AIRE's CARD revealed, a new structure for central tolerance provokes transcriptional plasticity.
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.
Ferguson
Brian J
BJ
Department of Pathology, Divisions of Immunology and Cellular Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom.
Alexander
Clare
C
Department of Pathology, Divisions of Immunology and Cellular Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom.
Rossi
Simona W
SW
Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.
Liiv
Ingrid
I
Molecular Pathology, University of Tartu, Biomedicum, 50411 Tartu, Estonia.
Rebane
Ana
A
Molecular Pathology, University of Tartu, Biomedicum, 50411 Tartu, Estonia.
Worth
Catherine L
CL
Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, United Kingdom.
Wong
Joyce
J
Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, United Kingdom.
Laan
Martti
M
Molecular Pathology, University of Tartu, Biomedicum, 50411 Tartu, Estonia.
Peterson
Pärt
P
Molecular Pathology, University of Tartu, Biomedicum, 50411 Tartu, Estonia.
Jenkinson
Eric J
EJ
Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.
Anderson
Graham
G
Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.
Scott
Hamish S
HS
Walter and Eliza Hall Institute of Medical Research, 3050 Melbourne, Australia.
Cooke
Anne
A
Department of Pathology, Divisions of Immunology and Cellular Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom.
Rich
Tina
T
Department of Pathology, Divisions of Immunology and Cellular Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom. Electronic address: T.Rich@vet.gla.ac.uk.
D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000276:immunology; D012984:Software; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D000096927:AIRE Protein
D017362:Cyclic AMP Response Element-Binding Protein; D053246:Receptor Activator of Nuclear Factor-kappa B; D014157:Transcription Factors; D000096927:AIRE Protein