Ubiquitin in the activation and attenuation of innate antiviral immunity

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

NLRC5 was initially described to enhance IFN-γ and IFN-α expression and inhibit NF-κB and IFN-β, in the latter case through sequestering the activated effector domains of RIG-I and MDA5 (Cui et al., 2010; Kuenzel et al., 2010) . NLRC5 has also been shown to bind and inhibit TBK1mediated IFN-β induction in HEK-293T cells, although NLRC5 −/− mice show relatively normal cytokine responses upon exposure to RLR-, TLR-, and NLR-activating stimuli (Kumar et al., 2011) . Still other findings indicate that the RIG -I :NLRC5 interaction also positively regulates IFN-β expression, and this interaction is targeted by the IAV-NS1 protein (Fig. 2, right; Neerincx et al., 2010; Ranjan et al., 2015) . These disparate conclusions may reflect cell-specific differences given that NLRC5 is predominantly expressed in hematopoietic cells or differences between mouse and human signaling pathways, suggesting that the NLRC5 regulatory framework is complex. Adding to this, ubiquitination plays an uncharacterized role in regulating NLRC5 upon LPS stimulation and may be induced by NLRC5 overexpression (Cui et al., 2010; Kuenzel et al., 2010) . Given the diversity of interactions that NLRC5 takes part in, it is likely that further PTMs will be shown to regulate NLRC5 during viral infection.