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¹ Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima 770-8503, Japan
² Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
³ CREST, Japan Science and Technology Corporation, Saitama 332-0012, Japan
⁴ Division of Microbiology, Department of Genome Sciences, Kobe University Graduate School of Medicine, Hyogo 650-0017, Japan
⁵ Department of Molecular Biology, Keio University School of Medicine, Tokyo 160-8582, Japan
⁶ Département Biologie des Genomes, Institut Jacques Monod, 75251 Paris, France

Address correspondence to Mitsuru Matsumoto, Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan. Phone: 81-88-633-7432; Fax: 81-88-633-7434; email: mitsuru{at}ier.tokushima-u.ac.jp

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.

Key Words: APECED • self-tolerance • transcriptional regulator • ubiquitylation • PHD domain

The online version of this article contains supplemental material.

Abbreviations used in this paper: AIRE, autoimmune regulator; APECED, autoimmune-polyendocrinopathy-candidiasis ectodermal dystrophy; GST, glutathione S-transferase; mTEC, medullary thymic epithelial cell; PHD, plant homeodomain; PRR, proline-rich region; Ub, ubiquitin.

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