Ubiquitin in the activation and attenuation of innate antiviral immunity

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

IRF3 degradation is undesirable at early stages of the innate immune response and is limited in several ways. The IRF3-Pin1 interaction is inhibited by the HECT (homologous to the E6-AP C terminus) domain and RCC1-like domain-containing protein 5 (HERC5), which ligates another ubiquitin-like protein, ISG15, onto IRF3 at Lys193, Lys360, and Lys366, thereby sustaining IRF3 activation (Shi et al., 2010) . TRIM21 is a ubiquitin E3 described to both inhibit the IRF3-Pin1 interaction and target IRF3 for proteasomal degradation (Higgs et al., 2008; Yang et al., 2009) . TRIM21 reportedly also targets IRF7 for degradation upon TLR7 or TLR9 activation (Higgs et al., 2010) , although the TRIM21-dependent IRF3/IFR7 ubiquitin acceptor sites remain undefined (Fig. 3) .