title: AIRE functions as an E3 ubiquitin ligase.
abstract: Autoimmune regulator (AIRE) gene mutation is responsible for the development of autoimmune-polyendocrinopathy-candidiasis ectodermal dystrophy, an organ-specific autoimmune disease with monogenic autosomal recessive inheritance. AIRE is predominantly expressed in medullary epithelial cells of the thymus and is considered to play important roles in the establishment of self-tolerance. AIRE contains two plant homeodomain (PHD) domains, and the novel role of PHD as an E3 ubiquitin (Ub) ligase has just emerged. Here we show that the first PHD (PHD1) of AIRE mediates E3 ligase activity. The significance of this finding was underscored by the fact that disease-causing missense mutations in the PHD1 (C311Y and P326Q) abolished its E3 ligase activity. These results add a novel enzymatic function for AIRE and suggest an indispensable role of the Ub proteasome pathway in the establishment of self-tolerance, in which AIRE is involved.
authors.affiliation: Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Uchida
authors.forename: Shigetsugu
authors.initials: S
authors.lastname: Hatakeyama
authors.forename: Akemi
authors.initials: A
authors.lastname: Matsushima
authors.forename: Hongwei
authors.initials: H
authors.lastname: Han
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishido
authors.forename: Hak
authors.initials: H
authors.lastname: Hotta
authors.forename: Jun
authors.initials: J
authors.lastname: Kudoh
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Shimizu
authors.forename: Vassilis
authors.initials: V
authors.lastname: Doucas
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kuroda
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D016884:Polyendocrinopathies, Autoimmune / Q000201:enzymology / Q000235:genetics; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017634:Self Tolerance; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000096927:AIRE Protein
chemical_list: D018076:DNA, Complementary; D011994:Recombinant Proteins; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D000096927:AIRE Protein