TNF:TNFR1:TRADD:TRAF2:K63polyUb-RIPK1:BIRC2,3:LUBAC recruits IKKA:IKBKB:IKBKG

K63-polyubiquitinated RIPK1 binds to IKBKG (NEMO), resulting in the recruitment of the IKK complex to the TNF-alpha receptor 1 (TNFR1) signaling complex (Ea CK et al. 2006).<p>In addition, the linear polyubiquitination has been implicated in the NF-kappa-B activation. The linear ubiquitin chain assembly complex (LUBAC) ligase consisting of HOIL-1L, HOIP, and SHARPIN, specifically generates linear polyubiquitin chains (Kirisako T et al. 2006; Walczak H et al. 2012). IKBKG (NEMO), a regulatory component of the IκB kinase (IKK) complex, is a substrate of LUBAC. LUBAC-mediated IKBKG ubiquitination enhances IKBKG interaction with the TNFR1 complex and stabilizes this protein complex to promote activation of NF-kappa-B (Haas TL et al. 2009).<p>Structural analysis revealed that NPL4 zinc finger 1 (NZF1) of HOIP can simultaneously bind both leucine zipper domains of NEMO (IKBKG) and ubiquitin and that both interactions are involved in the TNF alpha-mediated NF-kappa-B activation (Fujita H et al. 2014). In addition, NEMO (IKBKG) ubiquitination required RING-between-RING (RBR) domain of HOIL-1L (Smit JJ et al. 2013)

K63型多泛素化的RIPK1与IKBKG（NEMO）结合，导致IKK复合物被募集至TNF-α受体1（TNFR1）信号复合物中（Ea CK 等人，2006年）。此外，线性多泛素化在NF-κB激活中扮演了关键角色。由HOIL-1L、HOIP和SHARPIN组成的线性泛素链组装复合物（LUBAC）连接酶，特异性地生成线性泛素链（Kirisako T 等人，2006年；Walczak H 等人，2012年）。IKBKG（NEMO），作为IKK复合物的调控组分，是LUBAC的底物。LUBAC介导的IKBKG泛素化增强了IKBKG与TNFR1复合物的相互作用，并稳定该蛋白复合物以促进NF-κB的激活（Haas TL 等人，2009年）。结构分析揭示了HOIP的NPL4锌指1（NZF1）可以同时结合NEMO（IKBKG）的两个亮氨酸拉链结构域以及泛素，且这两种相互作用均参与了TNF-α介导的NF-κB激活（Fujita H 等人，2014年）。此外，NEMO（IKBKG）的泛素化需要HOIL-1L的RING-between-RING（RBR）结构域（Smit JJ 等人，2013年）。