id: O43918
gene_symbol: AIRE
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: AIRE is a nuclear autoimmune regulator expressed most prominently in medullary thymic epithelial cells, where it promotes central self-tolerance by enabling promiscuous expression of tissue-restricted antigen genes. The protein contains an HSR oligomerization domain, a SAND domain, and two PHD zinc fingers; PHD1 acts as a histone H3K4me0 reader that helps target AIRE to poorly active chromatin and supports transcriptional activation of self-antigen genes. AIRE also forms nuclear-body-like structures and interacts with chromatin and transcription/RNA-processing partners. Loss-of-function or dominant-negative AIRE variants impair these transcriptional tolerance programs and cause autoimmune polyendocrine syndrome type 1 or related organ-specific autoimmune phenotypes.
alternative_products:
- name: 1 (AIRE-1)
  id: O43918-1
- name: 2 (AIRE-2)
  id: O43918-2
  sequence_note: VSP_004089
- name: 3 (AIRE-3)
  id: O43918-3
  sequence_note: VSP_004089, VSP_004090
- name: '4'
  id: O43918-4
  sequence_note: VSP_004089, VSP_043529
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: AIRE is predominantly nuclear and is experimentally observed in nuclear dot or nuclear-body-like structures. Nuclear localization is consistent with its chromatin-reader and transcriptional regulatory role.
    action: ACCEPT
    reason: AIRE is a nuclear transcriptional regulator and multiple experimental and phylogenetic annotations support nuclear localization.
    additional_reference_ids:
    - PMID:11274163
    - PMID:14974083
    - PMID:26084028
    supported_by:
    - reference_id: PMID:11274163
      supporting_text: At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: AIRE promotes expression of tissue-restricted antigen genes and activates reporter or target gene expression; the Pol II transcription-regulation annotation is well supported.
    action: ACCEPT
    reason: AIRE positively regulates expression of tissue-restricted antigen and reporter genes; this Pol II transcription term is an appropriate core biological-process annotation.
    additional_reference_ids:
    - PMID:11274163
    - PMID:18292755
    - PMID:26084028
    supported_by:
    - reference_id: PMID:11274163
      supporting_text: we show that AIRE can activate the interferon beta minimal promoter in a transfection assay
    - reference_id: PMID:18292755
      supporting_text: in vivo AIRE binds to and activates promoters containing low levels of H3K4me3
- term:
    id: GO:0000977
    label: RNA polymerase II transcription regulatory region sequence-specific DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: AIRE oligomers bind specific A/T-rich DNA motifs in vitro and are linked to promoter-level regulation of Pol II-transcribed genes.
    action: ACCEPT
    reason: The original DNA-binding paper showed motif binding by AIRE oligomers, and AIRE functions in promoter-level transcriptional regulation. Retain this specific MF term.
    additional_reference_ids:
    - PMID:11533054
    - PMID:18292755
    supported_by:
    - reference_id: PMID:11533054
      supporting_text: AIRE dimers and tetramers, but not the monomers, can bind to G-doublets with the ATTGGTTA motif and the TTATTA-box.
- term:
    id: GO:0002458
    label: peripheral T cell tolerance induction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Peripheral tolerance is supported primarily by orthology/by-similarity evidence for extrathymic AIRE-expressing antigen-presenting cells; keep as non-core for this human review.
    action: KEEP_AS_NON_CORE
    reason: Peripheral tolerance is plausible and supported by mouse/orthology evidence, but the human core function remains thymic central tolerance through transcriptional control of tissue-restricted antigens.
    additional_reference_ids:
    - PMID:26084028
    supported_by:
    - reference_id: PMID:26084028
      supporting_text: The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
- term:
    id: GO:0002509
    label: central tolerance induction to self antigen
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: AIRE is crucial for central immunological tolerance and prevents autoimmunity by enabling thymic tissue-restricted antigen expression.
    action: ACCEPT
    reason: Central tolerance induction is the defining biological role of AIRE in medullary thymic epithelial cells and is directly tied to AIRE disease mechanisms.
    additional_reference_ids:
    - PMID:26084028
    - PMID:19446523
    - PMID:19302042
    supported_by:
    - reference_id: PMID:26084028
      supporting_text: The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
    - reference_id: PMID:19302042
      supporting_text: Aire plays an important role in T cell tolerance induction in the thymus
- term:
    id: GO:0003682
    label: chromatin binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: AIRE binds chromatin-associated histone H3 through PHD1 and engages promoters with low H3K4 trimethylation.
    action: ACCEPT
    reason: AIRE binds histone H3 and chromatin at target promoters, so chromatin binding is an appropriate molecular-function annotation.
    additional_reference_ids:
    - PMID:18292755
    - PMID:19446523
    supported_by:
    - reference_id: PMID:18292755
      supporting_text: in vivo AIRE binds to and activates promoters containing low levels of H3K4me3
    - reference_id: PMID:19446523
      supporting_text: The structure reveals a detailed network of interactions between the protein and the amino-terminal residues of histone H3
- term:
    id: GO:0006959
    label: humoral immune response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Humoral immune response is too broad and likely reflects autoimmune/antibody phenotypes or InterPro propagation rather than a direct AIRE role in humoral effector responses.
