Ubiquitin in the activation and attenuation of innate antiviral immunity

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

NOD2 features regularly in the immune signaling landscape, yet mechanisms of NOD2 regulation and cross-talk are only beginning to be revealed. Upon activation by MDP, NOD2 is ubiquitinated by TRIM27, leading to NOD2 degradation and NF-κB inhibition (Zurek et al., 2012) . NOD2 signaling is further suppressed by AIP4, which ubiquitinates Lys209 of receptor-interacting serine/threonine protein kinase 2 (RIPK2), the immediate downstream interacting partner of NOD2 (Fig. 2, right; Tao et al., 2009) . Conversely, NOD2-driven NF-κB activation is enhanced by LUB AC, a negative regulator of RLR signaling, as well as X-linked IAP (XIAP), which respectively ligate M1-and K63-linked polyubiquitin chains to NOD2 and RIPK2 (Damgaard et al., 2012) . These activating ubiquitin chains may be antagonized by the ubiquitin-editing enzyme A20 , which also disrupts ubiquitin-mediated TBK1 activation in the RLR signaling cascade as well as ubiquitin-mediated TRAF6 activation in the TLR cascade Parvatiyar et al., 2010) .