GNAQ Negatively Regulates Antiviral Innate Immune Responses in a Calcineurin-Dependent Manner.

Although guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) constitute the largest cell surface membrane receptor family and transduce thousands of extracellular signals into the cytoplasm, only four kinds of G protein α subunits (Gαs, Gαi/o, Gαq/11, and Gα12/13) are coupled to regulate cAMP or phosphatidylinositol signals. Growing evidence suggests that viruses tend to hijack GPCRs and harness their activated intracellular signaling pathways. Thus, understanding the roles of G protein signaling will further uncover the GPCR signaling pathways that are exploited by viruses. In this study, we demonstrate that the expression of GNAQ (Gq α subunit) was downregulated during viral infection and that small interfering RNA-mediated GNAQ knockdown protected host cells from both vesicular stomatitis virus (VSV) and HSV type 1 infection. Meanwhile, VSV and HSV type 1 replication was reduced significantly in Gnaq-deficient macrophages. Accordingly, the VSV distribution in the liver, spleen, and lung was reduced in Gnaq-deficient mice during VSV infection, and Gnaq-deficient mice were much more resistant to VSV infection than wild-type mice. Mechanistically, GNAQ limits type I IFN production through the canonical PLC-ß/Ca2+/CALNA signaling pathway, which has been demonstrated to dephosphorylate virus-activated TANK-binding kinase 1 (TBK1). Thus, our data demonstrate that GNAQ negatively regulates the antiviral innate immune responses in a calcineurin-dependent manner. These findings also provide insights into the function and cross-talk of the classic GPCR signaling pathway with antiviral innate immune responses and suggest a potential therapeutic role for GNAQ in controlling viral diseases.

Metabolite-Sensing G Protein Coupled Receptor TGR5 Protects Host From Viral Infection Through Amplifying Type I Interferon Responses.

The metabolite-sensing G protein-coupled receptors (GPCRs) bind to various metabolites and transmit signals that are important for proper immune and metabolic functions. However, the roles of metabolite-sensing GPCRs in viral infection are not well characterized. Here, we identified metabolite-sensing GPCR TGR5 as an interferon (IFN)-stimulated gene (ISG) which had increased expression following viral infection or IFN-ß stimulation in a STAT1-dependent manner. Most importantly, overexpression of TGR5 or treatment with the modified bile acid INT-777 broadly protected host cells from vesicular stomatitis virus (VSV), newcastle disease virus (NDV) and herpes simplex virus type 1 (HSV-1) infection. Furthermore, VSV and HSV-1 replication was increased significantly in Tgr5-deficient macrophages and the VSV distribution in liver, spleen and lungs was increased in Tgr5-deficient mice during VSV infection. Accordingly, Tgr5-deficient mice were much more susceptible to VSV infection than wild-type mice. Mechanistically, TGR5 facilitates type I interferon (IFN-I) production through the AKT/IRF3-signaling pathway, which is crucial in promoting antiviral innate immunity. Taken together, our data reveal a positive feedback loop regulating IRF3 signaling and suggest a potential therapeutic role for metabolite-sensing GPCRs in controlling viral diseases.