    action: MARK_AS_OVER_ANNOTATED
    reason: The literature supports self-tolerance and autoimmune phenotypes, not a direct AIRE role in humoral immune effector response. Keep this as an over-annotation rather than a core AIRE function.
    additional_reference_ids:
    - PMID:9398840
    - PMID:26084028
    supported_by:
    - reference_id: PMID:9398840
      supporting_text: This is the first report of a single-gene defect causing a systemic human autoimmune disease
- term:
    id: GO:0042393
    label: histone binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: AIRE PHD1 directly binds the N terminus of histone H3, preferentially recognizing non-methylated H3K4.
    action: ACCEPT
    reason: Direct biochemical and structural work supports AIRE PHD1 binding to histone H3, especially H3K4me0.
    additional_reference_ids:
    - PMID:18292755
    - PMID:19446523
    supported_by:
    - reference_id: PMID:19446523
      supporting_text: The structure reveals a detailed network of interactions between the protein and the amino-terminal residues of histone H3
    - reference_id: PMID:18292755
      supporting_text: preferentially binds to non-methylated H3K4 (H3K4me0)
- term:
    id: GO:0045060
    label: negative thymic T cell selection
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: AIRE-dependent thymic antigen expression supports negative selection of autoreactive thymocytes, making this a core biological-process consequence.
    action: ACCEPT
    reason: AIRE-dependent thymic expression of self-antigens supports deletion of autoreactive developing T cells; negative thymic T cell selection is a core process consequence.
    additional_reference_ids:
    - PMID:19446523
    - PMID:26084028
    - PMID:19302042
    supported_by:
    - reference_id: PMID:19446523
      supporting_text: Mechanisms of central tolerance are mediated in part through the expression of a wide array of otherwise tissue-specific self-antigens
    - reference_id: PMID:19302042
      supporting_text: The absence of Aire results in impaired clonal deletion of self-reactive thymocytes
- term:
    id: GO:0097536
    label: thymus epithelium morphogenesis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: AIRE influences the mTEC differentiation program, but thymus epithelial morphogenesis is a developmental consequence rather than the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: AIRE affects mTEC differentiation and thymic epithelial programs, but morphogenesis is downstream/developmental relative to the core chromatin-transcription tolerance function.
    additional_reference_ids:
    - PMID:26084028
    supported_by:
    - reference_id: PMID:26084028
      supporting_text: The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
- term:
    id: GO:2000410
    label: regulation of thymocyte migration
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: AIRE regulation of thymic chemokine programs can alter thymocyte migration; this is a downstream thymic microenvironment role, not the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: This mouse-derived thymic microenvironment annotation is plausible, but it is a downstream consequence of AIRE transcriptional programs rather than the core function.
    additional_reference_ids:
    - PMID:26084028
    supported_by:
    - reference_id: PMID:26084028
      supporting_text: The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
- term:
    id: GO:0002507
    label: tolerance induction
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: The broad tolerance-induction term is true but should be replaced by the more specific central tolerance and peripheral T cell tolerance terms already present in GOA.
    action: MODIFY
    reason: AIRE clearly induces immunological tolerance, but this broad automated term should be replaced by the specific central and peripheral tolerance terms already present.
    proposed_replacement_terms:
    - id: GO:0002509
      label: central tolerance induction to self antigen
    - id: GO:0002458
      label: peripheral T cell tolerance induction
    additional_reference_ids:
    - PMID:26084028
    - PMID:19302042
    supported_by:
    - reference_id: PMID:26084028
      supporting_text: The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
    - reference_id: PMID:19302042
      supporting_text: Aire plays an important role in T cell tolerance induction in the thymus
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: The generic DNA-binding annotation is directionally correct but less informative than the existing sequence-specific transcription regulatory region binding term.
    action: MODIFY
    reason: Generic DNA binding is less informative than the existing RNA polymerase II transcription regulatory region sequence-specific DNA binding annotation.
    proposed_replacement_terms:
    - id: GO:0000977
      label: RNA polymerase II transcription regulatory region sequence-specific DNA binding
    additional_reference_ids:
    - PMID:11533054
    supported_by:
    - reference_id: PMID:11533054
      supporting_text: AIRE dimers and tetramers, but not the monomers, can bind to G-doublets with the ATTGGTTA motif and the TTATTA-box.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: AIRE is predominantly nuclear and is experimentally observed in nuclear dot or nuclear-body-like structures. Nuclear localization is consistent with its chromatin-reader and transcriptional regulatory role.
    action: ACCEPT
    reason: AIRE is a nuclear transcriptional regulator and multiple experimental and phylogenetic annotations support nuclear localization.
    additional_reference_ids:
    - PMID:11274163
    - PMID:14974083
    - PMID:26084028
    supported_by:
    - reference_id: PMID:11274163
      supporting_text: At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: AIRE has experimentally observed cytoplasmic and microtubule-associated localization, but this is secondary to its nuclear transcriptional regulatory function.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasmic/microtubule-associated AIRE localization is experimentally observed, but the primary biological role is nuclear chromatin and transcriptional regulation.
    additional_reference_ids:
    - PMID:11274163
    - PMID:14974083
    supported_by:
    - reference_id: PMID:11274163
      supporting_text: At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies.
