Induction of OTUD1 by RNA viruses potently inhibits innate immune responses by promoting degradation of the MAVS/TRAF3/TRAF6 signalosome

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.在RNA病毒感染过程中，衔接蛋白线粒体抗病毒信号蛋白（MAVS）招募TRAF3与TRAF6形成信号小体，该复合物对于诱导I型干扰素（type I interferons, IFNs）和促炎细胞因子的产生至关重要。尽管学界对MAVS/TRAF3/TRAF6信号小体的激活机制已有充分研究，但该信号小体的负向调控机制仍知之甚少。本研究发现，RNA病毒可在感染早期通过依赖于核因子κB（NF-κB）的分子机制，特异性上调去泛素化酶OTUD1的表达。此外，OTUD1通过去除Smurf1的泛素化修饰，上调细胞内Smurf1的蛋白水平。值得注意的是，RNA病毒感染可促进Smurf1与MAVS、TRAF3及TRAF6的结合，进而导致MAVS/TRAF3/TRAF6信号小体各组分发生依赖于泛素化的降解，并最终显著抑制IFNs的产生。与此一致的是，OTUD1缺陷型小鼠可产生更多的抗病毒细胞因子，且对RNA病毒感染的抵抗力更强。本研究揭示了RNA病毒所利用的一种新型免疫逃逸机制，并阐明了在RNA病毒感染过程中，由OTUD1-Smurf1轴介导的MAVS/TRAF3/TRAF6信号通路负反馈环路。