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AIRE's CARD revealed, a new structure for central tolerance provokes transcriptional plasticity

Item Type:Article
Title:AIRE's CARD revealed, a new structure for central tolerance provokes transcriptional plasticity
Creators Name:Ferguson, B.J. and Alexander, C. and Rossi, S.W. and Liiv, I. and Rebane, A. and Worth, C.L. and Wong, J. and Laan, M. and Peterson, P. and Jenkinson, E.J. and Anderson, G. and Scott, H.S. and Cooke, A. and Rich, T.
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:Amino Acid Sequence, Biological Models, Cell Nucleus, Cyclic AMP Response Element-Binding Protein, Genetic Transcription, HeLa Cells, Immune Tolerance, Molecular Models, Molecular Sequence Data, Mutation, Protein Transport, Receptor Activator of Nuclear Factor-kappa B, Software, Tertiary Protein Structure, Thymus Gland, Transcription Factors, Transcriptional Activation, Animals, Mice
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:283
Number:3
Page Range:1723-1731
Date:18 January 2008
Official Publication:https://doi.org/10.1074/jbc.M707211200
PubMed:View item in PubMed

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