    - reference_id: PMID:14974083
      supporting_text: Most of the mutations altered the nucleus-cytoplasm distribution of AIRE and disturbed its association with nuclear dots and cytoplasmic filaments.
- term:
    id: GO:0006417
    label: regulation of translation
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: This annotation is an automated consequence of the InterPro translation-regulator mapping for AIRE and is not supported by the curated AIRE literature.
    action: REMOVE
    reason: AIRE is characterized as a transcriptional/chromatin regulator. The translation-regulation annotation is an automated ontology-link consequence of an unsupported InterPro translation-regulator activity mapping.
    additional_reference_ids:
    - PMID:11274163
    - PMID:18292755
    supported_by:
    - reference_id: PMID:11274163
      supporting_text: we show that AIRE can activate the interferon beta minimal promoter in a transfection assay
    - reference_id: PMID:18292755
      supporting_text: we show that AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger
- term:
    id: GO:0006955
    label: immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: AIRE is an immune-system regulator, but generic immune response loses the specific self-tolerance mechanism and should not be treated as a core annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: AIRE prevents autoimmunity through self-tolerance induction, but generic immune response is too broad and loses the specific mechanism. More specific tolerance terms are already present.
    additional_reference_ids:
    - PMID:26084028
    supported_by:
    - reference_id: PMID:26084028
      supporting_text: The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
- term:
    id: GO:0006959
    label: humoral immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Humoral immune response is too broad and likely reflects autoimmune/antibody phenotypes or InterPro propagation rather than a direct AIRE role in humoral effector responses.
    action: MARK_AS_OVER_ANNOTATED
    reason: The literature supports self-tolerance and autoimmune phenotypes, not a direct AIRE role in humoral immune effector response. Keep this as an over-annotation rather than a core AIRE function.
    additional_reference_ids:
    - PMID:9398840
    - PMID:26084028
    supported_by:
    - reference_id: PMID:9398840
      supporting_text: This is the first report of a single-gene defect causing a systemic human autoimmune disease
- term:
    id: GO:0045182
    label: translation regulator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: No direct translation-regulator molecular activity is supported for AIRE; the experimental evidence supports transcriptional and chromatin-regulatory activities instead.
    action: REMOVE
    reason: No curated AIRE evidence supports direct translation regulator activity. The better-supported molecular functions are histone binding, chromatin binding, sequence-specific DNA binding, and transcriptional regulation.
    additional_reference_ids:
    - PMID:11274163
    - PMID:18292755
    supported_by:
    - reference_id: PMID:11274163
      supporting_text: we show that AIRE can activate the interferon beta minimal promoter in a transfection assay
    - reference_id: PMID:18292755
      supporting_text: we show that AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: AIRE promotes expression of tissue-restricted antigen genes and activates reporter or target gene expression; the Pol II transcription-regulation annotation is well supported.
    action: ACCEPT
    reason: AIRE positively regulates expression of tissue-restricted antigen and reporter genes; this Pol II transcription term is an appropriate core biological-process annotation.
    additional_reference_ids:
    - PMID:11274163
    - PMID:18292755
    - PMID:26084028
    supported_by:
    - reference_id: PMID:11274163
      supporting_text: we show that AIRE can activate the interferon beta minimal promoter in a transfection assay
    - reference_id: PMID:18292755
      supporting_text: in vivo AIRE binds to and activates promoters containing low levels of H3K4me3
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17474147
  qualifier: enables
  review:
    summary: The interaction evidence is real, but protein binding is too generic and obscures the specific histone, chromatin, DAXX, PRKDC, and other transcriptional-complex interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: The high-throughput SH3 peptide interaction is valid as interaction evidence, but generic protein binding is not informative for AIRE function and should not be treated as a core molecular function.
    additional_reference_ids:
    - PMID:17474147
    - PMID:18292755
    - PMID:20085707
    - PMID:20185822
    supported_by:
    - reference_id: PMID:17474147
      supporting_text: a peptide target array composed of 1536 potential ligands
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18292755
  qualifier: enables
  review:
    summary: The interaction evidence is real, but protein binding is too generic and obscures the specific histone, chromatin, DAXX, PRKDC, and other transcriptional-complex interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: This interaction is better captured by the specific histone binding and chromatin binding annotations already present. Generic protein binding is over-annotation.
    additional_reference_ids:
    - PMID:17474147
    - PMID:18292755
    - PMID:20085707
    - PMID:20185822
    supported_by:
    - reference_id: PMID:18292755
      supporting_text: we show that AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20085707
  qualifier: enables
  review:
    summary: The interaction evidence is real, but protein binding is too generic and obscures the specific histone, chromatin, DAXX, PRKDC, and other transcriptional-complex interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: The interaction screen identifies transcriptional, chromatin, nuclear transport, and RNA-processing partners; protein binding is too generic for the functional conclusion.
