Proteomic Profiling of the TRAF3 Interactome Network Reveals a New Role for the ER-to-Golgi Transport Compartments in Innate Immunity

van Zuylen, Wendy J.; Doyon, Priscilla; Clément, Jean-François; Khan, Kashif Aziz; D'Ambrosio, Lisa M.; Dô, Florence; St-Amant-Verret, Myriam; Wissanji, Tasheen; Emery, Gregory; Gingras, Anne-Claude; Meloche, Sylvain; Servant, Marc J.

TRAF3 has originally been shown to associate with TNF receptors (e.g. BAFFR, CD40, LTbR, RANK, CD30, and Fn14), which are activators of the non-canonical NF-kB pathway [14] [15] [16] [17] . TRAF3 acts as a negative regulator in this pathway by promoting the recruitment of the TRAF2-cIAP1-cIAP2 E3 ligase complex to NF-kB-inducing kinase (NIK) in order to control its rapid turnover in resting cells [18, 19] . However, in the RLH pathway, the adaptor protein TRAF3 acts as a positive regulator. Its interaction with MAVS and TRADD is important to trigger IRF-3 phosphorylation through the adaptor molecule TANK and the IKK-related kinases TBK1 and IKKi [20, 21] . The TRADDmediated recruitment of FADD and RIP1 to MAVS also enhances the interaction between TANK and TRAF3. A model was then proposed in which TRADD simultaneously organizes FADD-and RIP1-mediated NF-kB signalling on one hand and TRAF3-and TANK-mediated IRF-3 signalling on the other [21, 22] . However, this possible mechanism of action requires further investigation to determine how TRAF3 is recruited to the mitochondrial adaptor protein MAVS upon viral infection.