The Journal of Immunology | 2019
Glycogen Synthase Kinase 3β Regulates Antiviral Responses of TLR3 via TRAF2–Src Axis
Abstract
Key Points GSK3β interacts with Src tyrosine kinase. Src positively regulates antiviral immune response. Src undergoes K63-linked ubiquitination by TRAF2. The protein tyrosine kinase Src regulates the synthesis of TLR3-mediated IFN-β via the TBK1–IFN regulatory factor 3 axis. However, the molecular mechanisms regulating Src activity in TLR3 signaling remain unclear. In this study, we report that GSK3β regulates Src phosphorylation via TNFR-associated factor 2 (TRAF2)–mediated Src ubiquitination. GSK3β deficiency in mouse embryonic fibroblasts significantly reduces polyinosinic:polycytidylic acid–induced IFN-β and IFN-stimulated gene expression, which is caused by diminished phosphorylation of Src at tyrosine 416. Src undergoes polyinosinic:polycytidylic acid–dependent lysine 63 chain ubiquitination, and TRAF2 is a direct E3 ligase for Src. Our study reveals novel mechanisms underlying TLR3-mediated antiviral responses mediated via the GSK3β–TRAF2–Src axis.