Ubiquitin in the activation and attenuation of innate antiviral immunity

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

cIAP2 is an E3 that, after itself being ubiquitinated by TRAF6, targets TRAF3 for degradation (Tseng et al., 2010) . This is important in promoting TLR4-mediated signaling and cytokine production at the expense of type I IFN production . Furthermore, TRAF6 itself promotes proinflammatory cytokine production at the expense of IFN-I. TRAF6 is activated by trans-autoubiquitination at K124, abolition of which eliminates NEMO ubiquitination and TAK1 activation (Lamothe et al., 2007) . This mechanism is exploited by HSV, which uses the virally encoded E3 infected cell polypeptide 0 (ICP0) to recruit USP7 to deubiquitinate NEMO and TRAF6 (Daubeuf et al., 2009 ). In addition, ICP0 directly catalyzes ubiquitination and degradation of MyD88 and TIR AP (Toll/interleukin-1 receptor domain-containing adaptor protein; van Lint et al., 2010) . Kaposi's sarcoma-associated herpesvirus (KSHV) encodes replication and transcription factor (RTA), an E3 that activates latent virus. This activation process involves suppression of antiviral cytokines, partly involving RTA-catalyzed ubiquitination and degradation of MyD88 and TRIF (Ahmad et al., 2011; Zhao et al., 2015) , thereby impairing all TLR-mediated immune signaling pathways.