TRAF3IP3 mediates the recruitment of TRAF3 to MAVS for antiviral innate immunity

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Abstract

RIG‐I‐MAVS antiviral signaling represents an important pathway to stimulate interferon production and confer innate immunity to the host. Upon binding to viral RNA and Riplet‐mediated polyubiquitination, RIG‐I promotes prion‐like aggregation and activation of MAVS. MAVS subsequently induces interferon production by activating two signaling pathways mediated by TBK1‐IRF3 and IKK‐NF‐κB respectively. However, the mechanism underlying the activation of MAVS downstream pathways remains elusive. Here, we demonstrated that activation of TBK1‐IRF3 by MAVS‐Region III depends on its multimerization state and identified TRAF3IP3 as a critical regulator for the downstream signaling. In response to virus infection, TRAF3IP3 is accumulated on mitochondria and thereby facilitates the recruitment of TRAF3 to MAVS for TBK1‐IRF3 activation. Traf3ip3‐deficient mice demonstrated a severely compromised potential to induce interferon production and were vulnerable to RNA virus infection. Our findings uncover that TRAF3IP3 is an important regulator for RIG‐I‐MAVS signaling, which bridges MAVS and TRAF3 for an effective antiviral innate immune response.

EMBO J (2019)38:e102075https://doi.org/10.15252/embj.2019102075