the poly (ADP-ribose) polymerase inhibitor (PARPi) treatment. Our findings demonstrate sm6A-DMs as potential oncogenic drivers, unveiling implications for synonymous mutations in tumorigenesis and beyond.
{"title":"Synonymous mutations promote tumorigenesis by disrupting m6A-dependent mRNA metabolism","authors":"Yiheng Lan, Zhen Xia, Qizhe Shao, Peng Lin, Jinhong Lu, Xiaoying Xiao, Mengyue Zheng, Di Chen, Yanmei Dou, Qi Xie","doi":"10.1016/j.cell.2025.01.026","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.026","url":null,"abstract":"Cancer cells acquire numerous mutations during tumorigenesis, including synonymous mutations that do not change the amino acid sequence of a protein. RNA N6-methyladenosine (m<sup>6</sup>A) is a post-transcriptional modification that plays critical roles in oncogenesis. Herein, we identified 12,849 mutations in the cancer genome with the potential to perturb m<sup>6</sup>A modification patterns, which we refer to as “m<sup>6</sup>A disruption mutations (m<sup>6</sup>A-DMs).” These are either synonymous m<sup>6</sup>A-DMs (sm<sup>6</sup>A-DMs) or missense m<sup>6</sup>A-DMs (mm<sup>6</sup>A-DMs) mutations, and the former is enriched within tumor suppressor genes, such as CDKN2A and BRCA2. Using epitranscriptomic editing, we demonstrate that manipulating m<sup>6</sup>A levels at specific sm<sup>6</sup>A-DM sites influences mRNA stability. Furthermore, introducing CDKN2A sm<sup>6</sup>A-DMs into cancer cells promotes tumor growth while BRCA2 sm<sup>6</sup>A-DMs sensitize tumors to the poly (ADP-ribose) polymerase inhibitor (PARPi) treatment. Our findings demonstrate sm<sup>6</sup>A-DMs as potential oncogenic drivers, unveiling implications for synonymous mutations in tumorigenesis and beyond.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"8 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401332","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}
Males of many species have evolved behavioral traits to both attract females and repel rivals. Here, we explore mate selection in Drosophila from both the male and female perspective to shed light on how these key components of sexual selection—female choice and male-male competition—work in concert to guide reproductive strategies. We find that male flies fend off competing suitors by interleaving their courtship of a female with aggressive wing flicks, which both repel competitors and generate a “song” that obscures the female’s auditory perception of other potential mates. Two higher-order circuit nodes—P1a and pC1x neurons—are coordinately recruited to allow males to flexibly interleave these agonistic actions with courtship displays, assuring they persistently pursue females until their rival falters. Together, our results suggest that female mating decisions are shaped by male-male interactions, underscoring how a male’s ability to subvert his rivals is central to his reproductive success.
{"title":"Male-male interactions shape mate selection in Drosophila","authors":"Tom Hindmarsh Sten, Rufei Li, Florian Hollunder, Shade Eleazer, Vanessa Ruta","doi":"10.1016/j.cell.2025.01.008","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.008","url":null,"abstract":"Males of many species have evolved behavioral traits to both attract females and repel rivals. Here, we explore mate selection in <em>Drosophila</em> from both the male and female perspective to shed light on how these key components of sexual selection—female choice and male-male competition—work in concert to guide reproductive strategies. We find that male flies fend off competing suitors by interleaving their courtship of a female with aggressive wing flicks, which both repel competitors and generate a “song” that obscures the female’s auditory perception of other potential mates. Two higher-order circuit nodes—P1a and pC1x neurons—are coordinately recruited to allow males to flexibly interleave these agonistic actions with courtship displays, assuring they persistently pursue females until their rival falters. Together, our results suggest that female mating decisions are shaped by male-male interactions, underscoring how a male’s ability to subvert his rivals is central to his reproductive success.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"15 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401333","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}
Parasitism with Striga poses a major threat to global food production. Striga germination and growth rely on strigolactones (SLs) exuded by crop roots under phosphate (Pi)-deficient conditions, although the mechanism of this host-parasite interaction remains elusive. In this study, transcriptomic and functional analyses of sorghum treated with Pi deficiency or the SL GR245DS identify two ABC transporter G (ABCG) transporters of SL, Sorghum biocolor strigolactones transporter 1 (SbSLT1) and SbSLT2. Using AlphaFold2 and amino acid conversion mutants, we identify highly conserved amino acids in SL transport channels essential for transport function. Sorghum lines with single or double knockouts of these transporters exhibit significantly reduced SL secretion from roots, leading to decreased Striga germination and parasitism in field experiments and consequently reducing the grain loss under Striga infestation. This study thus describes the mechanism of SL exudation in monocots and defines conserved residues essential for SL transporter function, offering a potential strategy for enhancing crop resistance to Striga parasitism.
