Ubiquitin in the activation and attenuation of innate antiviral immunity

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

The first virus-triggered RIG-I ubiquitination site described, K172, depends on the E3 activity of tripartite motif protein 25 (TRIM25; Gack et al., 2007) . Plausibly as a means of restricting escape mutant selection, this activation mechanism now appears to have evolved with partial redundancy using alternate E3s. TRIM4 was recently described to modify this same site in addition to two other CARD residues: K154 and K164 (Yan et al., 2014) . Furthermore, these same three residues are reportedly ubiquitinated by really interesting new gene (RING) finger protein-135 (RNF135; also termed Riplet/REUL; Gao et al., 2009) , although this is controversial ( Fig. 3 ; Oshiumi et al., 2010) . Underscoring the importance of these modifications, ubiquitin-specific protease 3 (USP3) and ubiquitin C-terminal hydrolase are DUbs that inhibit IFN-I production by removing such chains from RIG-I (Friedman et al., 2008; Cui et al., 2014) .