Abstract

During RNA virus infection, the adaptor protein MAVS recruits TRAF3 and TRAF6 to form a signalosome, which is critical to induce the production of type I interferons (IFNs) and proinflammatory cytokines. While activation of the MAVS/TRAF3/TRAF6 signalosome is well studied, the negative regulation of the signalosome remains largely unknown. Here we report that RNA viruses specifically promote the deubiquitinase OTUD1 expression by NF-κB-dependent mechanisms at the early stage of viral infection. Furthermore, OTUD1 upregulates protein levels of intracellular Smurf1 by removing Smurf1 ubiquitination. Importantly, RNA virus infection promotes the binding of Smurf1 to MAVS, TRAF3 and TRAF6, which leads to ubiquitination-dependent degradation of every component of the MAVS/TRAF3/TRAF6 signalosome and subsequent potent inhibition of IFNs production. Consistently, OTUD1-deficient mice produce more antiviral cytokines and are more resistant to RNA virus infection. Our findings reveal a novel immune evasion mechanism exploited by RNA viruses, and elucidate a negative feedback loop of MAVS/TRAF3/TRAF6 signaling mediated by the OTUD1-Smurf1 axis during RNA virus infection. Extensive studies have demonstrated redundant roles of multiple antiviral signaling pathways in host defense against viral infection. However, the strategies viruses have evolved to efficiently antagonize the complementary effect of alternative IFNs-inducing signaling remain largely unknown. Here we report that RNA viruses specifically promote the expression of the deubiquitinase OTUD1. RNA viruses-induced OTUD1 upregulates intracellular Smurf1 protein levels by deubiquitination modification, and promotes the binding of Smurf1 to MAVS, TRAF3 and TRAF6, which leads to degradation of every component of the MAVS/TRAF3/TRAF6 signalosome and inhibition of IFNs production. Our finding identifies a potent negative regulation of innate antiviral response, which could be crucial for RNA viruses to establish efficie