Glycogen synthase kinase 3β ubiquitination by TRAF6 regulates TLR3-mediated pro-inflammatory cytokine production

Nat Commun. 2015 Apr 1;6:6765. doi: 10.1038/ncomms7765.

Abstract

TRAF6 is critical for the production of inflammatory cytokines in various TLR-mediated signalling pathways. However, it is poorly understood how TRAF6 regulates TLR3 responses. Here we demonstrate that GSK3β interacts with TRAF6 and positively regulates the TLR3-mediated signalling. Suppression of GSK3β expression or its kinase activity drastically reduces the production of inflammatory cytokines and the induction of c-Fos by decreasing ERK and p38 phosphorylation. GSK3β physically associates with TRAF6 in a TLR3 ligand poly I:C-dependent manner. TRAF6 is determined to be a direct E3 ligase for GSK3β, and TRAF6-mediated GSK3β ubiquitination is essential for poly I:C-dependent cytokine production by promoting the TLR3 adaptor protein TRIF-assembled signalling complex.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / immunology
  • Animals
  • Cytokines / genetics
  • Cytokines / immunology*
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / immunology*
  • Glycogen Synthase Kinase 3 beta
  • HEK293 Cells
  • Humans
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology*
  • Inflammation
  • MAP Kinase Kinase Kinases / immunology
  • MAP Kinase Signaling System / immunology
  • Mice
  • Mice, Knockout
  • Phosphorylation / immunology
  • Poly I-C / immunology
  • Proto-Oncogene Proteins c-fos / immunology
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / immunology*
  • Toll-Like Receptor 3 / immunology*
  • Ubiquitination / genetics
  • Ubiquitination / immunology

Substances

  • Adaptor Proteins, Vesicular Transport
  • Cytokines
  • Proto-Oncogene Proteins c-fos
  • TICAM-1 protein, mouse
  • TLR3 protein, mouse
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptor 3
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Glycogen Synthase Kinase 3
  • Poly I-C