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.

In response to pathogens, such as viruses and bacteria, infected cells defend themselves by generating a set of cytokines called type I interferon (IFN). Since Type I IFN (namely IFN alpha and beta) are potent antiviral agents, understanding the cellular mechanisms by which infected cells produce type I IFN is required to identify novel cellular targets for future antiviral therapies. Notably, a protein called Tumor Necrosis Factor receptor-associated factor-3 (TRAF3) was demonstrated to be an essential mediator of this antiviral response. However, how TRAF3 reacts in response to a viral infection is still not totally understood. We now demonstrate that, through its capacity to interact with other proteins (namely Sec16A and p115) that normally control protein secretion, TRAF3 resides close to the nucleus in uninfected cells, in a region called the ER-to-Golgi Intermediate Compartment (ERGIC). Following viral infection, the ERGIC reorganizes into small punctate structures allowing TRAF3 to associate with Mitochondrial AntiViral Signaling (MAVS), an essential adaptor of the anti-viral type I IFN response. Thus, our study reveals an unpredicted role of the protein secretion system for the proper localization of TRAF3 and the antiviral response.