Ubiquitin in the activation and attenuation of innate antiviral immunity

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

MAVS aggregation is a key feature of RLR cascade activation, but how these aggregates are resolved during deactivation is only beginning to be clarified. In addition to ubiquitinating RIG-I and enhancing its association with MAVS, TRIM25 ubiquitinates MAVS at Lys7 and Lys10 and induces its partial proteolysis (Castanier et al., 2012) . This was proposed as a means of discharging the activated RLR signalosome from the mitochondrial recruitment platform and would begin to address how IRF3 and other RLR signalosome components traffic correctly after activation. More recently, Lys7 and Lys500 were shown to be polyubiquitinated by membrane-associated RING finger protein 5 (MAR CH5), a mitochondrial membrane-bound E3 that effectively dissolves MAVS aggregates by specifically targeting them for degradation. MAR CH5 is an important regulator of mitochondrial fission and fusion whose expression is up-regulated during infection (Yoo et al., 2015) . These mechanisms of MAVS aggregate resolution may be nonredundant, with the TRIM25 mechanism occurring throughout the immune response and the MAR CH5 mechanism amplifying gradually in an IFN-I negative feedback loop.