    additional_reference_ids:
    - PMID:17474147
    - PMID:18292755
    - PMID:20085707
    - PMID:20185822
    supported_by:
    - reference_id: PMID:20085707
      supporting_text: 'They fall into four major functional classes: nuclear transport, chromatin binding/structure, transcription and pre-mRNA processing.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20185822
  qualifier: enables
  review:
    summary: The interaction evidence is real, but protein binding is too generic and obscures the specific histone, chromatin, DAXX, PRKDC, and other transcriptional-complex interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: The DAXX interaction is real and functionally relevant to AIRE transcriptional activity, but generic protein binding is too broad as a GO molecular-function annotation.
    additional_reference_ids:
    - PMID:17474147
    - PMID:18292755
    - PMID:20085707
    - PMID:20185822
    supported_by:
    - reference_id: PMID:20185822
      supporting_text: led us to the discovery of a new AIRE-interacting protein called DAXX
    - reference_id: PMID:20185822
      supporting_text: DAXX exerts a strong repressive role on the transcriptional activity of AIRE.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:15712268
  qualifier: enables
  review:
    summary: AIRE homodimerization and higher-order oligomerization are experimentally supported and important for function, but they support rather than define the core transcriptional role.
    action: KEEP_AS_NON_CORE
    reason: AIRE oligomerization is functionally important and directly supported, but identical protein binding is a supporting molecular property rather than the central chromatin/transcription function.
    additional_reference_ids:
    - PMID:11533054
    - PMID:14974083
    - PMID:15712268
    - PMID:28540407
    supported_by:
    - reference_id: PMID:15712268
      supporting_text: both mutations negatively affected the homodimerization properties of the AIRE protein
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:20185822
  qualifier: enables
  review:
    summary: AIRE homodimerization and higher-order oligomerization are experimentally supported and important for function, but they support rather than define the core transcriptional role.
    action: KEEP_AS_NON_CORE
    reason: AIRE oligomerization is functionally important and directly supported, but identical protein binding is a supporting molecular property rather than the central chromatin/transcription function.
    additional_reference_ids:
    - PMID:11533054
    - PMID:14974083
    - PMID:15712268
    - PMID:28540407
    supported_by:
    - reference_id: PMID:15712268
      supporting_text: both mutations negatively affected the homodimerization properties of the AIRE protein
    - reference_id: PMID:28540407
      supporting_text: the mutant AIRE protein could not interact with the normal AIRE protein
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:28540407
  qualifier: enables
  review:
    summary: AIRE homodimerization and higher-order oligomerization are experimentally supported and important for function, but they support rather than define the core transcriptional role.
    action: KEEP_AS_NON_CORE
    reason: AIRE oligomerization is functionally important and directly supported, but identical protein binding is a supporting molecular property rather than the central chromatin/transcription function.
    additional_reference_ids:
    - PMID:11533054
    - PMID:14974083
    - PMID:15712268
    - PMID:28540407
    supported_by:
    - reference_id: PMID:28540407
      supporting_text: the mutant AIRE protein could not interact with the normal AIRE protein
- term:
    id: GO:0002458
    label: peripheral T cell tolerance induction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Peripheral tolerance is supported primarily by orthology/by-similarity evidence for extrathymic AIRE-expressing antigen-presenting cells; keep as non-core for this human review.
    action: KEEP_AS_NON_CORE
    reason: Peripheral tolerance is plausible and supported by mouse/orthology evidence, but the human core function remains thymic central tolerance through transcriptional control of tissue-restricted antigens.
    additional_reference_ids:
    - PMID:26084028
    supported_by:
    - reference_id: PMID:26084028
      supporting_text: The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
- term:
    id: GO:0016604
    label: nuclear body
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: AIRE localizes to discrete nuclear dots or nuclear-body-like structures; this supports the cellular component annotation, although the precise body identity is not the core function.
    action: ACCEPT
    reason: Nuclear-body-like dots are repeatedly reported for AIRE localization. This cellular-component term should be retained, while recognizing that the exact nuclear body subtype is not the core function.
    additional_reference_ids:
    - PMID:11274163
    - PMID:14974083
    supported_by:
    - reference_id: PMID:11274163
      supporting_text: At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies.
    - reference_id: PMID:14974083
      supporting_text: Most of the mutations altered the nucleus-cytoplasm distribution of AIRE and disturbed its association with nuclear dots and cytoplasmic filaments.
- term:
    id: GO:0032722
    label: positive regulation of chemokine production
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Chemokine production is a downstream thymic epithelial program attributed largely by mouse orthology; keep as non-core for AIRE.
    action: KEEP_AS_NON_CORE
    reason: Chemokine regulation is a downstream thymic epithelial effect and should be retained as non-core rather than elevated to AIRE core molecular function.
    additional_reference_ids:
    - PMID:26084028
    supported_by:
    - reference_id: PMID:26084028
      supporting_text: The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: AIRE homodimerization and higher-order oligomerization are experimentally supported and important for function, but they support rather than define the core transcriptional role.
    action: KEEP_AS_NON_CORE
    reason: AIRE oligomerization is functionally important and directly supported, but identical protein binding is a supporting molecular property rather than the central chromatin/transcription function.