{"title":"Resistance to Striga parasitism through reduction of strigolactone exudation","authors":"Jiayang Shi, Cuo Mei, Fengyong Ge, Qingliang Hu, Xinwei Ban, Ran Xia, Peiyong Xin, Shujing Cheng, Gaohua Zhang, Jiawei Nie, Shiqi Zhang, Xiaowei Ma, Yi Wang, Jinfang Chu, Yuhang Chen, Bing Wang, Weihua Wu, Jiayang Li, Qi Xie, Feifei Yu","doi":"10.1016/j.cell.2025.01.022","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.022","url":null,"abstract":"Parasitism with <em>Striga</em> poses a major threat to global food production. <em>Striga</em> germination and growth rely on strigolactones (SLs) exuded by crop roots under phosphate (Pi)-deficient conditions, although the mechanism of this host-parasite interaction remains elusive. In this study, transcriptomic and functional analyses of sorghum treated with Pi deficiency or the SL GR24<sup>5DS</sup> identify two ABC transporter G (ABCG) transporters of SL, <em>Sorghum biocolor</em> strigolactones transporter 1 (SbSLT1) and SbSLT2. Using AlphaFold2 and amino acid conversion mutants, we identify highly conserved amino acids in SL transport channels essential for transport function. Sorghum lines with single or double knockouts of these transporters exhibit significantly reduced SL secretion from roots, leading to decreased <em>Striga</em> germination and parasitism in field experiments and consequently reducing the grain loss under <em>Striga</em> infestation. This study thus describes the mechanism of SL exudation in monocots and defines conserved residues essential for SL transporter function, offering a potential strategy for enhancing crop resistance to <em>Striga</em> parasitism.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"31 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393365","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 : 2025-02-12DOI: 10.1016/j.cell.2025.01.027
Subhajit Poddar, Samuel D. Chauvin, Christopher H. Archer, Wei Qian, Jean A. Castillo-Badillo, Xin Yin, W. Miguel Disbennett, Cathrine A. Miner, Joe A. Holley, Teresa V. Naismith, W. Alexander Stinson, Xiaochao Wei, Yue Ning, Jiayuan Fu, Trini A. Ochoa, Nehalee Surve, Shivam A. Zaver, Kimberly A. Wodzanowski, Katherine R. Balka, Rajan Venkatraman, Jonathan J. Miner
Stimulator of interferon genes (STING) transmits signals downstream of the cytosolic DNA sensor cyclic guanosine monophosphate-AMP synthase (cGAS), leading to transcriptional upregulation of cytokines. However, components of the STING signaling pathway, such as IRF3 and IFNAR1, are not essential for autoinflammatory disease in STING gain-of-function (STING-associated vasculopathy with onset in infancy [SAVI]) mice. Recent discoveries revealed that STING also functions as a proton channel that deacidifies the Golgi apparatus. Because pH impacts Golgi enzyme activity, protein maturation, and trafficking, we hypothesized that STING proton channel activity influences multiple Golgi functions. Here, we show that STING-mediated proton efflux non-transcriptionally regulates Golgi trafficking of protein cargos. This process requires the Golgi-associated protein ArfGAP2, a cell-type-specific dual regulator of STING-mediated proton efflux and signaling. Deletion of ArfGAP2 in hematopoietic and endothelial cells markedly reduces STING-mediated cytokine and chemokine secretion, immune cell activation, and autoinflammatory pathology in SAVI mice. Thus, ArfGAP2 facilitates STING-mediated signaling and cytokine release in hematopoietic cells, significantly contributing to autoinflammatory disease pathogenesis.
