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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Vesicular Transport / immunology
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Animals
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Cytokines / genetics
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Cytokines / immunology*
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / immunology*
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Glycogen Synthase Kinase 3 beta
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HEK293 Cells
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Humans
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Immunity, Innate / genetics
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Immunity, Innate / immunology*
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Inflammation
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MAP Kinase Kinase Kinases / immunology
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MAP Kinase Signaling System / immunology
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Mice
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Mice, Knockout
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Phosphorylation / immunology
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Poly I-C / immunology
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Proto-Oncogene Proteins c-fos / immunology
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TNF Receptor-Associated Factor 6 / genetics
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TNF Receptor-Associated Factor 6 / immunology*
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Toll-Like Receptor 3 / immunology*
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Ubiquitination / genetics
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Ubiquitination / immunology
Substances
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Adaptor Proteins, Vesicular Transport
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Cytokines
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Proto-Oncogene Proteins c-fos
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TICAM-1 protein, mouse
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TLR3 protein, mouse
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TNF Receptor-Associated Factor 6
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Toll-Like Receptor 3
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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Glycogen Synthase Kinase 3
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Poly I-C