Pub Date : 2024-12-20DOI: 10.1016/j.cell.2024.11.031
Kevin Y. Chen, Marco De Giovanni, Ying Xu, Jinping An, Nikhita Kirthivasan, Erick Lu, Kan Jiang, Stephen Brooks, Serena Ranucci, Jiuling Yang, Shuto Kanameishi, Kenji Kabashima, Kevin Brulois, Michael Bscheider, Eugene C. Butcher, Jason G. Cyster
Sustained lymphocyte migration from blood into lymph nodes (LNs) is important for immune responses. The CC-chemokine receptor-7 (CCR7) ligand CCL21 is required for LN entry but is downregulated during inflammation, and it has been unclear how recruitment is maintained. Here, we show that the oxysterol biosynthetic enzyme cholesterol-25-hydroxylase (Ch25h) is upregulated in LN high endothelial venules during viral infection. Lymphocytes become dependent on oxysterols, generated through a transcellular endothelial-fibroblast metabolic pathway, and the receptor EBI2 for inflamed LN entry. Additionally, Langerhans cells are an oxysterol source. Ch25h is also expressed in inflamed peripheral endothelium, and EBI2 mediates B cell recruitment in a tumor model. Finally, we demonstrate that LN CCL19 is critical in lymphocyte recruitment during inflammation. Thus, our work explains how naive precursor trafficking is sustained in responding LNs, identifies a role for oxysterols in cell recruitment into inflamed tissues, and establishes a logic for the CCR7 two-ligand system.
{"title":"Inflammation switches the chemoattractant requirements for naive lymphocyte entry into lymph nodes","authors":"Kevin Y. Chen, Marco De Giovanni, Ying Xu, Jinping An, Nikhita Kirthivasan, Erick Lu, Kan Jiang, Stephen Brooks, Serena Ranucci, Jiuling Yang, Shuto Kanameishi, Kenji Kabashima, Kevin Brulois, Michael Bscheider, Eugene C. Butcher, Jason G. Cyster","doi":"10.1016/j.cell.2024.11.031","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.031","url":null,"abstract":"Sustained lymphocyte migration from blood into lymph nodes (LNs) is important for immune responses. The CC-chemokine receptor-7 (CCR7) ligand CCL21 is required for LN entry but is downregulated during inflammation, and it has been unclear how recruitment is maintained. Here, we show that the oxysterol biosynthetic enzyme cholesterol-25-hydroxylase (Ch25h) is upregulated in LN high endothelial venules during viral infection. Lymphocytes become dependent on oxysterols, generated through a transcellular endothelial-fibroblast metabolic pathway, and the receptor EBI2 for inflamed LN entry. Additionally, Langerhans cells are an oxysterol source. Ch25h is also expressed in inflamed peripheral endothelium, and EBI2 mediates B cell recruitment in a tumor model. Finally, we demonstrate that LN CCL19 is critical in lymphocyte recruitment during inflammation. Thus, our work explains how naive precursor trafficking is sustained in responding LNs, identifies a role for oxysterols in cell recruitment into inflamed tissues, and establishes a logic for the CCR7 two-ligand system.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"113 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857806","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 : 2024-12-20DOI: 10.1016/j.cell.2024.11.029
Lorena Benedetti, Ruolin Fan, Aubrey V. Weigel, Andrew S. Moore, Patrick R. Houlihan, Mark Kittisopikul, Grace Park, Alyson Petruncio, Philip M. Hubbard, Song Pang, C. Shan Xu, Harald F. Hess, Stephan Saalfeld, Vidhya Rangaraju, David E. Clapham, Pietro De Camilli, Timothy A. Ryan, Jennifer Lippincott-Schwartz
Neuronal dendrites must relay synaptic inputs over long distances, but the mechanisms by which activity-evoked intracellular signals propagate over macroscopic distances remain unclear. Here, we discovered a system of periodically arranged endoplasmic reticulum-plasma membrane (ER-PM) junctions tiling the plasma membrane of dendrites at ∼1 μm intervals, interlinked by a meshwork of ER tubules patterned in a ladder-like array. Populated with Junctophilin-linked plasma membrane voltage-gated Ca2+ channels and ER Ca2+-release channels (ryanodine receptors), ER-PM junctions are hubs for ER-PM crosstalk, fine-tuning of Ca2+ homeostasis, and local activation of the Ca2+/calmodulin-dependent protein kinase II. Local spine stimulation activates the Ca2+ modulatory machinery, facilitating signal transmission and ryanodine-receptor-dependent Ca2+ release at ER-PM junctions over 20 μm away. Thus, interconnected ER-PM junctions support signal propagation and Ca2+ release from the spine-adjacent ER. The capacity of this subcellular architecture to modify both local and distant membrane-proximal biochemistry potentially contributes to dendritic computations.