{"title":"ArfGAP2 promotes STING proton channel activity, cytokine transit, and autoinflammation","authors":"Subhajit Poddar, Samuel D. Chauvin, Christopher H. Archer, Wei Qian, Jean A. Castillo-Badillo, Xin Yin, W. Miguel Disbennett, Cathrine A. Miner, Joe A. Holley, Teresa V. Naismith, W. Alexander Stinson, Xiaochao Wei, Yue Ning, Jiayuan Fu, Trini A. Ochoa, Nehalee Surve, Shivam A. Zaver, Kimberly A. Wodzanowski, Katherine R. Balka, Rajan Venkatraman, Jonathan J. Miner","doi":"10.1016/j.cell.2025.01.027","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.027","url":null,"abstract":"Stimulator of interferon genes (STING) transmits signals downstream of the cytosolic DNA sensor cyclic guanosine monophosphate-AMP synthase (cGAS), leading to transcriptional upregulation of cytokines. However, components of the STING signaling pathway, such as IRF3 and IFNAR1, are not essential for autoinflammatory disease in STING gain-of-function (STING-associated vasculopathy with onset in infancy [SAVI]) mice. Recent discoveries revealed that STING also functions as a proton channel that deacidifies the Golgi apparatus. Because pH impacts Golgi enzyme activity, protein maturation, and trafficking, we hypothesized that STING proton channel activity influences multiple Golgi functions. Here, we show that STING-mediated proton efflux non-transcriptionally regulates Golgi trafficking of protein cargos. This process requires the Golgi-associated protein ArfGAP2, a cell-type-specific dual regulator of STING-mediated proton efflux and signaling. Deletion of ArfGAP2 in hematopoietic and endothelial cells markedly reduces STING-mediated cytokine and chemokine secretion, immune cell activation, and autoinflammatory pathology in SAVI mice. Thus, ArfGAP2 facilitates STING-mediated signaling and cytokine release in hematopoietic cells, significantly contributing to autoinflammatory disease pathogenesis.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"209 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393366","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 : 2025-02-11DOI: 10.1016/j.cell.2025.01.021
Alan Y. Hsu, Qingxiang Huang, Xiong Pi, Jianing Fu, Krishnan Raghunathan, Laxman Ghimire, Arumugam Balasubramanian, Xuemei Xie, Hongbo Yu, Fabien Loison, Viraga Haridas, Jiali Zha, Fei Liu, Shin-young Park, Kamal Bagale, Qian Ren, Yuping Fan, Yi Zheng, Jose A. Cancelas, Li Chai, Hongbo R. Luo
Although subsets with immunosuppressive properties exist, neutrophils are typically known for their pro-inflammatory role and pathogen clearance capabilities. Here, we reveal that neutrophils can paradoxically aid in resolving inflammation by actively producing anti-inflammatory extracellular vesicles. These large aging-neutrophil-derived vesicles (LAND-Vs) do not fit into classical vesicle categorizations due to their specific size, structure, or biogenesis pathway. They are protected from efferocytotic clearance by phagocytes due to surface “do not eat me” signals and accumulate in the resolution phase of inflammation. CD55 on LAND-Vs exerts a robust, sustained anti-inflammatory effect by inhibiting complement 3 convertase, thereby reducing neutrophil recruitment and tissue damage. CD55+ LAND-Vs originate in ordered lipid raft domains, where CD55 accumulates asymmetrically during neutrophil aging, and are subsequently formed through RhoA-dependent budding. Collectively, LAND-V emerges as a pivotal physiological immunomodulator and showcases functions that transcend the limited lifespan of neutrophils, offering a therapeutic target for inflammatory and infectious diseases.
