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https://hdl.handle.net/2440/53860
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Type: | Journal article |
Title: | AIRE'S CARD revealed, a new structure for the central tolerance provokes transcriptional plasticity |
Author: | Ferguson, B. Alexander, C. Rossi, S. Liiv, I. Rebane, A. Worth, C. Wong, J. Laan, M. Peterson, P. Jenkinson, E. Anderson, G. Scott, H. Cooke, A. Rich, T. |
Citation: | Journal of Biological Chemistry, 2008; 283(3):1723-1731 |
Publisher: | Amer Soc Biochemistry Molecular Biology Inc |
Issue Date: | 2008 |
ISSN: | 0021-9258 1083-351X |
Statement of Responsibility: | Brian J. Ferguson, Clare Alexander, Simona W. Rossi, Ingrid Liiv, Ana Rebane, Catherine L. Worth, Joyce Wong, Martti Laan, Pärt Peterson, Eric J. Jenkinson, Graham Anderson, Hamish S. Scott, Anne Cooke and Tina Rich |
Abstract: | 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. |
Keywords: | Thymus Gland Hela Cells Cell Nucleus Animals Humans Mice Transcription Factors Immune Tolerance Transcription, Genetic Amino Acid Sequence Protein Structure, Tertiary Protein Transport Mutation Models, Biological Models, Molecular Software Molecular Sequence Data Cyclic AMP Response Element-Binding Protein Receptor Activator of Nuclear Factor-kappa B Transcriptional Activation |
DOI: | 10.1074/jbc.M707211200 |
Published version: | http://dx.doi.org/10.1074/jbc.m707211200 |
Appears in Collections: | Aurora harvest 5 Medicine publications |
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