{"title":"Periodic ER-plasma membrane junctions support long-range Ca2+ signal integration in dendrites","authors":"Lorena Benedetti, Ruolin Fan, Aubrey V. Weigel, Andrew S. Moore, Patrick R. Houlihan, Mark Kittisopikul, Grace Park, Alyson Petruncio, Philip M. Hubbard, Song Pang, C. Shan Xu, Harald F. Hess, Stephan Saalfeld, Vidhya Rangaraju, David E. Clapham, Pietro De Camilli, Timothy A. Ryan, Jennifer Lippincott-Schwartz","doi":"10.1016/j.cell.2024.11.029","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.029","url":null,"abstract":"Neuronal dendrites must relay synaptic inputs over long distances, but the mechanisms by which activity-evoked intracellular signals propagate over macroscopic distances remain unclear. Here, we discovered a system of periodically arranged endoplasmic reticulum-plasma membrane (ER-PM) junctions tiling the plasma membrane of dendrites at ∼1 μm intervals, interlinked by a meshwork of ER tubules patterned in a ladder-like array. Populated with Junctophilin-linked plasma membrane voltage-gated Ca<sup>2+</sup> channels and ER Ca<sup>2+</sup>-release channels (ryanodine receptors), ER-PM junctions are hubs for ER-PM crosstalk, fine-tuning of Ca<sup>2+</sup> homeostasis, and local activation of the Ca<sup>2+</sup>/calmodulin-dependent protein kinase II. Local spine stimulation activates the Ca<sup>2+</sup> modulatory machinery, facilitating signal transmission and ryanodine-receptor-dependent Ca<sup>2+</sup> release at ER-PM junctions over 20 μm away. Thus, interconnected ER-PM junctions support signal propagation and Ca<sup>2+</sup> release from the spine-adjacent ER. The capacity of this subcellular architecture to modify both local and distant membrane-proximal biochemistry potentially contributes to dendritic computations.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"41 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867065","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 : 2024-12-19DOI: 10.1016/j.cell.2024.11.020
Kyle Burrows, Louis Ngai, Pailin Chiaranunt, Jacqueline Watt, Sarah Popple, Brian Forde, Saven Denha, Vitoria M. Olyntho, Siu Ling Tai, Eric Yixiao Cao, Susana Tejeda-Garibay, Joshua F.E. Koenig, Katrin D. Mayer-Barber, Catherine J. Streutker, Katrina K. Hoyer, Lisa C. Osborne, Jun Liu, Liam O’Mahony, Arthur Mortha
The underlying mechanisms used by the intestinal microbiota to shape disease outcomes of the host are poorly understood. Here, we show that the gut commensal protozoan, Tritrichomonas musculis (T.mu), remotely shapes the lung immune landscape to facilitate perivascular shielding of the airways by eosinophils. Lung-specific eosinophilia requires a tripartite immune network between gut-derived inflammatory group 2 innate lymphoid cells and lung-resident T cells and B cells. This network exacerbates the severity of allergic airway inflammation while hindering the systemic dissemination of pulmonary Mycobacterium tuberculosis. The identification of protozoan DNA sequences in the sputum of patients with severe allergic asthma further emphasizes the relevance of commensal protozoa in human disease. Collectively, these findings demonstrate that a commensal protozoan tunes pulmonary immunity via a gut-operated lung immune network, promoting both beneficial and detrimental disease outcomes in response to environmental airway allergens and pulmonary infections.
