Glycogen Synthase Kinase 3β Regulates Antiviral Responses of TLR3 via TRAF2-Src Axis

J Immunol. 2019 Dec 1;203(11):2990-2999. doi: 10.4049/jimmunol.1900685. Epub 2019 Oct 16.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Glycogen Synthase Kinase 3 beta / deficiency
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphorylation
  • RAW 264.7 Cells
  • TNF Receptor-Associated Factor 2 / metabolism*
  • Toll-Like Receptor 3 / metabolism*
  • Ubiquitination
  • src-Family Kinases / metabolism*

Substances

  • TLR3 protein, mouse
  • TNF Receptor-Associated Factor 2
  • TRAF2 protein, mouse
  • Toll-Like Receptor 3
  • src-Family Kinases
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse