title: AIRE's CARD revealed, a new structure for central tolerance provokes transcriptional plasticity.
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.
authors.affiliation: Department of Pathology, Divisions of Immunology and Cellular Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Ferguson
authors.affiliation: Department of Pathology, Divisions of Immunology and Cellular Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom.
authors.forename: Clare
authors.initials: C
authors.lastname: Alexander
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Simona W
authors.initials: SW
authors.lastname: Rossi
authors.affiliation: Molecular Pathology, University of Tartu, Biomedicum, 50411 Tartu, Estonia.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Liiv
authors.affiliation: Molecular Pathology, University of Tartu, Biomedicum, 50411 Tartu, Estonia.
authors.forename: Ana
authors.initials: A
authors.lastname: Rebane
authors.affiliation: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, United Kingdom.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Worth
authors.affiliation: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, United Kingdom.
authors.forename: Joyce
authors.initials: J
authors.lastname: Wong
authors.affiliation: Molecular Pathology, University of Tartu, Biomedicum, 50411 Tartu, Estonia.
authors.forename: Martti
authors.initials: M
authors.lastname: Laan
authors.affiliation: Molecular Pathology, University of Tartu, Biomedicum, 50411 Tartu, Estonia.
authors.forename: Pärt
authors.initials: P
authors.lastname: Peterson
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Jenkinson
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Anderson
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, 3050 Melbourne, Australia.
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Scott
authors.affiliation: Department of Pathology, Divisions of Immunology and Cellular Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom.
authors.forename: Anne
authors.initials: A
authors.lastname: Cooke
authors.affiliation: 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.
authors.forename: Tina
authors.initials: T
authors.lastname: Rich
mesh_terms: 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
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D053246:Receptor Activator of Nuclear Factor-kappa B; D014157:Transcription Factors; D000096927:AIRE Protein