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J. Biol. Chem., Vol. 279, Issue 32, 33984-33991, August 6, 2004

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Subcellular Expression of Autoimmune Regulator Is Organized in a Spatiotemporal Manner^*

Hiroko Akiyoshi, Shigetsugu Hatakeyama¶, Jukka Pitkänen||, Yasuhiro Mouri, Vassilis Doucas**, Jun Kudoh, Kyoko Tsurugaya, Daisuke Uchida, Akemi Matsushima, Kiyotaka Oshikawa¶, Keiichi I. Nakayama¶, Nobuyoshi Shimizu, Pärt Peterson||, and Mitsuru Matsumoto¶¶

From the Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima 770-8503, the ^¶Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, CREST, Japan Science and Technology Corp., Saitama 332-0012, Japan, ^||Institute of Medical Technology, University of Tampere and Tampere University Hospital, 33101 Tampere, Finland, the ^**Département Biologie des Genomes, Institut Jacques Monod, 75251 Paris Cedex 05, France, and the Department of Molecular Biology, Keio University School of Medicine, Tokyo 160-8582, Japan

Autoimmune regulator (AIRE) is responsible for the development of organ-specific autoimmune disease in a monogenic fashion. Rare and low levels of tissue expression together with the lack of AIRE-expressing cell lines have hampered a detailed analysis of the molecular dynamics of AIRE. Here we have established cell lines stably transfected with AIRE and studied the regulatory mechanisms for its subcellular expression. We found that nuclear body (NB) formation by AIRE was dependent on the cell cycle. Biochemical fractionation revealed that a significant proportion of AIRE is associated with the nuclear matrix, which directs the functional domains of chromatin to provide sites for gene regulation. Upon proteasome inhibition, AIRE NBs were increased with concomitant reduced expression in the cytoplasm, suggesting that subcellular targeting of AIRE is regulated by a ubiquitin-proteasome pathway. We also found that AIRE NBs compete for cAMP-response element-binding protein-binding protein/p300, a common coactivator of transcription, with the promyelocytic leukemia gene product. These results suggest that the transcriptional regulating activities of AIRE within a cell are controlled and organized in a spatiotemporal manner.

Received for publication, January 21, 2004 , and in revised form, April 29, 2004.

^* This work was supported in part by Special Coordination Funds of the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government (MEXT) (to M. M.), a Grant-in-Aid for Scientific Research from the MEXT (to S. H. and M. M.), the Tampere University Hospital Medical Research Fund, the Emil Aaltonen Foundation, the Finnish Medical Foundation, the Pirkanmaa Regional Fund of the Finnish Cultural Foundation (to J. P.), the Tampere University Hospital Medical Research Fund, the Finnish Academy, the Sigrid Juselius Foundation (to P. P.), Grant-in-Aid for Scientific Research (A) and Fund for "Research for the Future" Program from the Japan Society for the Promotion of Science and MEXT (to N. S.), and the CNRS (to V. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Figs. 1-3 and Movies 1 and 2.

Both authors contributed equally to this work.

Present address: Molecular Pathology, University of Tartu, Tartu 50414, Estonia.

^¶¶ To whom correspondence and reprint requests should be addressed: Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan. Tel.: 81-88-633-7432; Fax: 81-88-633-7434; E-mail: mitsuru{at}ier.tokushima-u.ac.jp.

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