{"title":"A gut commensal protozoan determines respiratory disease outcomes by shaping pulmonary immunity","authors":"Kyle Burrows, Louis Ngai, Pailin Chiaranunt, Jacqueline Watt, Sarah Popple, Brian Forde, Saven Denha, Vitoria M. Olyntho, Siu Ling Tai, Eric Yixiao Cao, Susana Tejeda-Garibay, Joshua F.E. Koenig, Katrin D. Mayer-Barber, Catherine J. Streutker, Katrina K. Hoyer, Lisa C. Osborne, Jun Liu, Liam O’Mahony, Arthur Mortha","doi":"10.1016/j.cell.2024.11.020","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.020","url":null,"abstract":"The underlying mechanisms used by the intestinal microbiota to shape disease outcomes of the host are poorly understood. Here, we show that the gut commensal protozoan, <em>Tritrichomonas musculis</em> (<em>T.mu</em>), remotely shapes the lung immune landscape to facilitate perivascular shielding of the airways by eosinophils. Lung-specific eosinophilia requires a tripartite immune network between gut-derived inflammatory group 2 innate lymphoid cells and lung-resident T cells and B cells. This network exacerbates the severity of allergic airway inflammation while hindering the systemic dissemination of pulmonary <em>Mycobacterium tuberculosis</em>. The identification of protozoan DNA sequences in the sputum of patients with severe allergic asthma further emphasizes the relevance of commensal protozoa in human disease. Collectively, these findings demonstrate that a commensal protozoan tunes pulmonary immunity via a gut-operated lung immune network, promoting both beneficial and detrimental disease outcomes in response to environmental airway allergens and pulmonary infections.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"9 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849611","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 : 2024-12-19DOI: 10.1016/j.cell.2024.11.012
Jason J. Liu, Beatrice Borsari, Yunyang Li, Susanna X. Liu, Yuan Gao, Xin Xin, Shaoke Lou, Matthew Jensen, Diego Garrido-Martín, Terril L. Verplaetse, Garrett Ash, Jing Zhang, Matthew J. Girgenti, Walter Roberts, Mark Gerstein
Psychiatric disorders are influenced by genetic and environmental factors. However, their study is hindered by limitations on precisely characterizing human behavior. New technologies such as wearable sensors show promise in surmounting these limitations in that they measure heterogeneous behavior in a quantitative and unbiased fashion. Here, we analyze wearable and genetic data from the Adolescent Brain Cognitive Development (ABCD) study. Leveraging >250 wearable-derived features as digital phenotypes, we show that an interpretable AI framework can objectively classify adolescents with psychiatric disorders more accurately than previously possible. To relate digital phenotypes to the underlying genetics, we show how they can be employed in univariate and multivariate genome-wide association studies (GWASs). Doing so, we identify 16 significant genetic loci and 37 psychiatric-associated genes, including ELFN1 and ADORA3, demonstrating that continuous, wearable-derived features give greater detection power than traditional case-control GWASs. Overall, we show how wearable technology can help uncover new linkages between behavior and genetics.
{"title":"Digital phenotyping from wearables using AI characterizes psychiatric disorders and identifies genetic associations","authors":"Jason J. Liu, Beatrice Borsari, Yunyang Li, Susanna X. Liu, Yuan Gao, Xin Xin, Shaoke Lou, Matthew Jensen, Diego Garrido-Martín, Terril L. Verplaetse, Garrett Ash, Jing Zhang, Matthew J. Girgenti, Walter Roberts, Mark Gerstein","doi":"10.1016/j.cell.2024.11.012","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.012","url":null,"abstract":"Psychiatric disorders are influenced by genetic and environmental factors. However, their study is hindered by limitations on precisely characterizing human behavior. New technologies such as wearable sensors show promise in surmounting these limitations in that they measure heterogeneous behavior in a quantitative and unbiased fashion. Here, we analyze wearable and genetic data from the Adolescent Brain Cognitive Development (ABCD) study. Leveraging >250 wearable-derived features as digital phenotypes, we show that an interpretable AI framework can objectively classify adolescents with psychiatric disorders more accurately than previously possible. To relate digital phenotypes to the underlying genetics, we show how they can be employed in univariate and multivariate genome-wide association studies (GWASs). Doing so, we identify 16 significant genetic loci and 37 psychiatric-associated genes, including <em>ELFN1</em> and <em>ADORA3</em>, demonstrating that continuous, wearable-derived features give greater detection power than traditional case-control GWASs. Overall, we show how wearable technology can help uncover new linkages between behavior and genetics.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"31 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849572","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 : 2024-12-19DOI: 10.1016/j.cell.2024.11.017
Toshimichi Yamada, Coralie Trentesaux, Jonathan M. Brunger, Yini Xiao, Adam J. Stevens, Iain Martyn, Petr Kasparek, Neha P. Shroff, Angelica Aguilar, Benoit G. Bruneau, Dario Boffelli, Ophir D. Klein, Wendell A. Lim
In vitro development relies primarily on treating progenitor cells with media-borne morphogens and thus lacks native-like spatial information. Here, we engineer morphogen-secreting organizer cells programmed to self-assemble, via cell adhesion, around mouse embryonic stem (ES) cells in defined architectures. By inducing the morphogen WNT3A and its antagonist DKK1 from organizer cells, we generated diverse morphogen gradients, varying in range and steepness. These gradients were strongly correlated with morphogenetic outcomes: the range of minimum-maximum WNT activity determined the resulting range of anterior-to-posterior (A-P) axis cell lineages. Strikingly, shallow WNT activity gradients, despite showing truncated A-P lineages, yielded higher-resolution tissue morphologies, such as a beating, chambered cardiac-like structure associated with an endothelial network. Thus, synthetic organizer cells, which integrate spatial, temporal, and biochemical information, provide a powerful way to systematically and flexibly direct the development of ES or other progenitor cells in different directions within the morphogenetic landscape.
