AIRE Functions as an E3 Ubiquitin Ligase

Daisuke Uchida, Shigetsugu Hatakeyama, Akemi Matsushima, Hongwei Han, Satoshi Ishido, Hak Hotta, Jun Kudoh, Nobuyoshi Shimizu, Vassilis Doucas, Keiichi I. Nakayama, Noriyuki Kuroda, Mitsuru Matsumoto

Research output: Contribution to journalArticlepeer-review

123 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)167-172
Number of pages6
JournalJournal of Experimental Medicine
Issue number2
Publication statusPublished - 2004 Jan 19
Externally publishedYes


  • PHD domain
  • Self-tolerance
  • Transcriptional regulator
  • Ubiquitylation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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