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

Publication date: Available online 3 March 2016
Source:Cell Reports
Author(s): Changying Jiang, Zhicheng Zhou, Yanping Quan, Shilei Zhang, Tingting Wang, Xueqiang Zhao, Clayton Morrison, Mark T. Heise, Wenqian He, Matthew S. Miller, Xin Lin
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.

Graphical abstract

Teaser

Jiang et al. reveal that CARMA3, a gene located in a host genomic locus that contributes to the host’s susceptibility to RNA respiratory virus infection, is a key molecule that controls the balance of pro-inflammatory and antiviral responses, through positively regulating NF-κB activation but negatively regulating IRF3 activation.


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