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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • B-Cell CLL-Lymphoma 10 Protein
  • CARD Signaling Adaptor Proteins / antagonists & inhibitors
  • CARD Signaling Adaptor Proteins / genetics
  • CARD Signaling Adaptor Proteins / immunology*
  • Cell Line
  • Cytokines / genetics
  • Cytokines / metabolism
  • DEAD Box Protein 58 / genetics
  • DEAD Box Protein 58 / metabolism
  • Disease Models, Animal
  • HEK293 Cells
  • Humans
  • Inflammation*
  • Interferon Regulatory Factor-3 / metabolism
  • Mice
  • Mice, Inbred BALB C
  • NF-kappa B / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Interference
  • RNA Virus Infections / immunology*
  • RNA Virus Infections / metabolism
  • RNA Virus Infections / pathology
  • Signal Transduction
  • Vesiculovirus / genetics
  • Vesiculovirus / immunology*
  • Vesiculovirus / physiology
  • Viral Load

Substances

  • Adaptor Proteins, Signal Transducing
  • B-Cell CLL-Lymphoma 10 Protein
  • Bcl10 protein, mouse
  • CARD Signaling Adaptor Proteins
  • Card10 protein, mouse
  • Cytokines
  • IPS-1 protein, mouse
  • Interferon Regulatory Factor-3
  • Irf3 protein, mouse
  • NF-kappa B
  • Tbk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proteasome Endopeptidase Complex
  • Ddx58 protein, mouse
  • DEAD Box Protein 58