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

• Published in: PLoS pathogens Vol. 17; no. 2; p. e1009300
• Main Authors: Zeng, Yan, Xu, Shuai, Wei, Yanli, Zhang, Xuegang, Wang, Qian, Jia, Yane, Wang, Wanbing, Han, Lu, Chen, Zhaoshan, Wang, Zhengxiang, Zhang, Bo, Chen, Hualan, Lei, Cao-Qi, Zhu, Qiyun
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.02.2021; Public Library of Science (PLoS)
• Subjects: Antiviral drugs; Autophagy; Avian flu; Biology and Life Sciences; Cell activation; Fatalities; Gene expression; Genes; Genetics; Genomes; Immune response; Infections; Influenza A; Innate immunity; Interferon; Interferon regulatory factor 3; Kinases; Lymphocytes; Lymphocytes T; Medicine and health sciences; Mutants; Mutation; NF-κB protein; Nonsense mutation; Nucleotides; Pandemics; Pathogens; Phosphorylation; Plasmids; Proteins; RANTES; Research and Analysis Methods; Retinoic acid; RNA-mediated interference; Signal transduction; Signaling; Transcription; Viral infections; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1009300

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.