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Originally published In Press as doi:10.1074/jbc.M908944199 on March 9, 2000

J. Biol. Chem., Vol. 275, Issue 22, 16802-16809, June 2, 2000
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The Autoimmune Regulator Protein Has Transcriptional Transactivating Properties and Interacts with the Common Coactivator CREB-binding Protein*

Jukka Pitkänenab, Vassilis Doucasc, Thomas Sternsdorfd, Toshihiro Nakajimae, Satoko Aratanif, Kirsten Jensend, Hans Willd, Perttu Vähämurtoa, Juha Ollilag, Mauno Vihinena, Hamish S. Scotth, Stylianos E. Antonarakishi, Jun Kudohjk, Nobuyoshi Shimizujk, Kai Krohna, and Pärt Petersona

From the a Institute of Medical Technology, University of Tampere and Tampere University Hospital, 33101 Tampere, Finland, the c Department of Genetics and Microbiology, University of Geneva Medical School, Geneva 1211, Switzerland, d Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg, Hamburg 20251, Germany, e Institute of Applied Biochemistry and TARA Center, University of Tsukuba, Ibaraki 305-8572 and PRESTO, Japan Science and Technology Corporation, Institute of Medical Science, St. Marianna University of Medicine, Kawasaki 276-8512, f Institute of Applied Biochemistry and TARA Center, University of Tsukuba, Ibaraki 305-8572, Japan, g Division of Biochemistry, Department of Biosciences, University of Helsinki, Helsinki 00014, Finland, h Division of Medical Genetics, University of Geneva Medical School and Division of Medical Genetics, University Hospital, Geneva 1211, Switzerland, and j Department of Molecular Biology, Keio University School of Medicine, Tokyo 160-8582, Japan

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy, caused by mutations in the autoimmune regulator (AIRE) gene, is an autosomal recessive autoimmune disease characterized by the breakdown of tolerance to organ-specific antigens. The 545 amino acid protein encoded by AIRE contains several structural motifs suggestive of a transcriptional regulator and bears similarity to cellular proteins involved in transcriptional control. We show here that AIRE fused to a heterologous DNA binding domain activates transcription from a reporter promoter, and the activation seen requires the full-length protein or more than one activation domain. At the structural level AIRE forms homodimers through the NH2-terminal domain, and molecular modeling for this domain suggests a four-helix bundle structure. In agreement, we show that the common transcriptional coactivator CREB-binding protein (CBP) interacts with AIRE in vitro and in yeast nuclei through the CH1 and CH3 conserved domains. We suggest that the transcriptional transactivation properties of AIRE together with its interaction with CBP might be important in its function as disease-causing mutations almost totally abolish the activation effect.

* This work was supported in part by the Tampere University Hospital Medical Research Fund Grants 99080, 99186, and 98191; the Novo Nordisc Foundation; the Finnish Academy Grants 45247 and 46066; the University of Geneva Grant ME5061 (to V. D.); the Japanese Ministry of Education, Science, Culture, and Sports; the Japanese Ministry of Health and Welfare; the Kanae Medical Foundation; the Uehara Memorial Foundation; the Naito Memorial Foundation; the Yamanouchi Memorial Foundation; Santen Pharmaceutical Co. Ltd.; and Kaken Pharmaceutical Co. Ltd. (to T. N. and S. A.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

b To whom correspondence should be addressed: Institute of Medical Technology, University of Tampere. Lenkkeilijänkatu 6, Fin-33101 Tampere, Finland. Tel.: +358-3-2158032; Fax: +358-3-2157332; E-mail: jp58218@uta.fi.

i Supported by Swiss FNRS 31-40500.94, Swiss FNRS 31-57149.99, and European Union/Swiss OFES 98-3039.

k Supported by Grants-in-aid for Scientific Research on Priority Areas and Scientific Research (A) from the Ministry of Education, Science, Sports and Culture of Japan and Fund for "Research for the Future" Program from the Japan Society for the Promotion of Science.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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