SHARPIN is a component of the NF-kB-activating linear ubiquitin chain assembly complex

摘要

Cpdm (chronic proliferative dermatitis) mice develop chronic dermatitis and an immunodeficiency with increased serum IgM~(1-3), symptoms that resemble those of patients with X-linked hyper-IgM syndrome and hypohydrotic ectodermal dysplasia (XHM-ED), which is caused by mutations in NEMO (NF-kB essential modulator; also known as IKBKG)~4-6. Spontaneous null mutations in the Sharpin (SHANK-associated RH domain interacting protein in postsynaptic density)~7 gene are responsible for the cpdm phenotype in mice~8. SHARPIN shows significant similarity to HOIL-1L (also known as RBCK1)~(8,9), acomponent of linear ubiquitin chain assembly complex (LUBAC), which induces NF-kB activation through conjugation of linear polyubiquitin chains to NEMO~(10-13). Here, we identify SHARPIN as an additional component of LUBAC. SHARPIN-containing complexes can linearly ubiquitinate NEMO and activated NF-kB. Thus, we re-define LUBAC as a complex containing SHARPIN, HOIL-1L, and HOIP (also known as RNF31). Deletion of SHARPIN drastically reduced the amount of LUBAC, which resulted in attenuated TNF-α-and CD40-mediated activation of NF-kB in mouse embryonic fibroblasts (MEFs) or B cells from cpdm mice. Considering the pleomorphic phenotype of cpdm mice, these results confirm the predicted role of LUBAC-mediated linear polyubiquitination in NF-kB activation induced by various stimuli, and strongly suggest the involvement of LUBAC-induced NF-kB activation in various disorders.