{"title":"Neutrophil-derived vesicles control complement activation to facilitate inflammation resolution","authors":"Alan Y. Hsu, Qingxiang Huang, Xiong Pi, Jianing Fu, Krishnan Raghunathan, Laxman Ghimire, Arumugam Balasubramanian, Xuemei Xie, Hongbo Yu, Fabien Loison, Viraga Haridas, Jiali Zha, Fei Liu, Shin-young Park, Kamal Bagale, Qian Ren, Yuping Fan, Yi Zheng, Jose A. Cancelas, Li Chai, Hongbo R. Luo","doi":"10.1016/j.cell.2025.01.021","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.021","url":null,"abstract":"Although subsets with immunosuppressive properties exist, neutrophils are typically known for their pro-inflammatory role and pathogen clearance capabilities. Here, we reveal that neutrophils can paradoxically aid in resolving inflammation by actively producing anti-inflammatory extracellular vesicles. These large aging-neutrophil-derived vesicles (LAND-Vs) do not fit into classical vesicle categorizations due to their specific size, structure, or biogenesis pathway. They are protected from efferocytotic clearance by phagocytes due to surface “do not eat me” signals and accumulate in the resolution phase of inflammation. CD55 on LAND-Vs exerts a robust, sustained anti-inflammatory effect by inhibiting complement 3 convertase, thereby reducing neutrophil recruitment and tissue damage. CD55<sup>+</sup> LAND-Vs originate in ordered lipid raft domains, where CD55 accumulates asymmetrically during neutrophil aging, and are subsequently formed through RhoA-dependent budding. Collectively, LAND-V emerges as a pivotal physiological immunomodulator and showcases functions that transcend the limited lifespan of neutrophils, offering a therapeutic target for inflammatory and infectious diseases.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"52 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143385017","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 : 2025-02-11DOI: 10.1016/j.cell.2025.01.025
Serena Lucotti, Yusuke Ogitani, Candia M. Kenific, Jacob Geri, Young Hun Kim, Jinghua Gu, Uthra Balaji, Linda Bojmar, Lee Shaashua, Yi Song, Michele Cioffi, Pernille Lauritzen, Oveen M. Joseph, Tetsuhiko Asao, Paul M. Grandgenett, Michael A. Hollingsworth, Christopher Peralta, Alexandra E. Pagano, Henrik Molina, Harry B. Lengel, David Lyden
Cancer is a systemic disease with complications beyond the primary tumor site. Among them, thrombosis is the second leading cause of death in patients with certain cancers (e.g., pancreatic ductal adenocarcinoma [PDAC]) and advanced-stage disease. Here, we demonstrate that pro-thrombotic small extracellular vesicles (sEVs) are secreted by C-X-C motif chemokine 13 (CXCL13)-reprogrammed interstitial macrophages in the non-metastatic lung microenvironment of multiple cancers, a niche that we define as the pro-thrombotic niche (PTN). These sEVs package clustered integrin β2 that dimerizes with integrin αX and interacts with platelet-bound glycoprotein (GP)Ib to induce platelet aggregation. Blocking integrin β2 decreases both sEV-induced thrombosis and lung metastasis. Importantly, sEV-β2 levels are elevated in the plasma of PDAC patients prior to thrombotic events compared with patients with no history of thrombosis. We show that lung PTN establishment is a systemic consequence of cancer progression and identify sEV-β2 as a prognostic biomarker of thrombosis risk as well as a target to prevent thrombosis and metastasis.
