Ubiquitin in the activation and attenuation of innate antiviral immunity

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

RNF135 enables RIG-I CARD activation by TRIM25 upon ubiquitinating RD residues K849 and K851. RNF135 knockdown inhibits interaction between RIG -I :TRIM25 and eliminates TBK1 recruitment (Oshiumi et al., 2009) , revealing an ordered functional interplay between ubiquitination and phosphorylation in coordinating RIG-I activation. Hepatitis C virus (HCV) NS3-4A protease exploits this concept by targeting RNF135 for proteolytic cleavage (Oshiumi et al., 2013) . Furthermore, numerous herpesviruses encode their own DUbs that inhibit IFN-I expression by stripping ubiquitin modifications from activated RIG-I (Inn et al., 2011b) . Accordingly, HCV and herpesvirus infections are treatable with IFN (Oberman and Panet, 1988; Nguyen et al., 2014) , although this can carry significant side effects. Endogenous IFN-I expression and self-regulation may be restored by defeating such mechanisms of viral antagonism.