{"title":"Synthetic organizer cells guide development via spatial and biochemical instructions","authors":"Toshimichi Yamada, Coralie Trentesaux, Jonathan M. Brunger, Yini Xiao, Adam J. Stevens, Iain Martyn, Petr Kasparek, Neha P. Shroff, Angelica Aguilar, Benoit G. Bruneau, Dario Boffelli, Ophir D. Klein, Wendell A. Lim","doi":"10.1016/j.cell.2024.11.017","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.017","url":null,"abstract":"<em>In vitro</em> development relies primarily on treating progenitor cells with media-borne morphogens and thus lacks native-like spatial information. Here, we engineer morphogen-secreting organizer cells programmed to self-assemble, via cell adhesion, around mouse embryonic stem (ES) cells in defined architectures. By inducing the morphogen WNT3A and its antagonist DKK1 from organizer cells, we generated diverse morphogen gradients, varying in range and steepness. These gradients were strongly correlated with morphogenetic outcomes: the range of minimum-maximum WNT activity determined the resulting range of anterior-to-posterior (A-P) axis cell lineages. Strikingly, shallow WNT activity gradients, despite showing truncated A-P lineages, yielded higher-resolution tissue morphologies, such as a beating, chambered cardiac-like structure associated with an endothelial network. Thus, synthetic organizer cells, which integrate spatial, temporal, and biochemical information, provide a powerful way to systematically and flexibly direct the development of ES or other progenitor cells in different directions within the morphogenetic landscape.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"53 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849570","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 : 2024-12-18DOI: 10.1016/j.cell.2024.11.010
Mark Zucker, Maria A. Perry, Samuel I. Gould, Arielle Elkrief, Anton Safonov, Rohit Thummalapalli, Miika Mehine, Debyani Chakravarty, A. Rose Brannon, Marc Ladanyi, Pedram Razavi, Mark T.A. Donoghue, Yonina R. Murciano-Goroff, Kristiana Grigoriadis, Nicholas McGranahan, Mariam Jamal-Hanjani, Charles Swanton, Yuan Chen, Ronglai Shen, Sarat Chandarlapaty, Chaitanya Bandlamudi
The canonical model of tumor suppressor gene (TSG)-mediated oncogenesis posits that loss of both alleles is necessary for inactivation. Here, through allele-specific analysis of sequencing data from 48,179 cancer patients, we define the prevalence, selective pressure for, and functional consequences of biallelic inactivation across TSGs. TSGs largely assort into distinct classes associated with either pan-cancer (Class 1) or lineage-specific (Class 2) patterns of selection for biallelic loss, although some TSGs are predominantly monoallelically inactivated (Class 3/4). We demonstrate that selection for biallelic inactivation can be utilized to identify driver genes in non-canonical contexts, including among variants of unknown significance (VUSs) of several TSGs such as KEAP1. Genomic, functional, and clinical data collectively indicate that KEAP1 VUSs phenocopy established KEAP1 oncogenic alleles and that zygosity, rather than variant classification, is predictive of therapeutic response. TSG zygosity is therefore a fundamental determinant of disease etiology and therapeutic sensitivity.