{"title":"Extracellular vesicles from the lung pro-thrombotic niche drive cancer-associated thrombosis and metastasis via integrin beta 2","authors":"Serena Lucotti, Yusuke Ogitani, Candia M. Kenific, Jacob Geri, Young Hun Kim, Jinghua Gu, Uthra Balaji, Linda Bojmar, Lee Shaashua, Yi Song, Michele Cioffi, Pernille Lauritzen, Oveen M. Joseph, Tetsuhiko Asao, Paul M. Grandgenett, Michael A. Hollingsworth, Christopher Peralta, Alexandra E. Pagano, Henrik Molina, Harry B. Lengel, David Lyden","doi":"10.1016/j.cell.2025.01.025","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.025","url":null,"abstract":"Cancer is a systemic disease with complications beyond the primary tumor site. Among them, thrombosis is the second leading cause of death in patients with certain cancers (e.g., pancreatic ductal adenocarcinoma [PDAC]) and advanced-stage disease. Here, we demonstrate that pro-thrombotic small extracellular vesicles (sEVs) are secreted by C-X-C motif chemokine 13 (CXCL13)-reprogrammed interstitial macrophages in the non-metastatic lung microenvironment of multiple cancers, a niche that we define as the pro-thrombotic niche (PTN). These sEVs package clustered integrin β<sub>2</sub> that dimerizes with integrin α<sub>X</sub> and interacts with platelet-bound glycoprotein (GP)Ib to induce platelet aggregation. Blocking integrin β<sub>2</sub> decreases both sEV-induced thrombosis and lung metastasis. Importantly, sEV-β<sub>2</sub> levels are elevated in the plasma of PDAC patients prior to thrombotic events compared with patients with no history of thrombosis. We show that lung PTN establishment is a systemic consequence of cancer progression and identify sEV-β<sub>2</sub> as a prognostic biomarker of thrombosis risk as well as a target to prevent thrombosis and metastasis.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"79 5 Pt 1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143385015","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 : 2025-02-11DOI: 10.1016/j.cell.2025.01.031
Nan Wang, Shasha Zhang, Peter Langfelder, Lalini Ramanathan, Fuying Gao, Mary Plascencia, Raymond Vaca, Xiaofeng Gu, Linna Deng, Leonardo E. Dionisio, Ha Vu, Emily Maciejewski, Jason Ernst, Brinda C. Prasad, Thomas F. Vogt, Steve Horvath, Jeffrey S. Aaronson, Jim Rosinski, X. William Yang
Huntington’s disease (HD) modifiers include mismatch-repair (MMR) genes, but their connections to neuronal pathogenesis remain unclear. Here, we genetically tested 9 HD genome-wide association study (GWAS)/MMR genes in mutant Huntingtin (mHtt) mice with 140 inherited CAG repeats (Q140). Knockout (KO) of genes encoding a distinct MMR complex either strongly (Msh3 and Pms1) or moderately (Msh2 and Mlh1) rescues phenotypes with early onset in striatal medium-spiny neurons (MSNs) and late onset in the cortical neurons: somatic CAG-repeat expansion, transcriptionopathy, and mHtt aggregation. Msh3 deficiency ameliorates open-chromatin dysregulation in Q140 neurons. Mechanistically, the fast linear rate of mHtt modal-CAG-repeat expansion in MSNs (8.8 repeats/month) is drastically reduced or stopped by MMR mutants. Msh3 or Pms1 deficiency prevents mHtt aggregation by keeping somatic MSN CAG length below 150. Importantly, Msh3 deficiency corrects synaptic, astrocytic, and locomotor defects in HD mice. Thus, Msh3 and Pms1 drive fast somatic mHtt CAG-expansion rates in HD-vulnerable neurons to elicit repeat-length/threshold-dependent, selective, and progressive pathogenesis in vivo.
{"title":"Distinct mismatch-repair complex genes set neuronal CAG-repeat expansion rate to drive selective pathogenesis in HD mice","authors":"Nan Wang, Shasha Zhang, Peter Langfelder, Lalini Ramanathan, Fuying Gao, Mary Plascencia, Raymond Vaca, Xiaofeng Gu, Linna Deng, Leonardo E. Dionisio, Ha Vu, Emily Maciejewski, Jason Ernst, Brinda C. Prasad, Thomas F. Vogt, Steve Horvath, Jeffrey S. Aaronson, Jim Rosinski, X. William Yang","doi":"10.1016/j.cell.2025.01.031","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.031","url":null,"abstract":"Huntington’s disease (HD) modifiers include mismatch-repair (MMR) genes, but their connections to neuronal pathogenesis remain unclear. Here, we genetically tested 9 HD genome-wide association study (GWAS)/MMR genes in mutant Huntingtin (mHtt) mice with 140 inherited CAG repeats (Q140). Knockout (KO) of genes encoding a distinct MMR