USP14 deubiquitinates NLRC5

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 K63-linked polyubiquitination of NLRC5 at K1178 (Meng Q et al. 2015). The ubiquitinated NLRC5 (K63-polyUb-NLRC5) showed lower ability to interact with IKBKB/CHUK thereby resulting in a decreased inhibitory function of NLRC5. Ubiquitin-specific protease 14 (USP14) was found to remove the polyUb chains from NLRC5 and thereby enhanced the NLRC5-mediated inhibition of NF-kB signaling (Meng Q et al. 2015).

NLRC5作为NF-κB信号通路的负调节因子，通过靶向IκB激酶（IKK）复合物（Cui J 等人，2010年）发挥作用。IKK复合物由两个催化亚基IKBKA（KKα或CHUK）和IKBKB（IKKβ）组成，并与调节亚基IKBKG（NEMO）相关联。NLRC5可直接结合CHUK和IKBKB，从而抑制其磷酸化和与IKBKG的相互作用（Cui J 等人，2010年）。NLRC5与IKBKB/CHUK的相互作用动态受到NLRC5在K1178位点的TRAF2或TRAF6依赖性K63连接多泛素化调控（Meng Q 等人，2015年）。泛素化NLRC5（K63-多泛素化-NLRC5）与IKBKB/CHUK的相互作用能力降低，从而导致NLRC5抑制功能的减弱。泛素特异性蛋白酶14（USP14）被发现能够从NLRC5上移除多泛素链，从而增强NLRC5介导的NF-κB信号抑制（Meng Q 等人，2015年）。