title: SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex.
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.
authors: Department of Biophysics and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Fuminori
authors: F
authors: Tokunaga
authors: Tomoko
authors: T
authors: Nakagawa
authors: Masaki
authors: M
authors: Nakahara
authors: Yasushi
authors: Y
authors: Saeki
authors: Masami
authors: M
authors: Taniguchi
authors: Shin-ichi
authors: S
authors: Sakata
authors: Keiji
authors: K
authors: Tanaka
authors: Hiroyasu
authors: H
authors: Nakano
authors: Kazuhiro
authors: K
authors: Iwai
mesh_terms: D000818:Animals; D023201:CD40 Ligand / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000737:chemistry / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D023201:CD40 Ligand; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases; C514981:NEMO protein, mouse; C425287:sharpin; C492590:Rnf31 protein, mouse; C000607389:Rbck1 protein, mouse