{"title":"Pan-cancer analysis of biallelic inactivation in tumor suppressor genes identifies KEAP1 zygosity as a predictive biomarker in lung cancer","authors":"Mark Zucker, Maria A. Perry, Samuel I. Gould, Arielle Elkrief, Anton Safonov, Rohit Thummalapalli, Miika Mehine, Debyani Chakravarty, A. Rose Brannon, Marc Ladanyi, Pedram Razavi, Mark T.A. Donoghue, Yonina R. Murciano-Goroff, Kristiana Grigoriadis, Nicholas McGranahan, Mariam Jamal-Hanjani, Charles Swanton, Yuan Chen, Ronglai Shen, Sarat Chandarlapaty, Chaitanya Bandlamudi","doi":"10.1016/j.cell.2024.11.010","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.010","url":null,"abstract":"The canonical model of tumor suppressor gene (TSG)-mediated oncogenesis posits that loss of both alleles is necessary for inactivation. Here, through allele-specific analysis of sequencing data from 48,179 cancer patients, we define the prevalence, selective pressure for, and functional consequences of biallelic inactivation across TSGs. TSGs largely assort into distinct classes associated with either pan-cancer (Class 1) or lineage-specific (Class 2) patterns of selection for biallelic loss, although some TSGs are predominantly monoallelically inactivated (Class 3/4). We demonstrate that selection for biallelic inactivation can be utilized to identify driver genes in non-canonical contexts, including among variants of unknown significance (VUSs) of several TSGs such as <em>KEAP1</em>. Genomic, functional, and clinical data collectively indicate that <em>KEAP1</em> VUSs phenocopy established <em>KEAP1</em> oncogenic alleles and that zygosity, rather than variant classification, is predictive of therapeutic response. TSG zygosity is therefore a fundamental determinant of disease etiology and therapeutic sensitivity.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"258 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841519","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 : 2024-12-18DOI: 10.1016/j.cell.2024.11.008
Elizabeth McFadden, Stephanie R. Monticelli, Albert Wang, Ajit R. Ramamohan, Thomas G. Batchelor, Ana I. Kuehne, Russell R. Bakken, Alexandra L. Tse, Kartik Chandran, Andrew S. Herbert, Jason S. McLellan
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tickborne virus that can cause severe disease in humans with case fatality rates of 10%–40%. Although structures of CCHFV glycoproteins GP38 and Gc have provided insights into viral entry and defined epitopes of neutralizing and protective antibodies, the structure of glycoprotein Gn and its interactions with GP38 and Gc have remained elusive. Here, we use structure-guided protein engineering to produce a stabilized GP38-Gn-Gc heterotrimeric glycoprotein complex (GP38-GnH-DS-Gc). A cryo-electron microscopy (cryo-EM) structure of this complex provides the molecular basis for GP38’s association on the viral surface, reveals the structure of Gn, and demonstrates that GP38-Gn restrains the Gc fusion loops in the prefusion conformation, facilitated by an N-linked glycan attached to Gn. Immunization with GP38-GnH-DS-Gc conferred 40% protection against lethal IbAr10200 challenge in mice. These data define the architecture of a GP38-Gn-Gc protomer and provide a template for structure-guided vaccine antigen development.
{"title":"Engineering and structures of Crimean-Congo hemorrhagic fever virus glycoprotein complexes","authors":"Elizabeth McFadden, Stephanie R. Monticelli, Albert Wang, Ajit R. Ramamohan, Thomas G. Batchelor, Ana I. Kuehne, Russell R. Bakken, Alexandra L. Tse, Kartik Chandran, Andrew S. Herbert, Jason S. McLellan","doi":"10.1016/j.cell.2024.11.008","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.008","url":null,"abstract":"Crimean-Congo hemorrhagic fever virus (CCHFV) is a tickborne virus that can cause severe disease in humans with case fatality rates of 10%–40%. Although structures of CCHFV glycoproteins GP38 and Gc have provided insights into viral entry and defined epitopes of neutralizing and protective antibodies, the structure of glycoprotein Gn and its interactions with GP38 and Gc have remained elusive. Here, we use structure-guided protein engineering to produce a stabilized GP38-Gn-Gc heterotrimeric glycoprotein complex (GP38-Gn<sup>H-DS</sup>-Gc). A cryo-electron microscopy (cryo-EM) structure of this complex provides the molecular basis for GP38’s association on the viral surface, reveals the structure of Gn, and demonstrates that GP38-Gn restrains the Gc fusion loops in the prefusion conformation, facilitated by an N-linked glycan attached to Gn. Immunization with GP38-Gn<sup>H-DS</sup>-Gc conferred 40% protection against lethal IbAr10200 challenge in mice. These data define the architecture of a GP38-Gn-Gc protomer and provide a template for structure-guided vaccine antigen development.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"10 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841518","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 : 2024-12-18DOI: 10.1016/j.cell.2024.11.014
