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).

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)