Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 198K) PPT slides of all figures Supplemental Material Index Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Uchida, D. Articles by Matsumoto, M. Search for Related Content PubMed PubMed Citation Articles by Uchida, D. Articles by Matsumoto, M. Pubmed/NCBI databases Gene GEO Profiles HomoloGene OMIM UniGene Genetics Home Reference Social Bookmarking                      What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Brooks, W. S., Helton, E. S., Banerjee, S., Venable, M., Johnson, L., Schoeb, T. R., Kesterson, R. A., Crawford, D. F. (2008). G2E3 Is a Dual Function Ubiquitin Ligase Required for Early Embryonic Development. J. Biol. Chem. 283: 22304-22315 [Abstract] [Full Text]  
• Wang, Z., Zhang, L., Qiao, A., Watson, K., Zhang, J., Fan, G.-H. (2008). Activation of CXCR4 Triggers Ubiquitination and Down-regulation of Major Histocompatibility Complex Class I (MHC-I) on Epithelioid Carcinoma HeLa Cells. J. Biol. Chem. 283: 3951-3959 [Abstract] [Full Text]  
• Schaller, C. E., Wang, C. L., Beck-Engeser, G., Goss, L., Scott, H. S., Anderson, M. S., Wabl, M. (2008). Expression of Aire and the Early Wave of Apoptosis in Spermatogenesis. J. Immunol. 180: 1338-1343 [Abstract] [Full Text]  
• Oven, I., Brdickova, N., Kohoutek, J., Vaupotic, T., Narat, M., Peterlin, B. M. (2007). AIRE Recruits P-TEFb for Transcriptional Elongation of Target Genes in Medullary Thymic Epithelial Cells. Mol. Cell. Biol. 27: 8815-8823 [Abstract] [Full Text]  
• Dul, B. E., Walworth, N. C. (2007). The Plant Homeodomain Fingers of Fission Yeast Msc1 Exhibit E3 Ubiquitin Ligase Activity. J. Biol. Chem. 282: 18397-18406 [Abstract] [Full Text]  
• Ruan, Q.-G., Tung, K., Eisenman, D., Setiady, Y., Eckenrode, S., Yi, B., Purohit, S., Zheng, W.-P., Zhang, Y., Peltonen, L., She, J.-X. (2007). The Autoimmune Regulator Directly Controls the Expression of Genes Critical for Thymic Epithelial Function. J. Immunol. 178: 7173-7180 [Abstract] [Full Text]  
• Gavanescu, I., Kessler, B., Ploegh, H., Benoist, C., Mathis, D. (2007). Loss of Aire-dependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunity. Proc. Natl. Acad. Sci. USA 104: 4583-4587 [Abstract] [Full Text]  
• Kekalainen, E., Tuovinen, H., Joensuu, J., Gylling, M., Franssila, R., Pontynen, N., Talvensaari, K., Perheentupa, J., Miettinen, A., Arstila, T. P. (2007). A Defect of Regulatory T Cells in Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy. J. Immunol. 178: 1208-1215 [Abstract] [Full Text]  
• Chen, C., Seth, A. K., Aplin, A. E. (2006). Genetic and Expression Aberrations of E3 Ubiquitin Ligases in Human Breast Cancer. Mol Cancer Res 4: 695-707 [Abstract] [Full Text]  
• Ohmura-Hoshino, M., Goto, E., Matsuki, Y., Aoki, M., Mito, M., Uematsu, M., Hotta, H., Ishido, S. (2006). A Novel Family of Membrane-Bound E3 Ubiquitin Ligases. J Biochem 140: 147-154 [Abstract] [Full Text]  
• Condemine, W., Takahashi, Y., Zhu, J., Puvion-Dutilleul, F., Guegan, S., Janin, A., de The, H. (2006). Characterization of endogenous human promyelocytic leukemia isoforms.. Cancer Res. 66: 6192-6198 [Abstract] [Full Text]  
• Wohlfert, E. A., Gorelik, L., Mittler, R., Flavell, R. A., Clark, R. B. (2006). Cutting Edge: Deficiency in the E3 Ubiquitin Ligase Cbl-b Results in a Multifunctional Defect in T Cell TGF-beta Sensitivity In Vitro and In Vivo. J. Immunol. 176: 1316-1320 [Abstract] [Full Text]  
• Dooley, J., Erickson, M., Farr, A. G. (2005). An Organized Medullary Epithelial Structure in the Normal Thymus Expresses Molecules of Respiratory Epithelium and Resembles the Epithelial Thymic Rudiment of Nude Mice. J. Immunol. 175: 4331-4337 [Abstract] [Full Text]  
• Johnnidis, J. B., Venanzi, E. S., Taxman, D. J., Ting, J. P.-Y., Benoist, C. O., Mathis, D. J. (2005). Chromosomal clustering of genes controlled by the aire transcription factor. Proc. Natl. Acad. Sci. USA 102: 7233-7238 [Abstract] [Full Text]  
• Bottomley, M. J., Stier, G., Pennacchini, D., Legube, G., Simon, B., Akhtar, A., Sattler, M., Musco, G. (2005). NMR Structure of the First PHD Finger of Autoimmune Regulator Protein (AIRE1): INSIGHTS INTO AUTOIMMUNE POLYENDOCRINOPATHY-CANDIDIASIS-ECTODERMAL DYSTROPHY (APECED) DISEASE. J. Biol. Chem. 280: 11505-11512 [Abstract] [Full Text]  
• Kuroda, N., Mitani, T., Takeda, N., Ishimaru, N., Arakaki, R., Hayashi, Y., Bando, Y., Izumi, K., Takahashi, T., Nomura, T., Sakaguchi, S., Ueno, T., Takahama, Y., Uchida, D., Sun, S., Kajiura, F., Mouri, Y., Han, H., Matsushima, A., Yamada, G., Matsumoto, M. (2005). Development of Autoimmunity against Transcriptionally Unrepressed Target Antigen in the Thymus of Aire-Deficient Mice. J. Immunol. 174: 1862-1870 [Abstract] [Full Text]  
• Dodd, R. B., Allen, M. D., Brown, S. E., Sanderson, C. M., Duncan, L. M., Lehner, P. J., Bycroft, M., Read, R. J. (2004). Solution Structure of the Kaposi's Sarcoma-associated Herpesvirus K3 N-terminal Domain Reveals a Novel E2-binding C4HC3-type RING Domain. J. Biol. Chem. 279: 53840-53847 [Abstract] [Full Text]  
• Akiyoshi, H., Hatakeyama, S., Pitkanen, J., Mouri, Y., Doucas, V., Kudoh, J., Tsurugaya, K., Uchida, D., Matsushima, A., Oshikawa, K., Nakayama, K. I., Shimizu, N., Peterson, P., Matsumoto, M. (2004). Subcellular Expression of Autoimmune Regulator Is Organized in a Spatiotemporal Manner. J. Biol. Chem. 279: 33984-33991 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS