[Seminar] Title: RIG-I/MAVS-mediated antiviral innate immune signaling

Viral infection can be sensed by PRRs, which leads to the rapid production of type I interferon (IFN) and proinflammatory cytokines and therefore induces an antiviral state in host cells. IFN was demonstrated to play a pivotal role against viral infection sixty years ago. RIG-I was found as a major PRR in 2004, which senses viral RNA and triggers a signaling cascade leading to the production of IFN. In 2005, MAVS, a mitochondrial protein, was identified as an adaptor protein critical for RIG-I signaling. MAVS activates downstream kinases TBK1 and IKK, which in turn activate transcription factors IRF3 and NF-kB and promote their translocations to the nucleus to turn on the expression of type I IFN and other cytokines. Upon binding to virus RNA, RIG-I induces MAVS to form prion-like aggregates, which is a hallmark of its activation and essential for propagating the antiviral signal. In the past few years, we have focused on this pathway: 1) we identified a novel region of MAVS (Region III) for its downstream TBK1/IRF3 activation, and further uncovered an autoinhibitory mechanism that is essential for suppressing MAVS activity in resting cells; 2) We determined that the sole E3 ubiquitin ligase essential for RIG-I activation upon virus infection is Riplet, not TRIM25, Mex3C or TRIM4 as previously reported. We then found that two ubiquitin enzymes (E2s) Ube2D3 and Ube2N are required for RIG-I activation, and revealed that Ube2D3-Riplet and Ube2N-Riplet pairs mediate two distinct molecular mechanisms for RIG-I activation; 3) We demonstrated that spontaneous aggregation is an intrinsic propensity of MAVS, and revealed a novel mechanism preventing its spontaneous aggregation in resting cells. This inhibitory mechanism ensures that MAVS only forms prion-like aggregates when induced by the RIG-I / vRNA / polyubiquitin complex upon virus infection.