AIRE

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: AIRE acts in the nucleus. Reason: The PAINT nuclear inference agrees with human nuclear-dot localization and nuclear chromatin/transcription assays. The broad compartment accurately includes the functional nuclear pool. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN005329562 SUPPORTS TRANSFER Nuclear IBD is supported by the mouse source and direct human localization. Cached PTHR46386 PAINT IBD examined; the underlying tree/MSA placement was not reconstructed. Supporting Evidence: PMID:11274163 At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies. PMID:18292755 in vivo AIRE binds to and activates promoters containing low levels of H3K4me3 in human embryonic kidney 293 cells.
GO:0045944 positive regulation of transcription by RNA polymerase II	IBA GO_REF:0000033	ACCEPT	Summary: AIRE promotes RNA polymerase II transcription. Reason: The ancestral assertion is directly corroborated by human promoter activation and target-transcript experiments. Transcriptional stimulation is integral to AIRE-dependent self-antigen expression. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN005329562 SUPPORTS TRANSFER Human and mouse descendant evidence grounds the transcription IBD. Cached PTHR46386 PAINT IBD examined; the underlying tree/MSA placement was not reconstructed. Supporting Evidence: PMID:11274163 we show that AIRE can activate the interferon beta minimal promoter in a transfection assay PMID:26084028 These missense PHD1 mutations suppressed gene expression driven by wild-type AIRE in a dominant-negative manner
GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: AIRE binds regulatory DNA motifs in vitro; native target choice has a different evidential scope. Reason: The PAINT IBD includes the human experimental annotation. PMID:11533054 used refolded recombinant human AIRE and synthetic EGR consensus, mutant competitor and selected ATTGGTTA/TTATTA oligonucleotides. Positive motif discrimination is real, and consensus regulatory DNA provides a defensible biochemical scope for the curated term. Retain this binding capacity as non-core: these assays do not identify the physiological AIRE target promoters or establish that sequence recognition drives thymic targeting. PMID:15649436 independently maps motif-binding regions; chromatin recruitment studies and the newer enhancer-condensate model establish additional targeting mechanisms, not a negative replication of the original EMSA. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN005329562 SUPPORTS TRANSFER Human experimental motif-binding evidence grounds this IBD; retain its biochemical capacity without claiming native target specificity. Cached PTHR46386 PAINT IBD examined; the underlying tree/MSA placement was not reconstructed. Supporting Evidence: PMID:11533054 AIRE dimers and tetramers, but not the monomers, can bind to G-doublets with the ATTGGTTA motif and the TTATTA-box.
GO:0002458 peripheral T cell tolerance induction	IBA GO_REF:0000033	UNDECIDED	Summary: Peripheral tolerogenic cells are established; the protein-specific donor mechanism remains unresolved. Reason: Mouse Q9Z0E3/Aire is the ortholog source; the MGI graph attaches this term to IDA J:208220, whose exact bibliographic mapping was not recovered. Independently, PMID:23993652 demonstrates tolerogenic mouse extrathymic Aire-expressing cells using an Aire-promoter-driven antigen transgene, and identifies human AIRE-positive lymph-node cells. This establishes the cell population and tolerance outcome, but the inspected experiments do not isolate the requirement for AIRE protein in the peripheral antigen-expression step. The gene-level participation and exact donor evidence remain unresolved; this is not evidence against peripheral AIRE function. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN002931439 UNRESOLVED Mouse IDA J:208220 is present; exact reference resolution and protein-specific peripheral mechanism remain unresolved. Cached PTHR46386 PAINT IBD examined; the underlying tree/MSA placement was not reconstructed.
GO:0002509 central tolerance induction to self antigen	IBA GO_REF:0000033	ACCEPT	Summary: AIRE supports central self-antigen tolerance. Reason: The PAINT assertion has human experimental grounding. AIRE-dependent transcription exposes developing thymocytes to otherwise tissue-restricted antigens, and disruptive human variants impair this program. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002931439 SUPPORTS TRANSFER Human central-tolerance evidence contributes to the IBD; this is expected experimental grounding. Cached PTHR46386 PAINT IBD examined; the underlying tree/MSA placement was not reconstructed. Supporting Evidence: PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity. PMID:26084028 These missense PHD1 mutations suppressed gene expression driven by wild-type AIRE in a dominant-negative manner
GO:0003682 chromatin binding	IBA GO_REF:0000033	ACCEPT	Summary: AIRE associates with chromatin through a histone-reader mechanism. Reason: Human PHD1 binds histone H3 and AIRE occupies target promoters in cellular chromatin assays. The ancestral chromatin-binding assertion is supported independently of any claim that AIRE is a sequence-specific native promoter selector. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN005329562 SUPPORTS TRANSFER Human chromatin-binding experiments ground the IBD. Cached PTHR46386 PAINT IBD examined; the underlying tree/MSA placement was not reconstructed. Supporting Evidence: PMID:18292755 in vivo AIRE binds to and activates promoters containing low levels of H3K4me3 in human embryonic kidney 293 cells. PMID:19446523 Here we report the three-dimensional solution structure of the first PHD finger of human AIRE bound to a histone H3 peptide.
