The C-Terminal Effector Domain of Non-Structural Protein 1 of Influenza A Virus Blocks IFN-ß Production by Targeting TNF Receptor-Associated Factor 3

Qian, Wei; Wei, Xiaoqin; Guo, Kelei; Li, Yongtao; Lin, Xian; Zou, Zhong; Zhou, Hongbo; Jin, Meilin

The NS1 protein acts as an antiviral antagonist protein capable of limiting IFN production. RIG-I recognizes and binds dsRNA structures with 5′-triphosphates upon infection to initiate the host antiviral response. During the course of viral infection, the NS1 protein of IAV inhibits host IFN responses either by sequestering viral dsRNA or by binding to RIG-I and TRIM25 or RIPLET proteins required for RIG-I activation and IFN signaling pathways (11, 16, 18, 19) . In this study, we found that the NS1 C-terminal ED (AA126 to 225) of H5N1 virus inhibits the activation of IFN-β pathway. To achieve a negative regulatory function in the cellular antiviral response, NS1/126-225 associates with TRAF3 to remove the Lys63-polyubiquitin chains on TRAF3 and to disrupt the MAVS-TRAF3 complex. NS1/126-225 also increases the recruitment of IKKε to MAVS, releasing TRAF3 from the mitochondria. This further decreases the level of K63linked ubiquitination of TRAF3, impairing IRF3 phosphorylation and reducing the production of IFN-β (Figure 9) .