Elimination of GPR146-mediated antiviral function through IRF3/HES1-signalling pathway

Summary As the most important host defence against viral infection, interferon ( IFN ) stimulates hundreds of antiviral genes ( ISG s) that together establish an ‘antiviral state’. However, the antiviral function of most ISG s in viral infection still need further exploration. Here, we demonstrated that the expression of G‐protein‐coupled receptor 146 ( GPR 146) is highly increased by both IFN ‐ β and IFN ‐ γ in a signal transducer and activator of transcription 1‐dependent signalling pathway. Most importantly, overexpression of GPR 146 protects the host cells from vesicular stomatitis virus and Newcastle disease virus infection but not from infection by herpes simplex virus. In contrast, the virus‐induced IFN ‐ β production changed little in Gpr146 ‐knockout cells. Furthermore, the Gpr146 ‐deficient mice showed similar susceptibility to wild‐type mice with vesicular stomatitis virus infection. Interestingly, the expression of GPR 146 in virus‐infected cells was strikingly reduced and can partially explain why the viral infection was little influenced in Gpr146 ‐knockout mice. Surprisingly, virus‐activated IFN regulatory factor 3 ( IRF3 ) signalling not only induces the expression of IFN but also represses GPR 146 expression through HES1 (hairy and enhancer of split‐1)‐mediated transcriptional activity to establish a dynamic equilibrium between pro‐viral and antiviral stages in host cells. Taken together, these data reveal the antiviral role of GPR 146 in fighting viral infection although the GPR 146‐mediated protection is eliminated by IRF 3/ HES 1‐signalling, which suggests a potential therapeutic significance of both GPR 146 and HES 1 signalling in viral infection.