TY - JOUR
T1 - AIRE's CARD Revealed, a New Structure for Central Tolerance Provokes Transcriptional Plasticity
AU - Ferguson, BJ
AU - Alexander, C
AU - Rossi, Simona
AU - Liiv, I
AU - Rebane, A
AU - Worth, CL
AU - Wong, J
AU - Laan, M
AU - Peterson, P
AU - Jenkinson, Eric
AU - Anderson, Graham
AU - Scott, HS
AU - Cooke, A
AU - Rich, T
PY - 2007/11/16
Y1 - 2007/11/16
N2 - 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.
AB - 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.
U2 - 10.1074/jbc.M707211200
DO - 10.1074/jbc.M707211200
M3 - Article
C2 - 17974569
SN - 1083-351X
VL - 283
SP - 1723
EP - 1731
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 3
ER -