Ubiquitin in the activation and attenuation of innate antiviral immunity

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

Reminiscent of IRF7, IRF3 residues Lys70 and Lys87 accept both polyubiquitin chains and SUMO, and competition between these modifications can determine the fate of IFN-I signal transduction. At steady state, the SUMO-conjugating enzyme ubiquitin carrier protein 9 (Ubc9) protects IRF3 from ubiquitin-mediated degradation by occupying these sites with SUMO. Alternatively, the deSUMOylating enzyme sentrin-specific protease 2 (SENP2) removes SUMO from IRF3, enabling its K48-linked polyubiquitination (Ran et al., 2011) . Subsequent work identified TRIM26 as an E3 that conjugates K48-linked polyubiquitin chains to these same sites ( Fig. 3 ; Wang et al., 2015) , triggering degradation of the active, nuclear-localized form of IRF3. Furthermore, activated IRF3 undergoes phosphorylation at Ser339. This promotes interaction with peptidyl-prolyl cis/ trans isomerase NIMA-interacting 1 (Pin1), a nuclear-localized protein that promotes IRF3 degradation (Saitoh et al., 2006) . The E3 recruited by Pin1 for this purpose is unknown; however, TRIM26 is also localized to the nucleus and seems a strong candidate.