    additional_reference_ids:
    - PMID:11533054
    - PMID:14974083
    - PMID:15712268
    - PMID:28540407
    supported_by:
    - reference_id: PMID:15712268
      supporting_text: both mutations negatively affected the homodimerization properties of the AIRE protein
- term:
    id: GO:0097536
    label: thymus epithelium morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: AIRE influences the mTEC differentiation program, but thymus epithelial morphogenesis is a developmental consequence rather than the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: AIRE affects mTEC differentiation and thymic epithelial programs, but morphogenesis is downstream/developmental relative to the core chromatin-transcription tolerance function.
    additional_reference_ids:
    - PMID:26084028
    supported_by:
    - reference_id: PMID:26084028
      supporting_text: The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
- term:
    id: GO:2000410
    label: regulation of thymocyte migration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: AIRE regulation of thymic chemokine programs can alter thymocyte migration; this is a downstream thymic microenvironment role, not the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: This mouse-derived thymic microenvironment annotation is plausible, but it is a downstream consequence of AIRE transcriptional programs rather than the core function.
    additional_reference_ids:
    - PMID:26084028
    supported_by:
    - reference_id: PMID:26084028
      supporting_text: The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:14974083
  qualifier: located_in
  review:
    summary: AIRE is predominantly nuclear and is experimentally observed in nuclear dot or nuclear-body-like structures. Nuclear localization is consistent with its chromatin-reader and transcriptional regulatory role.
    action: ACCEPT
    reason: AIRE is a nuclear transcriptional regulator and multiple experimental and phylogenetic annotations support nuclear localization.
    additional_reference_ids:
    - PMID:11274163
    - PMID:14974083
    - PMID:26084028
    supported_by:
    - reference_id: PMID:11274163
      supporting_text: At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:26084028
  qualifier: located_in
  review:
    summary: AIRE is predominantly nuclear and is experimentally observed in nuclear dot or nuclear-body-like structures. Nuclear localization is consistent with its chromatin-reader and transcriptional regulatory role.
    action: ACCEPT
    reason: AIRE is a nuclear transcriptional regulator and multiple experimental and phylogenetic annotations support nuclear localization.
    additional_reference_ids:
    - PMID:11274163
    - PMID:14974083
    - PMID:26084028
    supported_by:
    - reference_id: PMID:11274163
      supporting_text: At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:11274163
  qualifier: located_in
  review:
    summary: AIRE has experimentally observed cytoplasmic and microtubule-associated localization, but this is secondary to its nuclear transcriptional regulatory function.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasmic/microtubule-associated AIRE localization is experimentally observed, but the primary biological role is nuclear chromatin and transcriptional regulation.
    additional_reference_ids:
    - PMID:11274163
    - PMID:14974083
    supported_by:
    - reference_id: PMID:11274163
      supporting_text: At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies.
    - reference_id: PMID:14974083
      supporting_text: Most of the mutations altered the nucleus-cytoplasm distribution of AIRE and disturbed its association with nuclear dots and cytoplasmic filaments.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:14974083
  qualifier: located_in
  review:
    summary: AIRE has experimentally observed cytoplasmic and microtubule-associated localization, but this is secondary to its nuclear transcriptional regulatory function.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasmic/microtubule-associated AIRE localization is experimentally observed, but the primary biological role is nuclear chromatin and transcriptional regulation.
    additional_reference_ids:
    - PMID:11274163
    - PMID:14974083
    supported_by:
    - reference_id: PMID:11274163
      supporting_text: At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies.
    - reference_id: PMID:14974083
      supporting_text: Most of the mutations altered the nucleus-cytoplasm distribution of AIRE and disturbed its association with nuclear dots and cytoplasmic filaments.
- term:
    id: GO:0016604
    label: nuclear body
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: AIRE localizes to discrete nuclear dots or nuclear-body-like structures; this supports the cellular component annotation, although the precise body identity is not the core function.
    action: ACCEPT
    reason: Nuclear-body-like dots are repeatedly reported for AIRE localization. This cellular-component term should be retained, while recognizing that the exact nuclear body subtype is not the core function.
    additional_reference_ids:
    - PMID:11274163
    - PMID:14974083
    supported_by:
    - reference_id: PMID:11274163
      supporting_text: At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies.
    - reference_id: PMID:14974083
      supporting_text: Most of the mutations altered the nucleus-cytoplasm distribution of AIRE and disturbed its association with nuclear dots and cytoplasmic filaments.
- term:
    id: GO:0032722
    label: positive regulation of chemokine production
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Chemokine production is a downstream thymic epithelial program attributed largely by mouse orthology; keep as non-core for AIRE.
    action: KEEP_AS_NON_CORE
    reason: Chemokine regulation is a downstream thymic epithelial effect and should be retained as non-core rather than elevated to AIRE core molecular function.
    additional_reference_ids:
    - PMID:26084028
    supported_by:
    - reference_id: PMID:26084028
      supporting_text: The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
- term:
    id: GO:0097536
    label: thymus epithelium morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: AIRE influences the mTEC differentiation program, but thymus epithelial morphogenesis is a developmental consequence rather than the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: AIRE affects mTEC differentiation and thymic epithelial programs, but morphogenesis is downstream/developmental relative to the core chromatin-transcription tolerance function.
    additional_reference_ids:
    - PMID:26084028
    supported_by:
    - reference_id: PMID:26084028
      supporting_text: The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
- term:
    id: GO:2000410
    label: regulation of thymocyte migration
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: AIRE regulation of thymic chemokine programs can alter thymocyte migration; this is a downstream thymic microenvironment role, not the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: This mouse-derived thymic microenvironment annotation is plausible, but it is a downstream consequence of AIRE transcriptional programs rather than the core function.
    additional_reference_ids:
    - PMID:26084028
    supported_by:
    - reference_id: PMID:26084028
      supporting_text: The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
- term:
    id: GO:0002458
    label: peripheral T cell tolerance induction
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Peripheral tolerance is supported primarily by orthology/by-similarity evidence for extrathymic AIRE-expressing antigen-presenting cells; keep as non-core for this human review.
    action: KEEP_AS_NON_CORE
    reason: Peripheral tolerance is plausible and supported by mouse/orthology evidence, but the human core function remains thymic central tolerance through transcriptional control of tissue-restricted antigens.
    additional_reference_ids:
    - PMID:26084028
    supported_by:
    - reference_id: PMID:26084028
      supporting_text: The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
- term:
    id: GO:0002509
    label: central tolerance induction to self antigen
  evidence_type: IMP
  original_reference_id: PMID:26084028
  qualifier: involved_in
  review:
    summary: AIRE is crucial for central immunological tolerance and prevents autoimmunity by enabling thymic tissue-restricted antigen expression.
    action: ACCEPT
    reason: Central tolerance induction is the defining biological role of AIRE in medullary thymic epithelial cells and is directly tied to AIRE disease mechanisms.
    additional_reference_ids:
    - PMID:26084028
    - PMID:19446523
    - PMID:19302042
    supported_by:
    - reference_id: PMID:26084028
      supporting_text: The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
    - reference_id: PMID:19302042
      supporting_text: Aire plays an important role in T cell tolerance induction in the thymus
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IMP
  original_reference_id: PMID:26084028
  qualifier: involved_in
  review:
    summary: AIRE positively regulates target-gene expression, but the more precise Pol II positive-regulation term is already present and better captures the gene-expression output.
    action: MODIFY
    reason: The annotation captures AIRE-mediated gene activation, but positive regulation of transcription by RNA polymerase II is the more precise GO term already present for this protein.
    proposed_replacement_terms:
    - id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    additional_reference_ids:
    - PMID:11274163
    - PMID:18292755
    - PMID:26084028
    supported_by:
    - reference_id: PMID:26084028
      supporting_text: These missense PHD1 mutations suppressed gene expression driven by wild-type AIRE in a dominant-negative manner
    - reference_id: PMID:18292755
      supporting_text: in vivo AIRE binds to and activates promoters containing low levels of H3K4me3
- term:
    id: GO:0000977
    label: RNA polymerase II transcription regulatory region sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:11533054
  qualifier: enables
  review:
    summary: AIRE oligomers bind specific A/T-rich DNA motifs in vitro and are linked to promoter-level regulation of Pol II-transcribed genes.
    action: ACCEPT
    reason: The original DNA-binding paper showed motif binding by AIRE oligomers, and AIRE functions in promoter-level transcriptional regulation. Retain this specific MF term.
    additional_reference_ids:
    - PMID:11533054
    - PMID:18292755
    supported_by:
    - reference_id: PMID:11533054
      supporting_text: AIRE dimers and tetramers, but not the monomers, can bind to G-doublets with the ATTGGTTA motif and the TTATTA-box.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:11274163
  qualifier: involved_in
  review:
    summary: AIRE promotes expression of tissue-restricted antigen genes and activates reporter or target gene expression; the Pol II transcription-regulation annotation is well supported.
    action: ACCEPT
    reason: AIRE positively regulates expression of tissue-restricted antigen and reporter genes; this Pol II transcription term is an appropriate core biological-process annotation.
    additional_reference_ids:
    - PMID:11274163
    - PMID:18292755
    - PMID:26084028
    supported_by:
    - reference_id: PMID:11274163
      supporting_text: we show that AIRE can activate the interferon beta minimal promoter in a transfection assay
    - reference_id: PMID:18292755
      supporting_text: in vivo AIRE binds to and activates promoters containing low levels of H3K4me3
- term:
    id: GO:0003682
    label: chromatin binding
  evidence_type: IDA
  original_reference_id: PMID:18292755
  qualifier: enables
  review:
    summary: AIRE binds chromatin-associated histone H3 through PHD1 and engages promoters with low H3K4 trimethylation.
    action: ACCEPT
    reason: AIRE binds histone H3 and chromatin at target promoters, so chromatin binding is an appropriate molecular-function annotation.
    additional_reference_ids:
    - PMID:18292755
    - PMID:19446523
    supported_by:
    - reference_id: PMID:18292755
      supporting_text: in vivo AIRE binds to and activates promoters containing low levels of H3K4me3
    - reference_id: PMID:19446523
      supporting_text: The structure reveals a detailed network of interactions between the protein and the amino-terminal residues of histone H3
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:18292755
  qualifier: involved_in
  review:
    summary: AIRE regulates DNA-templated transcription through chromatin and promoter engagement, but this broad term should be replaced by positive regulation of Pol II transcription.
    action: MODIFY
    reason: The broad regulation term underspecifies both direction and transcription system. AIRE is better represented as a positive regulator of RNA polymerase II transcription.
    proposed_replacement_terms:
    - id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    additional_reference_ids:
    - PMID:11274163
    - PMID:18292755
    supported_by:
    - reference_id: PMID:18292755
      supporting_text: in vivo AIRE binds to and activates promoters containing low levels of H3K4me3
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IDA
  original_reference_id: PMID:19446523
  qualifier: enables
  review:
    summary: AIRE contains PHD zinc-finger domains, and structural work on PHD1 used zinc-bound protein. Zinc binding is real but structural/supporting rather than the main biological activity.
    action: KEEP_AS_NON_CORE
    reason: The PHD fingers are zinc-binding structural domains needed for histone recognition and transcriptional activity, but zinc ion binding is not the core evolved activity to emphasize.
    additional_reference_ids:
    - PMID:19446523
    supported_by:
    - reference_id: PMID:19446523
      supporting_text: two Zn finger-containing plant homeodomain (PHD) finger motifs and a SAND
- term:
    id: GO:0042393
    label: histone binding
  evidence_type: IDA
  original_reference_id: PMID:18292755
  qualifier: enables
  review:
    summary: AIRE PHD1 directly binds the N terminus of histone H3, preferentially recognizing non-methylated H3K4.
    action: ACCEPT
    reason: Direct biochemical and structural work supports AIRE PHD1 binding to histone H3, especially H3K4me0.
    additional_reference_ids:
    - PMID:18292755
    - PMID:19446523
    supported_by:
    - reference_id: PMID:18292755
      supporting_text: we show that AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger
    - reference_id: PMID:18292755
      supporting_text: preferentially binds to non-methylated H3K4 (H3K4me0)
- term:
    id: GO:0042393
    label: histone binding
  evidence_type: IDA
  original_reference_id: PMID:19446523
  qualifier: enables
  review:
    summary: AIRE PHD1 directly binds the N terminus of histone H3, preferentially recognizing non-methylated H3K4.
    action: ACCEPT
    reason: Direct biochemical and structural work supports AIRE PHD1 binding to histone H3, especially H3K4me0.
    additional_reference_ids:
    - PMID:18292755
    - PMID:19446523
    supported_by:
    - reference_id: PMID:19446523
      supporting_text: The structure reveals a detailed network of interactions between the protein and the amino-terminal residues of histone H3
    - reference_id: PMID:18292755
      supporting_text: preferentially binds to non-methylated H3K4 (H3K4me0)
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:18292755
  qualifier: involved_in
  review:
    summary: AIRE positively regulates target-gene expression, but the more precise Pol II positive-regulation term is already present and better captures the gene-expression output.
    action: MODIFY
    reason: The annotation captures AIRE-mediated gene activation, but positive regulation of transcription by RNA polymerase II is the more precise GO term already present for this protein.
    proposed_replacement_terms:
    - id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    additional_reference_ids:
    - PMID:11274163
    - PMID:18292755
    - PMID:26084028
    supported_by:
    - reference_id: PMID:26084028
      supporting_text: These missense PHD1 mutations suppressed gene expression driven by wild-type AIRE in a dominant-negative manner
    - reference_id: PMID:18292755
      supporting_text: in vivo AIRE binds to and activates promoters containing low levels of H3K4me3
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: TAS
  original_reference_id: PMID:9398839
  qualifier: located_in
  review:
    summary: AIRE is predominantly nuclear and is experimentally observed in nuclear dot or nuclear-body-like structures. Nuclear localization is consistent with its chromatin-reader and transcriptional regulatory role.
    action: ACCEPT
    reason: AIRE is a nuclear transcriptional regulator and multiple experimental and phylogenetic annotations support nuclear localization.
    additional_reference_ids:
    - PMID:11274163
    - PMID:14974083
    - PMID:26084028
    supported_by:
    - reference_id: PMID:11274163
      supporting_text: At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies.
- term:
    id: GO:0006955
    label: immune response
  evidence_type: TAS
  original_reference_id: PMID:9398840
  qualifier: involved_in
  review:
    summary: AIRE is an immune-system regulator, but generic immune response loses the specific self-tolerance mechanism and should not be treated as a core annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: AIRE prevents autoimmunity through self-tolerance induction, but generic immune response is too broad and loses the specific mechanism. More specific tolerance terms are already present.
    additional_reference_ids:
    - PMID:26084028
    supported_by:
    - reference_id: PMID:26084028
      supporting_text: The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: NAS
  original_reference_id: PMID:9398840
  qualifier: located_in
  review:
    summary: AIRE is predominantly nuclear and is experimentally observed in nuclear dot or nuclear-body-like structures. Nuclear localization is consistent with its chromatin-reader and transcriptional regulatory role.
    action: ACCEPT
    reason: AIRE is a nuclear transcriptional regulator and multiple experimental and phylogenetic annotations support nuclear localization.
    additional_reference_ids:
    - PMID:11274163
    - PMID:14974083
    - PMID:26084028
    supported_by:
    - reference_id: PMID:9398840
      supporting_text: encoding for a putative nuclear protein featuring two PHD-type zinc-finger motifs, suggesting its involvement in transcriptional regulation.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11274163
  title: Subcellular localization of the autoimmune regulator protein. characterization of nuclear targeting and transcriptional activation domain.
  findings: []
- id: PMID:11533054
  title: The autoimmune regulator (AIRE) is a DNA-binding protein.
  findings: []
- id: PMID:14974083
  title: APECED-causing mutations in AIRE reveal the functional domains of the protein.
  findings: []
- id: PMID:15712268
  title: Two novel mutations of the AIRE protein affecting its homodimerization properties.
  findings: []
- id: PMID:17474147
  title: Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening.
  findings: []
- id: PMID:18292755
  title: The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression.
  findings: []
- id: PMID:19302042
  title: Aire.
  findings: []
- id: PMID:19446523
  title: Structure and site-specific recognition of histone H3 by the PHD finger of human autoimmune regulator.
  findings: []
- id: PMID:20085707
  title: Aire's partners in the molecular control of immunological tolerance.
  findings: []
- id: PMID:20185822
  title: DAXX is a new AIRE-interacting protein.
  findings: []
- id: PMID:26084028
  title: Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases.
  findings: []
- id: PMID:28540407
  title: A new mutation site in the AIRE gene causes autoimmune polyendocrine syndrome type 1.
  findings: []
- id: PMID:9398839
  title: Positional cloning of the APECED gene.
  findings: []
- id: PMID:9398840
  title: An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains.
  findings: []
- id: file:human/AIRE/AIRE-notes.md
  title: AIRE PN batch curation notes
  findings: []
- id: file:human/AIRE/AIRE-deep-research-manual.md
  title: AIRE manual deep research fallback
  findings: []
- id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
  title: Proteostasis PN projected annotations report
  findings: []
core_functions:
- description: AIRE recognizes histone H3, especially H3K4me0, through its PHD1 zinc finger and uses this chromatin-reader function to activate otherwise weak or silent tissue-restricted antigen genes in thymic epithelial cells.
  molecular_function:
    id: GO:0042393
    label: histone binding
  directly_involved_in:
  - id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  - id: GO:0002509
    label: central tolerance induction to self antigen
  locations:
  - id: GO:0005634
    label: nucleus
  - id: GO:0016604
    label: nuclear body
  supported_by:
  - reference_id: PMID:18292755
    supporting_text: we show that AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger
  - reference_id: PMID:18292755
    supporting_text: preferentially binds to non-methylated H3K4 (H3K4me0)
  - reference_id: PMID:18292755
    supporting_text: in vivo AIRE binds to and activates promoters containing low levels of H3K4me3
  - reference_id: file:human/AIRE/AIRE-deep-research-manual.md
    supporting_text: AIRE's core molecular features are chromatin engagement, histone H3 recognition, DNA binding, transcriptional activation, and oligomerization.
  - reference_id: PMID:19302042
    supporting_text: Aire plays an important role in T cell tolerance induction in the thymus
  - reference_id: PMID:19302042
    supporting_text: Transcriptional regulation by Aire is unusual in being very broad, context-dependent, probabilistic, and noisy.
- description: AIRE oligomerizes and binds A/T-rich transcription regulatory DNA motifs, supporting promoter-level transcriptional regulation needed for thymic negative selection and self-tolerance.
  molecular_function:
    id: GO:0000977
    label: RNA polymerase II transcription regulatory region sequence-specific DNA binding
  directly_involved_in:
  - id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  - id: GO:0045060
    label: negative thymic T cell selection
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:11533054
    supporting_text: AIRE dimers and tetramers, but not the monomers, can bind to G-doublets with the ATTGGTTA motif and the TTATTA-box.
  - reference_id: PMID:26084028
    supporting_text: The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
  - reference_id: PMID:19302042
    supporting_text: The absence of Aire results in impaired clonal deletion of self-reactive thymocytes
  - reference_id: PMID:19302042
    supporting_text: Transcriptional regulation by Aire is unusual in being very broad, context-dependent, probabilistic, and noisy.
proposed_new_terms: []
suggested_questions:
- question: Does AIRE have direct ubiquitin protein ligase activity in physiological assays, or is its PN UPS placement based only on PHD/RING-variant domain-family context?
  experts:
  - Peterson P
  - Abramson J
  - Benoist C
  - Mathis D
suggested_experiments:
- hypothesis: AIRE lacks intrinsic ubiquitin E3 ligase activity despite its PN UPS RING-variant/PHD placement.
  description: Test purified full-length AIRE and isolated PHD-containing fragments in reconstituted E1/E2/ubiquitin transfer assays alongside positive-control RING and PHD-RING E3 ligases, then validate candidate substrate ubiquitylation in AIRE-reconstituted medullary thymic epithelial cells by ubiquitin remnant proteomics.
  experiment_type: in vitro ubiquitination assay and cellular ubiquitinomics