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Cell Rep. 2016 Mar 15;14(10):2389-401. doi: 10.1016/j.celrep.2016.02.031. Epub 2016 Mar 3.

CARMA3 Is a Host Factor Regulating the Balance of Inflammatory and Antiviral Responses against Viral Infection.

Author information

1
Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
2
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.
3
Institute for Immunology, Tsinghua University School of Medicine, Beijing 100084, China.
4
Department of Genetics, The University of North Carolina, Chapel Hill, NC 27599, USA.
5
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
6
Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
7
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.

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.

KEYWORDS:

CARD10; CARMA3; IRF3; NF-κB; viral infection

PMID:
26947079
PMCID:
PMC5842788
DOI:
10.1016/j.celrep.2016.02.031
[Indexed for MEDLINE]
Free PMC Article

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