NOD-like receptor C5 (NLRC5) functions as negative regulator of the NF-kappa B signaling pathway by targeting the I-kappa-B-kinase (IKK) complex (Cui J et al. 2010). The IKK complex consists of two catalytic subunits, IKBKA (KKα or CHUK) and IKBKB (IKKβ), associated with a regulatory subunit IKBKG (NEMO). NLRC5 directly binds to CHUK and IKBKB inhibiting their phosphorylation and interaction with IKBKG (Cui J et al. 2010). The dynamics of NLRC5 interaction with IKBKB/CHUK is regulated by TRAF2 or TRAF6-dependent ubiquitination of NLRC5 (Meng Q et al. 2015). Active TRAF2/6 catalyzed K63-linked polyubiquitination of NLRC5 at K1178 in human and mouse cells in response to LPS stimulation. The ubiquitinated NLRC5 (K63-polyUb-NLRC5) blocked NLRC5 interaction with IKBKB/CHUK thereby resulting in a decreased inhibitory function of NLRC5. The TRAF2/TRAF6-mediated ubiquitination of NLRC5 was reversely regulated by USP14 (Meng Q et al. 2015).