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

• Published in: Immunology 2017-09, Vol.152 (1), p.102-114
• Main Authors: Huang, Hongjun, Zhang, Na, Xiong, Qingqing, Chen, Ruoyu, Zhang, Chengfei, Wang, Ning, Wang, Li, Ren, Hua, Liu, Mingyao, Qian, Min, Du, Bing
• Format: Article
• Language: English
• Subjects: Animals; Antiviral activity; Antiviral state; Chlorocebus aethiops; Enhancer-of-split protein; G protein-coupled receptors; Genotype; GPR146; HEK293 Cells; Herpes simplex; Herpes Simplex - immunology; Herpes Simplex - metabolism; Herpes Simplex - prevention & control; Herpes Simplex - virology; Herpesvirus 1, Human - immunology; Herpesvirus 1, Human - metabolism; HES1; Host-Pathogen Interactions; Humans; Infections; Interferon; Interferon regulatory factor 3; Interferon Regulatory Factor-3 - immunology; Interferon Regulatory Factor-3 - metabolism; Interferon-beta - pharmacology; Interferon-gamma - pharmacology; IRF3; ISGs; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Macrophages, Peritoneal - virology; Mice; Mice, Inbred C57BL; Mice, Knockout; Newcastle disease; Newcastle Disease - immunology; Newcastle Disease - metabolism; Newcastle Disease - prevention & control; Newcastle Disease - virology; Newcastle disease virus - immunology; Newcastle disease virus - metabolism; Original; Phenotype; RAW 264.7 Cells; Receptors, G-Protein-Coupled - deficiency; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - immunology; RNA Interference; Signal Transduction; Signaling; Stomatitis; Transcription; Transcription Factor HES-1 - immunology; Transcription Factor HES-1 - metabolism; Transfection; Vero Cells; Vesicular Stomatitis - immunology; Vesicular Stomatitis - metabolism; Vesicular Stomatitis - prevention & control; Vesicular Stomatitis - virology; Vesicular stomatitis Indiana virus - immunology; Vesicular stomatitis Indiana virus - metabolism; viral infection; Viral infections; Virus Replication; Viruses; β-Interferon; γ-Interferon
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.12752

Summary As the most important host defence against viral infection, interferon (IFN) stimulates hundreds of antiviral genes (ISGs) that together establish an ‘antiviral state’. However, the antiviral function of most ISGs in viral infection still need further exploration. Here, we demonstrated that the expression of G‐protein‐coupled receptor 146 (GPR146) 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 GPR146 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 GPR146 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 GPR146 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 GPR146 in fighting viral infection although the GPR146‐mediated protection is eliminated by IRF3/HES1‐signalling, which suggests a potential therapeutic significance of both GPR146 and HES1 signalling in viral infection. As a typical interferon‐stimulated gene, Gpr146 selectively inhibits RNA virus propagation in host cells. Whereas viruses escape from GPR146‐mediated defences through suppression of GPR146 in IRF3/HES1‐signalling pathway.