complex either strongly (<em>Msh3</em> and <em>Pms1</em>) or moderately (<em>Msh2</em> and <em>Mlh1</em>) rescues phenotypes with early onset in striatal medium-spiny neurons (MSNs) and late onset in the cortical neurons: somatic CAG-repeat expansion, transcriptionopathy, and mHtt aggregation. Msh3 deficiency ameliorates open-chromatin dysregulation in Q140 neurons. Mechanistically, the fast linear rate of mHtt modal-CAG-repeat expansion in MSNs (8.8 repeats/month) is drastically reduced or stopped by MMR mutants. Msh3 or Pms1 deficiency prevents mHtt aggregation by keeping somatic MSN CAG length below 150. Importantly, Msh3 deficiency corrects synaptic, astrocytic, and locomotor defects in HD mice. Thus, Msh3 and Pms1 drive fast somatic mHtt CAG-expansion rates in HD-vulnerable neurons to elicit repeat-length/threshold-dependent, selective, and progressive pathogenesis <em>in vivo</em>.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"26 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143385016","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 : 2025-02-07DOI: 10.1016/j.cell.2024.12.031
Cheng-Bao Ma, Chen Liu, Young-Jun Park, Jingjing Tang, Jing Chen, Qing Xiong, Jimin Lee, Cameron Stewart, Daniel Asarnow, Jack Brown, M. Alejandra Tortorici, Xiao Yang, Ye-Hui Sun, Yuan-Mei Chen, Xiao Yu, Jun-Yu Si, Peng Liu, Fei Tong, Mei-Ling Huang, Jing Li, Huan Yan
The angiotensin-converting enzyme 2 (ACE2) receptor is shared by various coronaviruses with distinct receptor-binding domain (RBD) architectures, yet our understanding of these convergent acquisition events remains elusive. Here, we report that two bat MERS-related coronaviruses (MERSr-CoVs) infecting Pipistrellus nathusii (P.nat)—MOW15-22 and PnNL2018B—use ACE2 as their receptor, with narrow ortholog specificity. Cryoelectron microscopy structures of the MOW15-22/PnNL2018B RBD-ACE2 complexes unveil an unexpected and entirely distinct binding mode, mapping >45 Å away from that of any other known ACE2-using coronaviruses. Functional profiling of ACE2 orthologs from 105 mammalian species led to the identification of host tropism determinants, including an ACE2 N432-glycosylation restricting viral recognition, and the design of a soluble P.nat ACE2 mutant with potent viral neutralizing activity. Our findings reveal convergent acquisition of ACE2 usage for merbecoviruses found in European bats, underscoring the extraordinary diversity of ACE2 recognition modes among coronaviruses and the promiscuity of this receptor.
{"title":"Multiple independent acquisitions of ACE2 usage in MERS-related coronaviruses","authors":"Cheng-Bao Ma, Chen Liu, Young-Jun Park, Jingjing Tang, Jing Chen, Qing Xiong, Jimin Lee, Cameron Stewart, Daniel Asarnow, Jack Brown, M. Alejandra Tortorici, Xiao Yang, Ye-Hui Sun, Yuan-Mei Chen, Xiao Yu, Jun-Yu Si, Peng Liu, Fei Tong, Mei-Ling Huang, Jing Li, Huan Yan","doi":"10.1016/j.cell.2024.12.031","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.031","url":null,"abstract":"The angiotensin-converting enzyme 2 (ACE2) receptor is shared by various coronaviruses with distinct receptor-binding domain (RBD) architectures, yet our understanding of these convergent acquisition events remains elusive. Here, we report that two bat MERS-related coronaviruses (MERSr-CoVs) infecting <em>Pipistrellus nathusii</em> (<em>P.nat</em>)—MOW15-22 and PnNL2018B—use ACE2 as their receptor, with narrow ortholog specificity. Cryoelectron microscopy structures of the MOW15-22/PnNL2018B RBD-ACE2 complexes unveil an unexpected and entirely distinct binding mode, mapping >45 Å away from that of any other known ACE2-using coronaviruses. Functional profiling of ACE2 orthologs from 105 mammalian species led to the identification of host tropism determinants, including an ACE2 N432-glycosylation restricting viral recognition, and the design of a soluble <em>P.nat</em> ACE2 mutant with potent viral neutralizing activity. Our findings reveal convergent acquisition of ACE2 usage for merbecoviruses found in European bats, underscoring the extraordinary diversity of ACE2 recognition modes among coronaviruses and the promiscuity of this receptor.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"64 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143258256","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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