Research
SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex
| Journal | Nature 471:633-636, 2011(published Mar 31, 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 |
| Laboratory |
Cell Biology and Metabolism Group |
| 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. |
