Tumor necrosis factor (TNF) receptor associated factor 3 (TRAF3) is a ubiquitin ligase recruited to both MYD88- and TRIF-assembled signalling complexes [Hacker H et al 2006]. However, TRAF3 controls the production of interferon and proinflammatory cytokines in different ways [Tseng PH et al 2010]. Positive or negative type of regulation is dictated by TRAF3 subcellular distribution and its mode of ubiquitination. Thus, TRIF-mediated signaling initiated on endosomes triggers TRAF3 self-ubiquitination through noncanonical (K63-linked) polyubiquitination, which is essential for activation of IRF3/7 and the interferon response. In contrast, during MyD88-dependent signaling initiated from plasma membrane TRAF3 functions as a negative regulator of inflammatory cytokines and mitogen-activated protein kinases (MAPKs), unless it undergoes degradative (K48-linked) polyubiquitination mediated by TRAF6 and a pair of the ubiquitin ligases cIAP1 and cIAP2. The degradation of TRAF3 is essential for MAPK activation via TAK1 and MEKK1 [Tseng PH et al 2010].
Mino, T, Matsuzawa, A, Karin, M, Zhang, W, Tseng, PH, Vignali, DA
Perry, A, Saha, SK, Oganesyan, G, He, JQ, Guo, B, Shahangian, A, Cheng, G, Zarnegar, B
Hsu, LC, Raz, E, Häcker, G, Karin, M, Kamps, MP, Mann, M, Kratchmarova, I, Redecke, V, Blagoev, B, Häcker, H, Wagner, H, Wang, GG
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