Ubiquitin in the activation and attenuation of innate antiviral immunity

Heaton, Steven M.; Borg, Natalie A.; Dixit, Vishva M.

TRAF3 and TRAF6 are among the first molecules activated by MAVS in the RLR pathway (Fig. 2, middle) . Furthermore, there is increasing evidence of ubiquitin-mediated cross-talk between TRAFs. TRAF3 promotes IFN-I expression by activating TBK1/IRF3 (Parvatiyar et al., 2010) , whereas TRAF6 activates mitogen-activated protein kinase kinase kinase 1 (MEKK1) to activate NF-κB, which also enhances IFN-I expression (Yoshida et al., 2008) . Simultaneously, TRAF3 suppresses NF-κB by inhibiting IKK activation upon binding TRAF2 (Zarnegar et al., 2008) , likely as a mecha-nism to skew innate immune effector molecule expression as required. Inversely, the E3 cIAP2, after itself being ubiquitinated by TRAF6, promotes TRAF3 degradation by ligating K48-linked polyubiquitin chains to TRAF3 at residues K107 and K156, thereby restoring NF-κB activation (Tseng et al., 2010) . However, as well as degrading TRAF3, cIAP1/2 can also activate TRAF3 by catalyzing its K63-linked polyubiquitination ( Fig. 3 ; Mao et al., 2010) . This suggests that the context-dependent ubiquitination state of cIAP1/2 determines its effect on TRAF3. The E3 RNF166 was recently reported to ubiquitinate and activate both TRAF3 and TRAF6 . Finally, the RIG-I-activating E3 TRIM25 was reported to enhance MDA5-mediated NF-κB activation at the level of TRAF6 , although mechanistic details remain unclear.