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
© 2023 Reactome
