AIRE functions as an E3 ubiquitin ligase.
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.
Uchida
Daisuke
D
Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
Hatakeyama
Shigetsugu
S
Matsushima
Akemi
A
Han
Hongwei
H
Ishido
Satoshi
S
Hotta
Hak
H
Kudoh
Jun
J
Shimizu
Nobuyoshi
N
Doucas
Vassilis
V
Nakayama
Keiichi I
KI
Kuroda
Noriyuki
N
Matsumoto
Mitsuru
M
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
D018076:DNA, Complementary; D011994:Recombinant Proteins; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D000096927:AIRE Protein