The PB1 protein of influenza A virus inhibits the innate immune response by targeting MAVS for NBR1-mediated selective autophagic degradation

文献类型： 外文期刊

第一作者： Zeng, Yan

作者： Zeng, Yan;Xu, Shuai;Wei, Yanli;Zhang, Xuegang;Wang, Qian;Jia, Yane;Wang, Wanbing;Han, Lu;Chen, Zhaoshan;Wang, Zhengxiang;Zhu, Qiyun;Zhang, Bo;Chen, Hualan;Lei, Cao-Qi

作者机构：

期刊名称：PLOS PATHOGENS （ 影响因子：6.823； 五年影响因子：7.455 ）

ISSN： 1553-7366

年卷期： 2021 年 17 卷 2 期

页码：

收录情况： SCI

摘要： Author summary In 2013, H7N9 influenza viruses appeared in China and other countries resulting in 1, 567 human infections and 615 deaths. Understanding the cross-talk between virus and host is vital for the development of effective vaccines and therapeutics. Here, we identified the PB1 protein of H7N9 virus as a novel negative regulator that enhances the degradation of MAVS, an essential adaptor protein in the innate signaling pathway. Mechanistically, PB1 promoted the E3 ligase RNF5-mediated ubiquitination of MAVS and recruited the selective autophagic receptor NBR1 to associate with and deliver the ubiquitinated MAVS to the autophagosomes for degradation. Thus, the PB1-RNF5-MAVS-NBR1 axis inhibited innate immune antiviral response and facilitated virus replication by mediating MAVS degradation in an autophagosome-dependent manner. Our findings reveal a novel mechanism by which influenza virus negatively regulates the innate immune response. Influenza A virus (IAV) has evolved various strategies to counteract the innate immune response using different viral proteins. However, the mechanism is not fully elucidated. In this study, we identified the PB1 protein of H7N9 virus as a new negative regulator of virus- or poly(I:C)-stimulated IFN induction and specifically interacted with and destabilized MAVS. A subsequent study revealed that PB1 promoted E3 ligase RNF5 to catalyze K27-linked polyubiquitination of MAVS at Lys362 and Lys461. Moreover, we found that PB1 preferentially associated with a selective autophagic receptor neighbor of BRCA1 (NBR1) that recognizes ubiquitinated MAVS and delivers it to autophagosomes for degradation. The degradation cascade mediated by PB1 facilitates H7N9 virus infection by blocking the RIG-I-MAVS-mediated innate signaling pathway. Taken together, these data uncover a negative regulatory mechanism involving the PB1-RNF5-MAVS-NBR1 axis and provide insights into an evasion strategy employed by influenza virus that involves selective autophagy and innate signaling pathways.

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