CellPub Date : 2024-11-04DOI: 10.1016/j.cell.2024.10.010
Kautilya K. Jena, Julien Mambu, Daniel Boehmer, Benedetta Sposito, Virginie Millet, Joshua de Sousa Casal, Hayley I. Muendlein, Roberto Spreafico, Romain Fenouil, Lionel Spinelli, Sarah Wurbel, Chloé Riquier, Franck Galland, Philippe Naquet, Lionel Chasson, Megan Elkins, Vanessa Mitsialis, Natália Ketelut-Carneiro, Katlynn Bugda Gwilt, Jay R. Thiagarajah, Ivan Zanoni
{"title":"Type III interferons induce pyroptosis in gut epithelial cells and impair mucosal repair","authors":"Kautilya K. Jena, Julien Mambu, Daniel Boehmer, Benedetta Sposito, Virginie Millet, Joshua de Sousa Casal, Hayley I. Muendlein, Roberto Spreafico, Romain Fenouil, Lionel Spinelli, Sarah Wurbel, Chloé Riquier, Franck Galland, Philippe Naquet, Lionel Chasson, Megan Elkins, Vanessa Mitsialis, Natália Ketelut-Carneiro, Katlynn Bugda Gwilt, Jay R. Thiagarajah, Ivan Zanoni","doi":"10.1016/j.cell.2024.10.010","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.010","url":null,"abstract":"Tissue damage and repair are hallmarks of inflammation. Despite a wealth of information on the mechanisms that govern tissue damage, mechanistic insight into how inflammation affects repair is lacking. Here, we investigated how interferons influence tissue repair after damage to the intestinal mucosa. We found that type III, not type I or type II, interferons delay epithelial cell regeneration by inducing the upregulation of Z-DNA-binding protein 1 (ZBP1). Z-nucleic acids formed following intestinal damage are sensed by ZBP1, leading to caspase-8 activation and the cleavage of gasdermin C (GSDMC). Cleaved GSDMC drives epithelial cell death by pyroptosis and delays repair of the large or small intestine after colitis or irradiation, respectively. The type III interferon/ZBP1/caspase-8/GSDMC axis is also active in patients with inflammatory bowel disease (IBD). Our findings highlight the capacity of type III interferons to delay gut repair, which has implications for IBD patients or individuals exposed to radiation therapies.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"241 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2024-11-04DOI: 10.1016/j.cell.2024.10.019
Shuai Ma, Zhejun Ji, Bin Zhang, Lingling Geng, Yusheng Cai, Chao Nie, Jiaming Li, Yuesheng Zuo, Yuzhe Sun, Gang Xu, Beibei Liu, Jiaqi Ai, Feifei Liu, Liyun Zhao, Jiachen Zhang, Hui Zhang, Shuhui Sun, Haoyan Huang, Yiyuan Zhang, Yanxia Ye, Guang-Hui Liu
{"title":"Spatial transcriptomic landscape unveils immunoglobin-associated senescence as a hallmark of aging","authors":"Shuai Ma, Zhejun Ji, Bin Zhang, Lingling Geng, Yusheng Cai, Chao Nie, Jiaming Li, Yuesheng Zuo, Yuzhe Sun, Gang Xu, Beibei Liu, Jiaqi Ai, Feifei Liu, Liyun Zhao, Jiachen Zhang, Hui Zhang, Shuhui Sun, Haoyan Huang, Yiyuan Zhang, Yanxia Ye, Guang-Hui Liu","doi":"10.1016/j.cell.2024.10.019","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.019","url":null,"abstract":"To systematically characterize the loss of tissue integrity and organ dysfunction resulting from aging, we produced an in-depth spatial transcriptomic profile of nine tissues in male mice during aging. We showed that senescence-sensitive spots (SSSs) colocalized with elevated entropy in organizational structure and that the aggregation of immunoglobulin-expressing cells is a characteristic feature of the microenvironment surrounding SSSs. Immunoglobulin G (IgG) accumulated across the aged tissues in both male and female mice, and a similar phenomenon was observed in human tissues, suggesting the potential of the abnormal elevation of immunoglobulins as an evolutionarily conserved feature in aging. Furthermore, we observed that IgG could induce a pro-senescent state in macrophages and microglia, thereby exacerbating tissue aging, and that targeted reduction of IgG mitigated aging across various tissues in male mice. This study provides a high-resolution spatial depiction of aging and indicates the pivotal role of immunoglobulin-associated senescence during the aging process.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"36 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Selective degradation of multimeric proteins by TRIM21-based molecular glue and PROTAC degraders","authors":"Panrui Lu, Yalong Cheng, Lei Xue, Xintong Ren, Xilong Xu, Chenglong Chen, Longzhi Cao, Jiaojiao Li, Qingcui Wu, Shan Sun, Junjie Hou, Wei Jia, Wei Wang, Yan Ma, Zhaodi Jiang, Chao Li, Xiangbing Qi, Niu Huang, Ting Han","doi":"10.1016/j.cell.2024.10.015","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.015","url":null,"abstract":"Targeted protein degradation (TPD) utilizes molecular glues or proteolysis-targeting chimeras (PROTACs) to eliminate disease-causing proteins by promoting their interaction with E3 ubiquitin ligases. Current TPD approaches are limited by reliance on a small number of constitutively active E3 ubiquitin ligases. Here, we report that (<em>S</em>)-ACE-OH, a metabolite of the antipsychotic drug acepromazine, acts as a molecular glue to induce an interaction between the E3 ubiquitin ligase TRIM21 and the nucleoporin NUP98, leading to the degradation of nuclear pore proteins and disruption of nucleocytoplasmic trafficking. Functionalization of acepromazine into PROTACs enabled selective degradation of multimeric proteins, such as those within biomolecular condensates, while sparing monomeric proteins. This selectivity is consistent with the requirement of substrate-induced clustering for TRIM21 activation. As aberrant protein assemblies cause diseases such as autoimmunity, neurodegeneration, and cancer, our findings highlight the potential of TRIM21-based multimer-selective degraders as a strategy to tackle the direct causes of these diseases.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"33 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2024-10-31DOI: 10.1016/j.cell.2024.09.022
Shanghua Gao, Ada Fang, Yepeng Huang, Valentina Giunchiglia, Ayush Noori, Jonathan Richard Schwarz, Yasha Ektefaie, Jovana Kondic, Marinka Zitnik
{"title":"Empowering biomedical discovery with AI agents","authors":"Shanghua Gao, Ada Fang, Yepeng Huang, Valentina Giunchiglia, Ayush Noori, Jonathan Richard Schwarz, Yasha Ektefaie, Jovana Kondic, Marinka Zitnik","doi":"10.1016/j.cell.2024.09.022","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.022","url":null,"abstract":"We envision “AI scientists” as systems capable of skeptical learning and reasoning that empower biomedical research through collaborative agents that integrate AI models and biomedical tools with experimental platforms. Rather than taking humans out of the discovery process, biomedical AI agents combine human creativity and expertise with AI’s ability to analyze large datasets, navigate hypothesis spaces, and execute repetitive tasks. AI agents are poised to be proficient in various tasks, planning discovery workflows and performing self-assessment to identify and mitigate gaps in their knowledge. These agents use large language models and generative models to feature structured memory for continual learning and use machine learning tools to incorporate scientific knowledge, biological principles, and theories. AI agents can impact areas ranging from virtual cell simulation, programmable control of phenotypes, and the design of cellular circuits to developing new therapies.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"239 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2024-10-30DOI: 10.1016/j.cell.2024.09.048
Lina Herhaus, Uxía Gestal-Mato, Vinay V. Eapen, Igor Mačinković, Henry J. Bailey, Cristian Prieto-Garcia, Mohit Misra, Anne-Claire Jacomin, Aparna Viswanathan Ammanath, Ivan Bagarić, Jolina Michaelis, Joshua Vollrath, Ramachandra M. Bhaskara, Georg Bündgen, Adriana Covarrubias-Pinto, Koraljka Husnjak, Jonathan Zöller, Ajami Gikandi, Sara Ribičić, Tobias Bopp, Ivan Dikic
{"title":"IRGQ-mediated autophagy in MHC class I quality control promotes tumor immune evasion","authors":"Lina Herhaus, Uxía Gestal-Mato, Vinay V. Eapen, Igor Mačinković, Henry J. Bailey, Cristian Prieto-Garcia, Mohit Misra, Anne-Claire Jacomin, Aparna Viswanathan Ammanath, Ivan Bagarić, Jolina Michaelis, Joshua Vollrath, Ramachandra M. Bhaskara, Georg Bündgen, Adriana Covarrubias-Pinto, Koraljka Husnjak, Jonathan Zöller, Ajami Gikandi, Sara Ribičić, Tobias Bopp, Ivan Dikic","doi":"10.1016/j.cell.2024.09.048","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.048","url":null,"abstract":"The autophagy-lysosome system directs the degradation of a wide variety of cargo and is also involved in tumor progression. Here, we show that the immunity-related GTPase family Q protein (IRGQ), an uncharacterized protein to date, acts in the quality control of major histocompatibility complex class I (MHC class I) molecules. IRGQ directs misfolded MHC class I toward lysosomal degradation through its binding mode to GABARAPL2 and LC3B. In the absence of IRGQ, free MHC class I heavy chains do not only accumulate in the cell but are also transported to the cell surface, thereby promoting an immune response. Mice and human patients suffering from hepatocellular carcinoma show improved survival rates with reduced IRGQ levels due to increased reactivity of CD8+ T cells toward IRGQ knockout tumor cells. Thus, we reveal IRGQ as a regulator of MHC class I quality control, mediating tumor immune evasion.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"5 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2024-10-30DOI: 10.1016/j.cell.2024.09.033
Ivan N. Zheludev, Robert C. Edgar, Maria Jose Lopez-Galiano, Marcos de la Peña, Artem Babaian, Ami S. Bhatt, Andrew Z. Fire
{"title":"Viroid-like colonists of human microbiomes","authors":"Ivan N. Zheludev, Robert C. Edgar, Maria Jose Lopez-Galiano, Marcos de la Peña, Artem Babaian, Ami S. Bhatt, Andrew Z. Fire","doi":"10.1016/j.cell.2024.09.033","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.033","url":null,"abstract":"Here, we describe “obelisks,” a class of heritable RNA elements sharing several properties: (1) apparently circular RNA ∼1 kb genome assemblies, (2) predicted rod-like genome-wide secondary structures, and (3) open reading frames encoding a novel “Oblin” protein superfamily. A subset of obelisks includes a variant hammerhead self-cleaving ribozyme. Obelisks form their own phylogenetic group without detectable similarity to known biological agents. Surveying globally, we identified 29,959 distinct obelisks (clustered at 90% sequence identity) from diverse ecological niches. Obelisks are prevalent in human microbiomes, with detection in ∼7% (29/440) and ∼50% (17/32) of queried stool and oral metatranscriptomes, respectively. We establish <em>Streptococcus sanguinis</em> as a cellular host of a specific obelisk and find that this obelisk’s maintenance is not essential for bacterial growth. Our observations identify obelisks as a class of diverse RNAs of yet-to-be-determined impact that have colonized and gone unnoticed in human and global microbiomes.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"63 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2024-10-30DOI: 10.1016/j.cell.2024.10.006
Gurkan Mollaoglu, Alexander Tepper, Chiara Falcomatà, Hunter T. Potak, Luisanna Pia, Angelo Amabile, Jaime Mateus-Tique, Noam Rabinovich, Matthew D. Park, Nelson M. LaMarche, Rachel Brody, Lindsay Browning, Jia-Ren Lin, Dmitriy Zamarin, Peter K. Sorger, Sandro Santagata, Miriam Merad, Alessia Baccarini, Brian D. Brown
{"title":"Ovarian cancer-derived IL-4 promotes immunotherapy resistance","authors":"Gurkan Mollaoglu, Alexander Tepper, Chiara Falcomatà, Hunter T. Potak, Luisanna Pia, Angelo Amabile, Jaime Mateus-Tique, Noam Rabinovich, Matthew D. Park, Nelson M. LaMarche, Rachel Brody, Lindsay Browning, Jia-Ren Lin, Dmitriy Zamarin, Peter K. Sorger, Sandro Santagata, Miriam Merad, Alessia Baccarini, Brian D. Brown","doi":"10.1016/j.cell.2024.10.006","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.006","url":null,"abstract":"Ovarian cancer is resistant to immunotherapy, and this is influenced by the immunosuppressed tumor microenvironment (TME) dominated by macrophages. Resistance is also affected by intratumoral heterogeneity, whose development is poorly understood. To identify regulators of ovarian cancer immunity, we employed a spatial functional genomics screen (Perturb-map), focused on receptor/ligands hypothesized to be involved in tumor-macrophage communication. Perturb-map recapitulated tumor heterogeneity and revealed that interleukin-4 (IL-4) promotes resistance to anti-PD-1. We find ovarian cancer cells are the key source of IL-4, which directs the formation of an immunosuppressive TME via macrophage control. IL-4 loss was not compensated by nearby IL-4-expressing clones, revealing short-range regulation of TME composition dictating tumor evolution. Our studies show heterogeneous TMEs can emerge from localized altered expression of cancer-derived cytokines/chemokines that establish immune-rich and immune-excluded neighborhoods, which drive clone selection and immunotherapy resistance. They also demonstrate the potential of targeting IL-4 signaling to enhance ovarian cancer response to immunotherapy.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"65 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2024-10-30DOI: 10.1016/j.cell.2024.10.004
Brandon R. Munn, Eli J. Müller, Itia Favre-Bulle, Ethan Scott, Joseph T. Lizier, Michael Breakspear, James M. Shine
{"title":"Multiscale organization of neuronal activity unifies scale-dependent theories of brain function","authors":"Brandon R. Munn, Eli J. Müller, Itia Favre-Bulle, Ethan Scott, Joseph T. Lizier, Michael Breakspear, James M. Shine","doi":"10.1016/j.cell.2024.10.004","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.004","url":null,"abstract":"Brain recordings collected at different resolutions support distinct signatures of neural coding, leading to scale-dependent theories of brain function. Here, we show that these disparate signatures emerge from a heavy-tailed, multiscale functional organization of neuronal activity observed across calcium-imaging recordings collected from the whole brains of zebrafish and <em>C. elegans</em> as well as from sensory regions in <em>Drosophila</em>, mice, and macaques. Network simulations demonstrate that this conserved hierarchical structure enhances information processing. Finally, we find that this organization is maintained despite significant cross-scale reconfiguration of cellular coordination during behavior. Our findings suggest that this nonlinear organization of neuronal activity is a universal principle conserved for its ability to adaptively link behavior to neural dynamics across multiple spatiotemporal scales while balancing functional resiliency and information processing efficiency.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"3 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2024-10-29DOI: 10.1016/j.cell.2024.10.005
Liyen Loh, Philippa M. Saunders, Camilla Faoro, Neus Font-Porterias, Neda Nemat-Gorgani, Genelle F. Harrison, Suraju Sadeeq, Luca Hensen, Shu Cheng Wong, Jacqueline Widjaja, E. Bridie Clemens, Shiying Zhu, Katherine M. Kichula, Sudan Tao, Faming Zhu, Gonzalo Montero-Martin, Marcelo Fernandez-Vina, Lisbeth A. Guethlein, Julian P. Vivian, Jane Davies, Paul J. Norman
{"title":"An archaic HLA class I receptor allele diversifies natural killer cell-driven immunity in First Nations peoples of Oceania","authors":"Liyen Loh, Philippa M. Saunders, Camilla Faoro, Neus Font-Porterias, Neda Nemat-Gorgani, Genelle F. Harrison, Suraju Sadeeq, Luca Hensen, Shu Cheng Wong, Jacqueline Widjaja, E. Bridie Clemens, Shiying Zhu, Katherine M. Kichula, Sudan Tao, Faming Zhu, Gonzalo Montero-Martin, Marcelo Fernandez-Vina, Lisbeth A. Guethlein, Julian P. Vivian, Jane Davies, Paul J. Norman","doi":"10.1016/j.cell.2024.10.005","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.005","url":null,"abstract":"Genetic variation in host immunity impacts the disproportionate burden of infectious diseases that can be experienced by First Nations peoples. Polymorphic human leukocyte antigen (HLA) class I and killer cell immunoglobulin-like receptors (KIRs) are key regulators of natural killer (NK) cells, which mediate early infection control. How this variation impacts their responses across populations is unclear. We show that HLA-A<sup>∗</sup>24:02 became the dominant ligand for inhibitory KIR3DL1 in First Nations peoples across Oceania, through positive natural selection. We identify KIR3DL1<sup>∗</sup>114, widespread across and unique to Oceania, as an allele lineage derived from archaic humans. KIR3DL1<sup>∗</sup>114<sup>+</sup>NK cells from First Nations Australian donors are inhibited through binding HLA-A<sup>∗</sup>24:02. The KIR3DL1<sup>∗</sup>114 lineage is defined by phenylalanine at residue 166. Structural and binding studies show phenylalanine 166 forms multiple unique contacts with HLA-peptide complexes, increasing both affinity and specificity. Accordingly, assessing immunogenetic variation and the functional implications for immunity are fundamental toward understanding population-based disease associations.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"103 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142536565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Structure-guided discovery of bile acid derivatives for treating liver diseases without causing itch","authors":"Jun Yang, Tianjun Zhao, Junping Fan, Huaibin Zou, Guangyi Lan, Fusheng Guo, Yaocheng Shi, Han Ke, Huasheng Yu, Zongwei Yue, Xin Wang, Yingjie Bai, Shuai Li, Yingjun Liu, Xiaoming Wang, Yu Chen, Yulong Li, Xiaoguang Lei","doi":"10.1016/j.cell.2024.10.001","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.001","url":null,"abstract":"Chronic itch is a debilitating symptom profoundly impacting the quality of life in patients with liver diseases like cholestasis. Activation of the human G-protein coupled receptor, MRGPRX4 (hX4), by bile acids (BAs) is implicated in promoting cholestasis itch. However, the detailed underlying mechanisms remain elusive. Here, we identified 3-sulfated BAs that are elevated in cholestatic patients with itch symptoms. We solved the cryo-EM structure of hX4-Gq in a complex with 3-phosphated deoxycholic acid (DCA-3P), a mimic of the endogenous 3-sulfated deoxycholic acid (DCA-3S). This structure revealed an unprecedented ligand-binding pocket in MRGPR family proteins, highlighting the crucial role of the 3-hydroxyl (3-OH) group on BAs in activating hX4. Guided by this structural information, we designed and developed compound 7 (C7), a BA derivative lacking the 3-OH. Notably, C7 effectively alleviates hepatic injury and fibrosis in liver disease models while significantly mitigating the itch side effects.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"237 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142536564","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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