ID:AIRE_HUMAN DESCRIPTION: RecName: Full=Autoimmune regulator; AltName: Full=Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy protein; Short=APECED protein; FUNCTION: Transcriptional regulator that binds to DNA as a dimer or as a tetramer, but not as a monomer. Binds to G-doublets in an A/T-rich environment; the preferred motif is a tandem repeat of 5'-. ATTGGTTA-3' combined with a 5'-TTATTA-3' box. Binds to nucleosomes (By similarity). Binds to chromatin and interacts selectively with histone H3 that is not methylated at 'Lys-4', not phosphorylated at 'Thr-3' and not methylated at 'Arg-2'. Functions as a sensor of histone H3 modifications that are important for the epigenetic regulation of gene expression. Functions as a transcriptional activator and promotes the expression of otherwise tissue-specific self-antigens in the thymus, which is important for self tolerance and the avoidance of autoimmune reactions. SUBUNIT: Homodimer and homotetramer. Interacts with CREBBP. Interacts preferentially with histone H3 that is not methylated at 'Lys-4'. Binds with lower affinity to histone H3 that is monomethylated at 'Lys-4'. Trimethylation of histone H3 at 'Lys-4' or phosphorylation at 'Thr-3' abolish the interaction. Binds with lower affinity to histone H3 that is acetylated at 'Lys-4', or that is acetylated at 'Lys-9' or trimethylated at 'Lys-9'. Binds histone H3 that is dimethylated at 'Arg-2' with very low affinity. INTERACTION: Q9UER7:DAXX; NbExp=5; IntAct=EBI-1753081, EBI-77321; P16333:NCK1; NbExp=2; IntAct=EBI-1753081, EBI-389883; P78527:PRKDC; NbExp=2; IntAct=EBI-1753081, EBI-352053; SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Note=Associated with tubular structures and in discrete nuclear dots resembling ND10 nuclear bodies. May shuttle between nucleus and cytoplasm. TISSUE SPECIFICITY: Widely expressed. Expressed at higher level in thymus (medullary epithelial cells and monocyte-dendritic cells), pancreas, adrenal cortex and testis. Expressed at lower level in the spleen, fetal liver and lymph nodes. Isoform 2 and isoform 3 seem to be less frequently expressed than isoform 1, if at all. DOMAIN: The L-X-X-L-L repeats may be implicated in binding to nuclear receptors. DOMAIN: The HSR domain is required for localization on tubular structures (N-terminal part) and for homodimerization. DOMAIN: Interacts via the first PHD domain with the N-terminus of histone H3 that is not methylated at 'Lys-4'. Disruption of the first PHD domain has been shown to lead to reduced transcriptional activity and to localization of the protein mainly in the cytoplasm in small granules. While the PHD zinc fingers are necessary for the transactivation capacity of the protein, other regions also modulate this function. PTM: Phosphorylated. Phosphorylation could trigger oligomerization. DISEASE: Defects in AIRE are a cause of autoimmune poly- endocrinopathy candidiasis ectodermal dystrophy (APS1) [MIM:240300]. An autosomal recessive disease characterized by the combination of chronic mucocutaneous candidiasis, hypoparathyroidism and Addison disease. Symptoms of mucocutaneous candidiasis manifest first, followed by hypotension or fatigue occurring as a result of Addison disease. APS1 is associated with other autoimmune disorders including diabetes mellitus, vitiligo, alopecia, hepatitis, pernicious anemia and primary hypothyroidism. DISEASE: Note=Most of the mutations alter the nucleus-cytoplasm distribution of AIRE and disturb its association with nuclear dots and cytoplasmic filaments. Most of the mutations also decrease transactivation of the protein. The HSR domain is responsible for the homomultimerization activity of AIRE. All the missense mutations of the HSR and the SAND domains decrease this activity, but those in other domains do not. The AIRE protein is present in soluble high-molecular-weight complexes. Mutations in the HSR domain and deletion of PHD zinc fingers disturb the formation of these complexes. SIMILARITY: Contains 1 HSR domain. SIMILARITY: Contains 2 PHD-type zinc fingers. SIMILARITY: Contains 1 SAND domain. WEB RESOURCE: Name=AIREbase; Note=AIRE mutation db; URL="http://bioinf.uta.fi/AIREbase/"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/AIRE"; WEB RESOURCE: Name=Mendelian genes autoimmune regulator (AIRE); Note=Leiden Open Variation Database (LOVD); URL="http://www.lovd.nl/AIRE";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on O43918
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0000977 RNA polymerase II regulatory region sequence-specific DNA binding GO:0000981 RNA polymerase II transcription factor activity, sequence-specific DNA binding GO:0001228 transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding GO:0003677 DNA binding GO:0003682 chromatin binding GO:0003712 transcription cofactor activity GO:0005515 protein binding GO:0008270 zinc ion binding GO:0042393 histone binding GO:0042802 identical protein binding GO:0044212 transcription regulatory region DNA binding GO:0045182 translation regulator activity GO:0046872 metal ion binding
Biological Process: GO:0002458 peripheral T cell tolerance induction GO:0002509 central tolerance induction to self antigen GO:0006351 transcription, DNA-templated GO:0006355 regulation of transcription, DNA-templated GO:0006366 transcription from RNA polymerase II promoter GO:0006417 regulation of translation GO:0006955 immune response GO:0006959 humoral immune response GO:0032602 chemokine production GO:0045060 negative thymic T cell selection GO:0045893 positive regulation of transcription, DNA-templated GO:0045944 positive regulation of transcription from RNA polymerase II promoter GO:0097536 thymus epithelium morphogenesis GO:2000410 regulation of thymocyte migration
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
