Substitution of S179P in the Lyssavirus Phosphoprotein Impairs Its Interferon Antagonistic Function
Zongmei Wang, Yueming Yuan, Yuan Zhang, Chengguang Zhang, Baokun Sui, Jianqing Zhao, Ming Zhou, Huanchun Chen, Zhen F. Fu, Ling Zhao
Abstract
Interferon (IFN) and the IFN-induced cellular antiviral response constitute the first line of defense against viral invasion. Evading host innate immunity, especially IFN signaling, is the key step required for lyssaviruses to establish infection. In this study, S179 of lyssavirus phosphoprotein (lyssavirus-P) was identified as the key site for antagonizing IFN-I production. Mechanistically, lyssavirus-P containing S179 specifically targets the key kinase IKKε and disrupts its interaction with TRAF3 and IRF3. S179P mutation in the P protein of the typical lyssavirus rabies virus (RABV) attenuated its pathogenicity in a mouse model. Our findings provide deep insight into the immune evasion strategies of lyssaviruses, which is helpful for the development of effective antiviral therapeutics.