Disruption of Type I Interferon Signaling by NSs Protein of Severe Fever with Thrombocytopenia Syndrome Virus via Hijacking STAT2 and STAT1 into Inclusion Bodies.

　　Ning YJ, Feng K, Min YQ, Cao WC, Wang M, Deng F, Hu Z, Wang H.

     J Virol. 2015 Jan 28. pii: JVI.00154-15.

　  Abstract

　　Type I interferon (IFN) system including IFN induction and signaling is the critical component of the host defense line against viral infection, which in turn, is also a vulnerable target for viral immune evasion. Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging bunyavirus. Previous data have shown that SFTSV can interfere with the early induction of type I IFNs through targeting host kinases TBK1/IKK?. In this study, we demonstrated that SFTSV can also suppress type I IFN-triggered signaling and hence interferon-stimulated gene (ISG) expression. Interestingly, we observed the significant inhibition of IFN signaling in cells transfected with the plasmids encoding the nonstructural protein (NSs) but not the nucleocapsid protein (NP), indicating the role of NSs as an antagonist of IFN signaling. Furthermore, co-immunoprecipitation (Co-IP) and pull-down assays indicated that NSs interacts with the cellular signal transducer and activator of transcription 2 (STAT2) and the DNA-binding domain of STAT2 may contribute to the NSs-STAT2 interaction. Combined with confocal microscopy analyses we demonstrated that NSs sequesters STAT2 and STAT1 into viral inclusion bodies (IBs) and impairs IFN-induced STAT2 phosphorylation and nuclear translocation of both STATs, resulting in the inhibition of IFN signaling and ISG expression. SFTSV NSs-mediated hijacking of STATs in IBs represents a novel mechanism of viral suppression of IFN signaling, highlighting the role of viral IBs as the virus-built "jail" sequestering some crucial host factors and thus interfering with the corresponding cellular processes.

　　IMPORTANCE:

　　SFTSV is an emerging bunyavirus which can cause a severe haemorrhagic fever-like disease with high case fatality rates in humans, posing a serious health threat. However, there are no specific antivirals available and the pathogenesis and virus-host interactions are largely unclear. Here, we demonstrated that SFTSV can inhibit type I interferon (IFN) antiviral signaling by the nonstructral protein (NSs)-mediated hijacking of STAT2 and STAT1 into viral inclusion bodies (IBs), highlighting the interesting role of viral IBs in virus-host interactions as the virus-built "jail". Sequestering signaling molecules into IBs represents a novel and perhaps also general mechanism of viral suppression of IFN signaling, understanding of which may benefit the study on the viral pathogenesis and the development of antiviral therapies.

　　http://www.ncbi.nlm.nih.gov/pubmed/25631085