Erica L. Huey, Josef Turecek, Michelle M. Delisle, Ofer Mazor, Gabriel E. Romero, Malvika Dua, Zoe K. Sarafis, Alexis Hobble, Kevin T. Booth, Lisa V. Goodrich, David P. Corey, David D. Ginty
Vibrations are ubiquitous in nature, shaping behavior across the animal kingdom. For mammals, mechanical vibrations acting on the body are detected by mechanoreceptors of the skin and deep tissues and processed by the somatosensory system, while sound waves traveling through air are captured by the cochlea and encoded in the auditory system. Here, we report that mechanical vibrations detected by the body’s Pacinian corpuscle neurons, which are distinguished by their ability to entrain to high-frequency (40–1,000 Hz) environmental vibrations, are prominently encoded by neurons in the lateral cortex of the inferior colliculus (LCIC) of the midbrain. Remarkably, most LCIC neurons receive convergent Pacinian and auditory input and respond more strongly to coincident tactile-auditory stimulation than to either modality alone. Moreover, the LCIC is required for behavioral responses to high-frequency mechanical vibrations. Thus, environmental vibrations captured by Pacinian corpuscles are encoded in the auditory midbrain to mediate behavior.
{"title":"The auditory midbrain mediates tactile vibration sensing","authors":"Erica L. Huey, Josef Turecek, Michelle M. Delisle, Ofer Mazor, Gabriel E. Romero, Malvika Dua, Zoe K. Sarafis, Alexis Hobble, Kevin T. Booth, Lisa V. Goodrich, David P. Corey, David D. Ginty","doi":"10.1016/j.cell.2024.11.014","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.014","url":null,"abstract":"Vibrations are ubiquitous in nature, shaping behavior across the animal kingdom. For mammals, mechanical vibrations acting on the body are detected by mechanoreceptors of the skin and deep tissues and processed by the somatosensory system, while sound waves traveling through air are captured by the cochlea and encoded in the auditory system. Here, we report that mechanical vibrations detected by the body’s Pacinian corpuscle neurons, which are distinguished by their ability to entrain to high-frequency (40–1,000 Hz) environmental vibrations, are prominently encoded by neurons in the lateral cortex of the inferior colliculus (LCIC) of the midbrain. Remarkably, most LCIC neurons receive convergent Pacinian and auditory input and respond more strongly to coincident tactile-auditory stimulation than to either modality alone. Moreover, the LCIC is required for behavioral responses to high-frequency mechanical vibrations. Thus, environmental vibrations captured by Pacinian corpuscles are encoded in the auditory midbrain to mediate behavior.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"48 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841457","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}
Long-term durable remission in patients with B cell malignancies following chimeric antigen receptor (CAR)-T cell immunotherapy remains unsatisfactory, often due to antigen escape. Malignant B cell transformation and oncogenic growth relies on efficient ATP synthesis, although the underlying mechanisms remain unclear. Here, we report that YTHDF2 facilitates energy supply and antigen escape in B cell malignancies, and its overexpression alone is sufficient to cause B cell transformation and tumorigenesis. Mechanistically, YTHDF2 functions as a dual reader where it stabilizes mRNAs as a 5-methylcytosine (m5C) reader via recruiting PABPC1, thereby enhancing their expression and ATP synthesis. Concomitantly, YTHDF2 also promotes immune evasion by destabilizing other mRNAs as an N6-methyladenosine (m6A) reader. Small-molecule-mediated targeting of YTHDF2 suppresses aggressive B cell malignancies and sensitizes them to CAR-T cell therapy.
