Ko Ryeojin, Park Jin Hee, Ha Hyunil, Choi Yongwon, Lee Soo Young
Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Nat Commun. 2015 Apr 1;6:6765. doi: 10.1038/ncomms7765.
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.
TRAF6对于各种TLR介导的信号通路中炎性细胞因子的产生至关重要。然而，目前对于TRAF6如何调节TLR3反应的了解还很少。在此我们证明，GSK3β与TRAF6相互作用并正向调节TLR3介导的信号传导。抑制GSK3β的表达或其激酶活性会通过降低ERK和p38磷酸化，大幅减少炎性细胞因子的产生以及c-Fos的诱导。GSK3β以TLR3配体多聚肌苷酸-胞苷酸（poly I:C）依赖性方式与TRAF6发生物理结合。已确定TRAF6是GSK3β的直接E3连接酶，并且TRAF6介导的GSK3β泛素化对于通过促进TLR3接头蛋白TRIF组装的信号复合物产生poly I:C依赖性细胞因子至关重要。
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