Ubiquitin in the activation and attenuation of innate antiviral immunity

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

In contrast to the three RLR receptors, the 22 NLRs have diverse expression patterns and largely under-characterized functions. The NLRs are well recognized for their roles in regulating NF-κB activation and antibacterial immunity; however, at least five members have emerging roles in antiviral immune signaling: NOD1, NOD2, NLRC5 (NLR family CARD domain-containing protein 5), NLRP4 (NAC HT, LRR, and PYD domain-containing protein 4), and NLRX1 (NLR family member X1; Fig. 2, right) . Although NLRs recruit E3s and modulate the ubiquitination of other proteins, including several in the RLR cascade, the role of PTMs in NLR regulation remains under-defined. NLR regulation and innate immune signaling cross-talk. The PRRs NOD1 and NOD2 are the best characterized NLRs. NOD1 is expressed ubiquitously, whereas NOD2 is expressed mainly in cells of myeloid and lymphoid origin and is up-regulated during bacterial and viral infection. The classic NOD2-activating ligand is bacterial muramyl dipeptide (MDP), which promotes NF-κB activation. However, NOD2 also promotes IFN-I expression during infection by numerous RNA viruses, in part through recognizing single-stranded RNA (ssRNA) and interacting with MAVS. NOD2 may also promote IFN-I expression during infection by particular DNA viruses by an undefined mechanism (Sabbah et al., 2009; Kapoor et al., 2014) . Accordingly, NOD2 dysfunction leads to inefficient innate and adaptive immune responses to viral infection (Lupfer et al., 2014) .