Ubiquitin in the activation and attenuation of innate antiviral immunity

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

The linear ubiquitin assembly complex (LUB AC), containing SHA NK-associated RH domain-interacting protein (SHA RPIN), heme-oxidized IRP2 ubiquitin ligase 1L (HOIL-1L), and HOIL-1-interacting protein (HOIP), was proposed to negatively regulate RLR-mediated IFN-I expression via two independent mechanisms (Inn et al., 2011a) . First, HOIL-1L competes with TRIM25 for RIG-I CARD binding, abrogating the RIG -I :MAVS interaction. Second, HOIP promotes M1-and K48-linked polyubiquitination of TRIM25 and induces its proteasomal degradation, thereby decreasing TRIM25-mediated activation of RIG-I. If LUB AC were capable of ligating K48-linked polyubiquitin chains to substrates, TRIM25 would be the first example to our knowledge.