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

• Published in: The EMBO journal 2019-09, Vol.38 (18), p.e102075-n/a
• Main Authors: Zhu, Wenting, Li, Jiaxin, Zhang, Rui, Cai, Yixiang, Wang, Changwan, Qi, Shishi, Chen, She, Liang, Xiaozhen, Qi, Nan, Hou, Fajian
• Format: Article
• Language: English
• Subjects: Activation; Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - metabolism; Animals; Cell Line; Disease Models, Animal; EMBO19; EMBO23; HEK293 Cells; HeLa Cells; Humans; Immune response; Immune system; Immunity; Immunity, Innate; Infections; Innate immunity; Interferon; Interferon regulatory factor 3; Interferon Regulatory Factor-3 - metabolism; MAVS; Mice; Microtubule-Associated Proteins - metabolism; Mitochondria; Mitochondria - metabolism; Protein Multimerization; Protein-Serine-Threonine Kinases - metabolism; Recruitment; RIG‐I; RNA viruses; Signal transduction; Signaling; TNF Receptor-Associated Factor 3 - genetics; TNF Receptor-Associated Factor 3 - metabolism; TRAF3IP3; Virus Diseases - genetics; Virus Diseases - immunology; Viruses
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.2019102075

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. Synopsis TRAF3IP3 mediates TRAF3 recruitment to MAVS and promotes RIG‐I‐MAVS antiviral signaling to stimulate type I interferon induction and antiviral innate immunity. Multimerization of MAVS‐Region III is essential for its downstream TBK1‐IRF3 activation. TRAF3IP3 mediates TRAF3 recruitment to MAVS‐Region III and promotes TBK1‐IRF3 activation upon virus infection. TRAF3IP3 plays an important role in interferon induction and antiviral innate immunity against RNA virus infection in vivo . Graphical Abstract The TRAF3 interacting protein 3, TRAF3IP3, promotes RIG‐I‐MAVS signaling to stimulate type I interferon production and protection against RNA virus infection.