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.
Bibliographical noteFunding Information:
We thank Dr J. Woodgett (Ontario Cancer Institute) for MEFs and plasmids. We also thank Drs I.H. Choi (Yonsei University College of Medicine), J.K. Chung, J.H. Seol (Seoul National University), T. Ishitani (Kyushu University) and W.S. Ryu (Yonsei University) for sharing cell lines and plasmids. We thank Dr J. Kim (Ewha Womans University) for critical review of the manuscript. This work was supported by the National Research Foundation of Korea grant funded by the Korea Government (Ministry of Science, ICT & Future Planning) (No. 2013R1A2A1A05005153; No. 2012R1A5A1048236; No. 2012M3A9C5048708). Y.C. was supported in part by grants from National Institutes of Health (AI064909 and AI08627).
© 2015 Macmillan Publishers Limited. All rights reserved.