title: Glycogen synthase kinase 3β ubiquitination by TRAF6 regulates TLR3-mediated pro-inflammatory cytokine production.
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.
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
authors.forename: Ryeojin
authors.initials: R
authors.lastname: Ko
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Hyunil
authors.initials: H
authors.lastname: Ha
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Lee
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology; D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000276:immunology*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D007249:Inflammation; D020930:MAP Kinase Kinase Kinases / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000276:immunology; D011070:Poly I-C / Q000276:immunology; D016760:Proto-Oncogene Proteins c-fos / Q000276:immunology; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000276:immunology*; D054875:Ubiquitination / Q000235:genetics / Q000276:immunology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D020930:MAP Kinase Kinase Kinases; D011070:Poly I-C; D016760:Proto-Oncogene Proteins c-fos; D048029:TNF Receptor-Associated Factor 6; D051196:Toll-Like Receptor 3; D000099151:MAP Kinase Kinase Kinase 7; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse
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