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J. Biol. Chem., Vol. 283, Issue 3, 1723-1731, January 18, 2008

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AIRE's CARD Revealed, a New Structure for Central Tolerance Provokes Transcriptional Plasticity^*

Brian J. Ferguson¹, Clare Alexander¹, Simona W. Rossi², Ingrid Liiv^¶3, Ana Rebane^¶3, Catherine L. Worth^||4, Joyce Wong^||4, Martti Laan^¶3, Pärt Peterson^¶3, Eric J. Jenkinson², Graham Anderson², Hamish S. Scott^**5, Anne Cooke, and Tina Rich⁶

From the Department of Pathology, Divisions of Immunology and Cellular Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom, Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom, ^¶Molecular Pathology, University of Tartu, Biomedicum, 50411 Tartu, Estonia, the ^||Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, United Kingdom, and ^**Walter and Eliza Hall Institute of Medical Research, 3050 Melbourne, Australia

Developing T cells encounter peripheral self-antigens in the thymus in order to delete autoreactive clones. It is now known that the autoimmune regulator protein (AIRE), which is expressed in thymic medullary epithelial cells, plays a key role in regulating the thymic transcription of these peripheral tissue-specific antigens. Mutations in the AIRE gene are associated with a severe multiorgan autoimmune syndrome (APECED), and autoimmune reactivities are manifest in AIRE-deficient mice. Functional AIRE protein is expressed as distinct nuclear puncta, although no structural basis existed to explain their relevance to disease. In addressing the cell biologic basis for APECED, we made the unexpected discovery that an AIRE mutation hot spot lies in a caspase recruitment domain. Combined homology modeling and in vitro data now show how APECED mutations influence the activity of this transcriptional regulator. We also provide novel in vivo evidence for AIRE's association with a global transcription cofactor, which may underlie AIRE's focal, genome-wide, alteration of the transcriptome.

Received for publication, August 28, 2007 , and in revised form, October 22, 2007.

^* This work was supported by Biotechnology and Biological Sciences Research Council Grants BBC5098231 (to T. R. and B. J. F.) and BBSB0370X (to T. R., A. C., and C. E. A.). 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 supplemental Figs. S1-S4.

¹ Both authors contributed equally to this work and should be considered joint first authors.

² Supported by a Medical Research Council Programme Grant and the European Union Thymaide Project.

³ Supported by the grants from Wellcome Trust and European Union Framework Program 6 (Thymaide and Euraps) and by Estonian Science Foundation Grants 6663 and 6490.

⁴ Supported by Biotechnology and Biological Sciences Research Council studentships.

⁵ Supported by National Health and Medical Research Council Fellowships 171601 and 461204, National Health and Medical Research Council Program Grants 257501 and 264573, Eurothymaide, 6th Framework Program of the European Union, and the Nossal Leadership Award from the Walter and Eliza Hall Institute of Medical Research.

⁶ To whom correspondence should be addressed: Institute of Comparative Medicine, University of Glasgow, G61 1QH, UK, Scotland, UK. Tel.: 44-141-3308213; Fax: 44-141-3305602; E-mail: T.Rich{at}vet.gla.ac.uk.

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