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FLASH GENE
Symbol AIRE contributors: mct - updated : 11-07-2017
HGNC name autoimmune regulator
HGNC id 360
Corresponding disease
PGA1 autoimmune polyglandular disease type I
Location 21q22.3      Physical location : 45.705.762 - 45.718.110
Synonym name
  • autoimmune regulator (autoimmune polyendocrinopathy candidiasis
  • ectodermal dystrophy)
  • APECED protein
  • Synonym symbol(s) APS1, APSI, AIRE1, APECED, PGA1
    DNA
    TYPE functioning gene
    STRUCTURE 12.35 kb     14 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    cytosine-phosphate-guanine/HTF
    text structure
  • CpG methylation in the promoter of the AIRE gene has been suggested to control its tissue-specific expression pattern (promoter hypomethylation is necessary but not sufficient for tissue-specific regulation of the AIRE gene)
  • MAPPING cloned Y linked N status confirmed
    Map cen - TMEM1 - D21S1460 - C21orf33 - D21S1912 - D21S25 - AIRE - D21S1461 - PFKL PFKL - D21S400 - TRPC7 /D21S154 - D21S171 - qter
    Physical map
    KIAA0179 21q22.3 pituitary tumor-transforming 1 interacting protein PDXK 21q22.3 pyridoxal (pyridoxine, vitamin B6) kinase C21orf124 21q22.3 chromosome 21 open reading frame 124 C21orf97 21q22.3 chromosome 21 open reading frame 97 CSTB 21q22.3 cystatin B (stefin B) D21S2056E 21q22.3 DNA segment on chromosome 21 (unique) 2056 expressed sequence LOC284837 21q22.3 hypothetical protein LOC284837 MYL6P 21q22.3 myosin, light polypeptide 6, pseudogene AGPAT3 21q22.3 1-acylglycerol-3-phosphate O-acyltransferase 3 TMEM1 21q22.3 transmembrane protein 1 H2AFZP 21q22.3 H2A histone family, member Z, pseudogene PWP2H 21q22.3 PWP2 periodic tryptophan protein homolog (yeast) C21orf33 21q22.3 chromosome 21 open reading frame 33 C21orf32 21q22.3 chromosome 21 open reading frame 32 ICOSL 21q22.3 inducible T-cell co-stimulator ligand DNMT3L 21q22.3 DNA (cytosine-5-)-methyltransferase 3-like AIRE 21q22.3 autoimmune regulator (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy) PFKL 21q22.3 phosphofructokinase, liver C21orf2 21q22.3 chromosome 21 open reading frame 2 TRPM2 21q22.3 transient receptor potential cation channel, subfamily M, member 2 LRRC3 21q22.3 leucine-rich repeat-containing 3 C21orf29 21q22.3 chromosome 21 open reading frame 29 C21orf90 21q22.1 chromosome 21 open reading frame 90 KRTAP10-10 21q22.3 keratin associated protein 10-10 KRTAP12-2 21q22.3 keratin associated protein 12-2 IMMTP 21q22.3 inner membrane protein, mitochondrial (mitofilin) pseudogene KRTAP12-1 21q22.3 keratin associated protein 12-1 UBE2G2 21q22.3 ubiquitin-conjugating enzyme E2G 2 (UBC7 homolog, yeast) SMT3H1 21q22.3 SMT3 suppressor of mif two 3 homolog 1 (yeast) PTTG1IP 21q22.3 pituitary tumor-transforming 1 interacting protein
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    14 splicing initiation site 2257 58 545 - 2009 19124002
    8 splicing initiation site 1963 - 348 weakly expressed 2009 19124002
    EXPRESSION
    Rna function B cells
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Lymphoid/Immunethymusmedulla    Homo sapiens
    Reproductivemale systemtestis    Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialbarrier lining    Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Lymphoid/Immuneepithelial cell Homo sapiens
    Lymphoid/Immunelymphocyte Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal
    Text liver
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N-terminal homogeneously staining region (HSR) of Sp100 and Sp140 proteins and functioning as a dimerization domain, this HSR/CARD domain together with a nuclear localization signal is sufficient to induce apoptosis
  • a DEAF-1 domain
  • two nuclear localization signals (NLS)
  • two putative DNA binding sequences referred as the SAND domain
  • a proline-rich region between
  • two PHD-type (C4-H-C3) zinc finger domains (the two PHD domains can bind to specific DNA sequence motifs), and PHD2 was required for AIRE to interact with sets of protein partners involved in chromatin structure/binding or transcription but not with those implicated in pre-mRNA processing
  • a leucine zipper motif within the first PHD domain
  • four dispersed nuclear receptor-binding LXXLL motifs
  • mono polymer homomer , heteromer , dimer , tetramer
    HOMOLOGY
    interspecies homolog to murine Aire
    Homologene
    FAMILY
    CATEGORY transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytoskeleton
    intracellular,nucleus,nucleoplasm,nuclear bodies,nuclear speckles
    text separated from the PML bodies and colocalizing with cytoskeletal filaments
    basic FUNCTION
  • may be involved in the regulation of gene expression
  • autoimmune regulator gene, transactivating transcription through heteromeric molecular interactions regulated by homomultimerization
  • promotes the establishment of self-tolerance by regulating gene expression in the thymus
  • with PIAS1 interact functionally to regulate the activities of the target genes of AIRE
  • functions as a transcriptional regulator, and has a central role in the development of immunological tolerance
  • has a critical role in dendritic cells responses to microbial stimuli
  • able to promote ectopic gene expression from chromatin associated with histone modifications characteristic to inactive genes, and of tissue-specific genes from chromatin lacking transcriptionally active histone H3 modifications
  • may be involved in structural changes of larger chromatin regions
  • regulates the expression of differentiation-associated genes and self-renewal of embryonic stem cells
  • transcription factor involved in the presentation of tissue-restricted antigens during T-cell development in the thymus
  • transcription factor that induces the expression of a large subset of otherwise strictly tissue restricted antigens in medullary thymic epithelial cells, thereby enabling their presentation to developing T cells for negative selection
  • AIRE requires CDK9 to activate transcription elongation and co-transcriptional processing of target genes
  • has a central role in the transcriptional regulation of self-antigens in medullary thymic epithelial cells, which is necessary for negative selection of autoreactive T cells
  • the pathways behind AIRE-induced apoptosis may be directly linked to the induction of central tolerance in thymus
  • AIRE-induced cellular stress and apoptosis are associated with GAPDH translocation into the nuclei
  • impacts immunological tolerance by regulating the expression of a large set of genes in thymic medullary epithelial cells
  • multidomain protein that performs a fundamental function in the thymus and possibly in the secondary lymphoid organs: the regulation, especially in the sense of activation, of the process of gene transcription in cell lines deputed to the presentation of self-antigens to the maturing T lymphocytes
  • plays a remarkable role as a regulator of central tolerance by controlling the promiscuous expression of tissue-specific antigens in thymic medullary epithelial cells
  • fundamental role of AIRE and promiscuous gene expression (pGE), namely, central tolerance, in the predisposition to autoimmunity of Down syndrome individuals
  • key factor in thymic negative selection of autoreactive T cells by promoting the ectopic expression of tissue-specific genes in the thymic medullary epithelium
  • presence of AIRE can trigger molecular events leading to an altered chromatin landscape and the enhanced transcription of low-expressed genes
  • CELLULAR PROCESS nucleotide, transcription
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA DNA binding, through HSR/CARD domain and AAs R113 and K114 that are key elements involved in AIRE binding to DNA
    RNA
    small molecule metal binding,
  • Zn2+
  • protein
  • AIRE gene is a downstream target for the Ets family of transcription factors
  • interaction with TP63 through a SAND domain and a transactivation domain, respectively (involvement of AIRE and TP63 in the regulation of HLA class II)
  • increases the expression of its target genes, S100A8, involucrin and insulin
  • interacting with DAXX
  • AIRE-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development
  • interacts with proteins involved in nuclear transport, DNA-damage response, chromatin remodeling, transcription and pre-mRNA-splicing
  • correlation between the presence of AIRE and proteasomal breakdown of CCNB2, which leads us to speculate that CCNB2 could be a target of AIRE E3-ubiquitin ligase activity
  • AIRE-induced apoptosis pathway is associated with GAPDH nuclear translocation and induction of NO-induced cellular stress in AIRE-expressing cells
  • AIRE interacts with the transcriptional coactivator and acetyltransferase CREBBP and synergistically cooperates with it in transcriptional activation
  • interaction of AIRE with deacetylases complexes inhibits its transcriptional activity and is probably responsible for the instability of AIRE, which becomes more susceptible to degradation in the proteasome
  • CDK9 is required for the transition from initiation to elongation of transcription, and its AIRE interaction ensures proper expression of AIRE-responsive tissue-specific antigens in the thymus
  • promote DNA breaks via its interaction with topoisomerase 2 (TOP2A)
  • cell & other
    REGULATION
    Other is modified post-translationally by phosphorylation and ubiquitylation
    ASSOCIATED DISORDERS
    corresponding disease(s) PGA1
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    decreased AIRE expression and global thymic hypofunction in Down syndrome (Trisomy 21)
    constitutional germinal mutation      
    could specifically affect human insulin gene expression in thymic epithelial cells through INS-VNTR and subsequently induce either insulin tolerance or autoimmunity
    constitutional     --low  
    significantly reduced by 2-fold in Down syndrome thymuses compared with controls
    Susceptibility
  • to vitiligo
  • to rheumatoid arthritis
  • to melanoma
  • Variant & Polymorphism SNP
  • Ser278Arg polymorphism not associated with increased risk for alopecia areata, in German population
  • strong association between AIRE 7215C and vitiligo
  • SNPs rs1055311, rs1800520 and rs1800522 were significantly more frequent in healthy subjects than in melanoma patients
  • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS