Andrew G. Harrison, Duomeng Yang, Jason G. Cahoon, Tingting Geng, Ziming Cao, Timofey A. Karginov, Youjia Hu, Xin Li, Conner C. Chiari, Yibing Qyang, Anthony T. Vella, Zhichao Fan, Sivapriya Kailasan Vanaja, Vijay A. Rathinam, Carol A. Witczak, Jonathan S. Bogan, Penghua Wang
{"title":"UBXN9 控制着 GLUT4 介导的 RIG-I 样受体和信号传导的空间限制","authors":"Andrew G. Harrison, Duomeng Yang, Jason G. Cahoon, Tingting Geng, Ziming Cao, Timofey A. Karginov, Youjia Hu, Xin Li, Conner C. Chiari, Yibing Qyang, Anthony T. Vella, Zhichao Fan, Sivapriya Kailasan Vanaja, Vijay A. Rathinam, Carol A. Witczak, Jonathan S. Bogan, Penghua Wang","doi":"10.1038/s41590-024-02004-7","DOIUrl":null,"url":null,"abstract":"The cytoplasmic RIG-I-like receptors (RLRs) recognize viral RNA and initiate innate antiviral immunity. RLR signaling also triggers glycolytic reprogramming through glucose transporters (GLUTs), whose role in antiviral immunity is elusive. Here, we unveil that insulin-responsive GLUT4 inhibits RLR signaling independently of glucose uptake in adipose and muscle tissues. At steady state, GLUT4 is trapped at the Golgi matrix by ubiquitin regulatory X domain 9 (UBXN9, TUG). Following RNA virus infection, GLUT4 is released and translocated to the cell surface where it spatially segregates a significant pool of cytosolic RLRs, preventing them from activating IFN-β responses. UBXN9 deletion prompts constitutive GLUT4 translocation, sequestration of RLRs and attenuation of antiviral immunity, whereas GLUT4 deletion heightens RLR signaling. Notably, reduced GLUT4 expression is uniquely associated with human inflammatory myopathies characterized by hyperactive interferon responses. Overall, our results demonstrate a noncanonical UBXN9-GLUT4 axis that controls antiviral immunity via plasma membrane tethering of cytosolic RLRs. Wang and colleagues show that in skeletal muscle cells and cardiomyocytes, the glucose transporter GLUT4 is a negative regulator of RIG-I-like receptor signaling during viral infection by redistributing RIG-I and MDA5 to the plasma membrane and attenuating interferon responses.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"25 12","pages":"2234-2246"},"PeriodicalIF":27.7000,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"UBXN9 governs GLUT4-mediated spatial confinement of RIG-I-like receptors and signaling\",\"authors\":\"Andrew G. Harrison, Duomeng Yang, Jason G. Cahoon, Tingting Geng, Ziming Cao, Timofey A. Karginov, Youjia Hu, Xin Li, Conner C. Chiari, Yibing Qyang, Anthony T. Vella, Zhichao Fan, Sivapriya Kailasan Vanaja, Vijay A. Rathinam, Carol A. Witczak, Jonathan S. Bogan, Penghua Wang\",\"doi\":\"10.1038/s41590-024-02004-7\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"The cytoplasmic RIG-I-like receptors (RLRs) recognize viral RNA and initiate innate antiviral immunity. RLR signaling also triggers glycolytic reprogramming through glucose transporters (GLUTs), whose role in antiviral immunity is elusive. Here, we unveil that insulin-responsive GLUT4 inhibits RLR signaling independently of glucose uptake in adipose and muscle tissues. At steady state, GLUT4 is trapped at the Golgi matrix by ubiquitin regulatory X domain 9 (UBXN9, TUG). Following RNA virus infection, GLUT4 is released and translocated to the cell surface where it spatially segregates a significant pool of cytosolic RLRs, preventing them from activating IFN-β responses. UBXN9 deletion prompts constitutive GLUT4 translocation, sequestration of RLRs and attenuation of antiviral immunity, whereas GLUT4 deletion heightens RLR signaling. Notably, reduced GLUT4 expression is uniquely associated with human inflammatory myopathies characterized by hyperactive interferon responses. Overall, our results demonstrate a noncanonical UBXN9-GLUT4 axis that controls antiviral immunity via plasma membrane tethering of cytosolic RLRs. Wang and colleagues show that in skeletal muscle cells and cardiomyocytes, the glucose transporter GLUT4 is a negative regulator of RIG-I-like receptor signaling during viral infection by redistributing RIG-I and MDA5 to the plasma membrane and attenuating interferon responses.\",\"PeriodicalId\":19032,\"journal\":{\"name\":\"Nature Immunology\",\"volume\":\"25 12\",\"pages\":\"2234-2246\"},\"PeriodicalIF\":27.7000,\"publicationDate\":\"2024-11-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.nature.com/articles/s41590-024-02004-7\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Immunology","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s41590-024-02004-7","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
UBXN9 governs GLUT4-mediated spatial confinement of RIG-I-like receptors and signaling
The cytoplasmic RIG-I-like receptors (RLRs) recognize viral RNA and initiate innate antiviral immunity. RLR signaling also triggers glycolytic reprogramming through glucose transporters (GLUTs), whose role in antiviral immunity is elusive. Here, we unveil that insulin-responsive GLUT4 inhibits RLR signaling independently of glucose uptake in adipose and muscle tissues. At steady state, GLUT4 is trapped at the Golgi matrix by ubiquitin regulatory X domain 9 (UBXN9, TUG). Following RNA virus infection, GLUT4 is released and translocated to the cell surface where it spatially segregates a significant pool of cytosolic RLRs, preventing them from activating IFN-β responses. UBXN9 deletion prompts constitutive GLUT4 translocation, sequestration of RLRs and attenuation of antiviral immunity, whereas GLUT4 deletion heightens RLR signaling. Notably, reduced GLUT4 expression is uniquely associated with human inflammatory myopathies characterized by hyperactive interferon responses. Overall, our results demonstrate a noncanonical UBXN9-GLUT4 axis that controls antiviral immunity via plasma membrane tethering of cytosolic RLRs. Wang and colleagues show that in skeletal muscle cells and cardiomyocytes, the glucose transporter GLUT4 is a negative regulator of RIG-I-like receptor signaling during viral infection by redistributing RIG-I and MDA5 to the plasma membrane and attenuating interferon responses.
期刊介绍:
Nature Immunology is a monthly journal that publishes the highest quality research in all areas of immunology. The editorial decisions are made by a team of full-time professional editors. The journal prioritizes work that provides translational and/or fundamental insight into the workings of the immune system. It covers a wide range of topics including innate immunity and inflammation, development, immune receptors, signaling and apoptosis, antigen presentation, gene regulation and recombination, cellular and systemic immunity, vaccines, immune tolerance, autoimmunity, tumor immunology, and microbial immunopathology. In addition to publishing significant original research, Nature Immunology also includes comments, News and Views, research highlights, matters arising from readers, and reviews of the literature. The journal serves as a major conduit of top-quality information for the immunology community.