Ubiquitin in the activation and attenuation of innate antiviral immunity

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

Complete MAVS degradation is independently promoted by the E3s RNF5, RNF125, atrophin-1-interacting protein 4 (AIP4; also termed ITCH), SMAD ubiquitination regulatory factor 1 (Smurf1), and Smurf2 (Fig. 3) . RNF5 polyubiquitinates MAVS at Lys362 and Lys461, whereas the adjacent residues Lys371 and Lys420 are polyubiquitinated by AIP4 upon recruitment by poly(rC)-binding protein 1 (PCBP1) or PCBP2 (You et al., 2009; Zhong et al., 2010; Zhou et al., 2012) . AIP4 additionally inhibits IFN-I as well as NF-κB activation by ubiquitinating the inhibitor of apoptosis protein 1 (cIAP1), targeting it for lysosomal degradation (Tigno-Aranjuez et al., 2013) . cIAP1 is an E3 that activates TRAF3/6 during viral infection (Mao et al., 2010) , revealing that AIP4 broadly and multiply inhibits NLR-, RLR-, and TLR-mediated immune signaling. The acceptor site or sites for RNF125-induced MAVS ubiquitination are unknown; however, given that RNF125 also ubiquitinates the activated CARDs of RIG-I and MDA5 (Arimoto et al., 2007) , the MAVS CARD appears a likely candidate. NEDD4 family-interacting protein 1 (Ndfip1) binds MAVS and recruits Smurf1 and possibly Smurf2, facilitating ubiquitination of unknown sites within MAVS (Wang et al., 2012c; Pan et al., 2014) . Moreover, numerous TRAFs, including TRAF3 and TRAF6, interact with MAVS, and Smurf1 also targets these for degradation (Li et al., 2010a) . Finally, Lys500 was reported as a single site of IFN-I-activating polyubiquitination by an unknown E3, inhibiting NF-κB activation by sequestering IKKε (Paz et al., 2009 ).