Graduate School of Frontier Biosciences, Osaka University

Japanese

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

Journal Nature 471, 633-636 (2011)
Authors Tokunaga, F. (1), Nakagawa T. (1), Nakahara, M. (1), Saeki, Y. (2), Taniguchi, M. (1), Sataka, S.-I. (1), Tanaka, K. (3), Nakano, H. (3), and Iwai, K. (1, 4)
  1. Department of Biophysics and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
  2. Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan
  3. Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
  4. Cell Biology and Metabolism Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan

Title SHARPIN is a component of the NF-κB activating linear ubiquitin chain assembly complex
PubMed 21455180
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). Spontaneous null mutations in the Sharpin gene are responsible for the cpdm phenotype in mice. SHARPIN shows significant similarity to HOIL-1L, 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. 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 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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