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

F Tokunaga, T Nakagawa, M Nakahara, Y Saeki… - Nature, 2011 - nature.com
F Tokunaga, T Nakagawa, M Nakahara, Y Saeki, M Taniguchi, S Sakata, K Tanaka
Nature, 2011nature.com
Cpdm (chronic proliferative dermatitis) mice develop chronic dermatitis and an
immunodeficiency with increased serum IgM,,, 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-κB essential modulator; also known as IKBKG),,.
Spontaneous null mutations in the Sharpin (SHANK-associated RH domain interacting
protein in postsynaptic density) gene are responsible for the cpdm phenotype in mice …
Abstract
Cpdm (chronic proliferative dermatitis) mice develop chronic dermatitis and an immunodeficiency with increased serum IgM,,, 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-κB essential modulator; also known as IKBKG),,. Spontaneous null mutations in the Sharpin (SHANK-associated RH domain interacting protein in postsynaptic density) gene are responsible for the cpdm phenotype in mice. SHARPIN shows significant similarity to HOIL-1L (also known as RBCK1),, a component of linear ubiquitin chain assembly complex (LUBAC), which induces NF-κB activation through conjugation of linear polyubiquitin chains to NEMO,,,. Here, we identify SHARPIN as an additional component of LUBAC. SHARPIN-containing complexes can linearly ubiquitinate NEMO and activated NF-κB. 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-κB 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-κB activation induced by various stimuli, and strongly suggest the involvement of LUBAC-induced NF-κB activation in various disorders.
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