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 induce MAVS-mediated NF-κB and IRF3 activation to promote inflammatory and antiviral responses, respectively. Here, we 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 due to less inflammation and stronger ability to clear infected virus. Together, our studies reveal the role of CARMA3 in regulating the balance of host anti-viral and pro-inflammatory responses against RNA virus infection.

Inhibition of MALT1 Decreases Neuroinflammation and Pathogenicity of Virulent Rabies Virus in Mice

“…Remarkably, in the latter study, MALT1 was entirely dispensable for RIG-I-induced NF-B activation, but its role in RIG-I-mediated IFN regulatory factor 3 (IRF3) activation and type I interferon production remains to be determined. In this context, CARD10, another protein known to be engaged in a signaling module with BCL10 and MALT1, was also shown to positively regulate RIG-I-mediated activation of NF-B and proinflammatory cytokine expression in mouse embryonic fibroblasts and lung epithelial cells but to negatively regulate RIG-Imediated activation of IRF3 and type I IFN expression by suppressing oligomerization of the adaptor protein MAVS (57). In agreement, CARD10-deficient mice had a lower viral load and higher production of type I IFN 1 day after intranasal infection with VSV.…”

Influenza Virus in Community-Acquired Pneumonia: Current Understanding and Knowledge Gaps

“…CARMA3 was identified as one of the key regulators in this process. 105,106 It is a scaffold guanylate kinase-like protein with a caspase recruitment domain and membrane…”

“…CARMA3 was involved in the RIG-I-MAVS pathway, and was shown to play a negative role in regulating host antiviral responses, but a positive role in inducing proinflammatory cytokines leading to immunopathology. 105 Other PRRs such as C-type lectin receptors, TLRs, and formyl peptide receptors are also involved in the initial inflammatory responses [107][108][109][110][111] (►Table 1).…”

The CARMA3-BCL10-MALT1 (CBM) complex contributes to DNA damage-induced NF-κB activation and cell survival

“…Upon different stimuli, all CARMA proteins can form a complex with BCL10 and MALT1, and the CARMA-BCL10-MALT1 (CBM) complex functions to activate NF-κB signaling (Pomerantz et al, 2002 ; Grabiner et al, 2007 ; Jiang et al, 2011 ). Besides in NF-κB signaling, CBM complex is also involved in antiviral innate immune response by suppressing IRF3-type I IFN expression through inhibiting the formation of MAVS oligomerization in mitochondrion (Jiang et al, 2016 ). CARMA3 was reported to be relatively overexpressed in many tumor cells and associated with the malignant behavior of cancer cells (Li et al, 2012 ; Pan et al, 2016 ).…”

“…Our previous studies show that overexpressed CARMA3 is K63-linked polyubiquitination, which may regulate NF-κB activation (Jiang et al, 2016 ). To determine how DNA damage regulates CBM complex, we co-expressed CARMA3 together with K48- and K63-linked ubiquitin, and found that DNA damage significantly induced K63-linked polyubiquitination (Fig.…”