title: CARMA3 Is a Host Factor Regulating the Balance of Inflammatory and Antiviral Responses against Viral Infection.
abstract: Host response to RNA virus infection is sensed by RNA sensors such as RIG-I, which induces MAVS-mediated NF-κB and IRF3 activation to promote inflammatory and antiviral responses, respectively. Here, we have found that CARMA3, a scaffold protein previously shown to mediate NF-κB activation induced by GPCR and EGFR, positively regulates MAVS-induced NF-κB activation. However, our data suggest that CARMA3 sequesters MAVS from forming high-molecular-weight aggregates, thereby suppressing TBK1/IRF3 activation. Interestingly, following NF-κB activation upon virus infection, CARMA3 is targeted for proteasome-dependent degradation, which releases MAVS to activate IRF3. When challenged with vesicular stomatitis virus or influenza A virus, CARMA3-deficient mice showed reduced disease symptoms compared to those of wild-type mice as a result of less inflammation and a stronger ability to clear infected virus. Altogether, our results reveal the role of CARMA3 in regulating the balance of host antiviral and pro-inflammatory responses against RNA virus infection.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Changying
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; Cancer Biology Program, The University of Texas, Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Quan
authors.affiliation: Institute for Immunology, Tsinghua University School of Medicine, Beijing 100084, China.
authors.forename: Shilei
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Institute for Immunology, Tsinghua University School of Medicine, Beijing 100084, China.
authors.forename: Xueqiang
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Genetics, The University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Clayton
authors.initials: C
authors.lastname: Morrison
authors.affiliation: Department of Genetics, The University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Heise
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Wenqian
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Miller
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; Cancer Biology Program, The University of Texas, Graduate School of Biomedical Sciences, Houston, TX 77030, USA; Institute for Immunology, Tsinghua University School of Medicine, Beijing 100084, China. Electronic address: xllin@mdanderson.org.
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D000071457:DEAD Box Protein 58 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D012327:RNA Virus Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D018116:Vesiculovirus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D019562:Viral Load
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins; D016207:Cytokines; D000071457:DEAD Box Protein 58; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; C488088:Bcl10 protein, mouse; C498975:Card10 protein, mouse; C512612:MAVS protein, mouse; C494233:Irf3 protein, mouse; C498588:Tbk1 protein, mouse; C503356:Ddx58 protein, mouse
keywords: CARD10; CARMA3; IRF3; NF-κB; viral infection