Ubiquitin in the activation and attenuation of innate antiviral immunity

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

Viruses are obligate intracellular parasites that facilitate their own replication by manipulating the host cell environment. Thus, the ubiquitin modification system presents a key manipulation target for viruses to circumvent antiviral signaling pathways. Methods for this include substrate molecular mimicry, binding and blocking E3-substrate pairs, expressing virally encoded E3s/DUbs, and hijacking host E3s/DUbs. Additionally, a novel mechanism involving ubiquitin chain packaging into nascent virions for subsequent redeployment Viral infection activates danger signals that are transmitted via the retinoic acid-inducible gene 1-like receptor (RLR), nucleotide-binding oligomerization domain-like receptor (NLR), and Toll-like receptor (TLR) protein signaling cascades. This places host cells in an antiviral posture by up-regulating antiviral cytokines including type-I interferon (IFN-I). Ubiquitin modifications and cross-talk between proteins within these signaling cascades potentiate IFN-I expression, and inversely, a growing number of viruses are found to weaponize the ubiquitin modification system to suppress IFN-I. Here we review how host-and virus-directed ubiquitin modification of proteins in the RLR, NLR, and TLR antiviral signaling cascades modulate IFN-I expression.