B 细胞恶性肿瘤患者接受嵌合抗原受体（CAR）-T 细胞免疫疗法后的长期持久缓解仍不令人满意，原因往往是抗原逃逸。恶性 B 细胞的转化和致癌生长依赖于高效的 ATP 合成，但其潜在机制仍不清楚。在这里，我们报告了 YTHDF2 在 B 细胞恶性肿瘤中促进能量供应和抗原逃避，并且仅其过表达就足以导致 B 细胞转化和肿瘤发生。从机理上讲，YTHDF2具有双重阅读功能，它作为5-甲基胞嘧啶（m5C）阅读器通过招募PABPC1稳定mRNA，从而增强它们的表达和ATP合成。同时，YTHDF2 还能作为 N6-甲基腺苷（m6A）阅读器破坏其他 mRNA 的稳定性，从而促进免疫逃避。小分子介导的 YTHDF2 靶向可抑制侵袭性 B 细胞恶性肿瘤，并使其对 CAR-T 细胞疗法敏感。
{"title":"YTHDF2 promotes ATP synthesis and immune evasion in B cell malignancies","authors":"Zhenhua Chen, Chengwu Zeng, Lu Yang, Yuan Che, Meiling Chen, Lillian Sau, Bintao Wang, Keren Zhou, Yu Chen, Ying Qing, Chao Shen, Tingjian Zhang, Mark Wunderlich, Dong Wu, Wei Li, Kitty Wang, Keith Leung, Miao Sun, Tingting Tang, Xin He, Jianjun Chen","doi":"10.1016/j.cell.2024.11.007","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.007","url":null,"abstract":"Long-term durable remission in patients with B cell malignancies following chimeric antigen receptor (CAR)-T cell immunotherapy remains unsatisfactory, often due to antigen escape. Malignant B cell transformation and oncogenic growth relies on efficient ATP synthesis, although the underlying mechanisms remain unclear. Here, we report that YTHDF2 facilitates energy supply and antigen escape in B cell malignancies, and its overexpression alone is sufficient to cause B cell transformation and tumorigenesis. Mechanistically, YTHDF2 functions as a dual reader where it stabilizes mRNAs as a 5-methylcytosine (m<sup>5</sup>C) reader via recruiting PABPC1, thereby enhancing their expression and ATP synthesis. Concomitantly, YTHDF2 also promotes immune evasion by destabilizing other mRNAs as an <em>N</em><sup>6</sup>-methyladenosine (m<sup>6</sup>A) reader. Small-molecule-mediated targeting of YTHDF2 suppresses aggressive B cell malignancies and sensitizes them to CAR-T cell therapy.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"101 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832850","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}
Intermittent fasting has gained global popularity for its potential health benefits, although its impact on somatic stem cells and tissue biology remains elusive. Here, we report that commonly used intermittent fasting regimens inhibit hair follicle regeneration by selectively inducing apoptosis in activated hair follicle stem cells (HFSCs). This effect is independent of calorie reduction, circadian rhythm alterations, or the mTORC1 cellular nutrient-sensing mechanism. Instead, fasting activates crosstalk between adrenal glands and dermal adipocytes in the skin, triggering the rapid release of free fatty acids into the niche, which in turn disrupts the normal metabolism of HFSCs and elevates their cellular reactive oxygen species levels, causing oxidative damage and apoptosis. A randomized clinical trial (NCT05800730) indicates that intermittent fasting inhibits human hair growth. Our study uncovers an inhibitory effect of intermittent fasting on tissue regeneration and identifies interorgan communication that eliminates activated HFSCs and halts tissue regeneration during periods of unstable nutrient supply.
{"title":"Intermittent fasting triggers interorgan communication to suppress hair follicle regeneration","authors":"Han Chen, Chao Liu, Shiyao Cui, Yingqian Xia, Ke Zhang, Hanxiao Cheng, Jingyu Peng, Xiaoling Yu, Luyang Li, Hualin Yu, Jufang Zhang, Ju-Sheng Zheng, Bing Zhang","doi":"10.1016/j.cell.2024.11.004","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.004","url":null,"abstract":"Intermittent fasting has gained global popularity for its potential health benefits, although its impact on somatic stem cells and tissue biology remains elusive. Here, we report that commonly used intermittent fasting regimens inhibit hair follicle regeneration by selectively inducing apoptosis in activated hair follicle stem cells (HFSCs). This effect is independent of calorie reduction, circadian rhythm alterations, or the mTORC1 cellular nutrient-sensing mechanism. Instead, fasting activates crosstalk between adrenal glands and dermal adipocytes in the skin, triggering the rapid release of free fatty acids into the niche, which in turn disrupts the normal metabolism of HFSCs and elevates their cellular reactive oxygen species levels, causing oxidative damage and apoptosis. A randomized clinical trial (NCT05800730) indicates that intermittent fasting inhibits human hair growth. Our study uncovers an inhibitory effect of intermittent fasting on tissue regeneration and identifies interorgan communication that eliminates activated HFSCs and halts tissue regeneration during periods of unstable nutrient supply.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"16 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816154","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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