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

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. [Display omitted] •Deficiency of CARMA3 results in the host resistance to RNA viral infection•CARMA3 positively regulates RIG-I/MAVS-mediated NF-κB activation•CARMA3 negatively regulates RIG-I/MAVS-mediated TBK1/IRF3 activation•CARMA3 negatively suppresses MAVS oligomerization in mitochondran 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.