GO:0006959 humoral immune response	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: AIRE has a B-cell-context role in regulating humoral antibody responses. Reason: The PAINT IBD is grounded in mouse IMP J:77873 (PMID:11854172); the full original donor assay remains unrecovered. Independent primary evidence in PMID:38260362 reports AIRE-AID interaction and B-cell antibody-diversification effects, including human-cell observations. The revised eLife reviewed-preprint version 2 (2026-09-21; DOI:10.7554/eLife.110530.2) and its positive public evidence assessment were inspected. This supports retention of the broad humoral-response annotation as a B-cell context, without making it the principal thymic core or retrospectively attributing the new mechanism to the original donor study. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002931439 UNRESOLVED Mouse IMP J:77873 maps to PMID:11854172; full assay scope remains unresolved. Cached PTHR46386 PAINT IBD examined; the underlying tree/MSA placement was not reconstructed. Independent B-cell evidence supports the target annotation; it does not resolve this original source mechanism.
GO:0042393 histone binding	IBA GO_REF:0000033	ACCEPT	Summary: AIRE PHD1 directly recognizes histone H3. Reason: The human biochemical annotation contributing to the PAINT IBD is corroborated by a human PHD1-H3 complex structure. H3K4 methylation sensitivity gives the binding its chromatin-reader specificity. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN005329562 SUPPORTS TRANSFER Human histone-binding experiments ground the IBD. Cached PTHR46386 PAINT IBD examined; the underlying tree/MSA placement was not reconstructed. Supporting Evidence: PMID:18292755 we show that AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger (AIRE-PHD1) and preferentially binds to non-methylated H3K4 (H3K4me0). PMID:19446523 Here we report the three-dimensional solution structure of the first PHD finger of human AIRE bound to a histone H3 peptide.
GO:0045060 negative thymic T cell selection	IBA GO_REF:0000033	ACCEPT	Summary: AIRE transcriptional activity contributes to negative thymic selection. Reason: AIRE supplies the transcriptional program for self-antigen presentation to developing T cells. Human functional genetics and the established thymic mechanism support the conserved process. The mouse graph confirms an IGI donor annotation at J:196474, although that record was not independently mapped to a paper in this audit; the broader mechanism is independently supported, not inferred from donor count. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002931439 SUPPORTS TRANSFER Mouse IGI J:196474 is present; precise bibliographic mapping was not recovered, while the conserved selection mechanism is independently supported. Cached PTHR46386 PAINT IBD examined; the underlying tree/MSA placement was not reconstructed. Supporting Evidence: PMID:19302042 The absence of Aire results in impaired clonal deletion of self-reactive thymocytes PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
GO:0097536 thymus epithelium morphogenesis	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Aire contributes to the medullary epithelial differentiation program. Reason: Mouse donor PMID:19015306 combines Aire-locus genetics with analysis of medullary epithelial organization and differentiation, including altered cell morphology and reduced terminal differentiation markers. This supports the existing developmental process in a thymic epithelial context. Retain it as non-core alongside the primary chromatin/transcription mechanism; do not recast the phenotype as a direct structural constituent activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002931439 SUPPORTS TRANSFER Mouse IMP J:141379 maps to PMID:19015306. Cached PTHR46386 PAINT IBD examined; the underlying tree/MSA placement was not reconstructed.
GO:2000410 regulation of thymocyte migration	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: AIRE-dependent thymic chemokines regulate thymocyte migration. Reason: Mouse donor PMID:19923453 reports reduced CCR4/CCR7 ligands and delayed CD4-positive thymocyte emigration in Aire-deficient animals, with chemokine and migration effects in gain-of-expression experiments. The regulator changes the thymic environment; it is not a motility motor in the migrating thymocyte. This existing regulatory process is defensible and context-specific. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002931439 SUPPORTS TRANSFER Mouse IMP J:157503 maps to PMID:19923453. Cached PTHR46386 PAINT IBD examined; the underlying tree/MSA placement was not reconstructed.
GO:0002507 tolerance induction	IEA GO_REF:0000117	MODIFY	Summary: Central self-antigen tolerance is the best-established specific tolerance process. Reason: The broad ARBA tolerance term is biologically sound. Human genetics and transcriptional assays justify refinement to central tolerance induction to self antigen. Do not also propose peripheral tolerance as a replacement while its source-specific participation remains unresolved. The ARBA rule predicates themselves were not inspected. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00088939 UNRESOLVED Exact rule predicates were not inspected; the annotation judgment uses independent human evidence. Proposed replacements: central tolerance induction to self antigen Supporting Evidence: PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
GO:0003677 DNA binding	IEA GO_REF:0000002	MODIFY	Summary: Recombinant AIRE shows sequence-selective DNA binding. Reason: The SAND/AIRE InterPro mappings supply broad DNA binding. Human competition EMSAs with recombinant AIRE establish discrimination between selected synthetic sequences and mutant competitors, supporting refinement to sequence-specific DNA binding. This biochemical capacity is distinct from demonstrating selection of endogenous RNA polymerase II regulatory regions. The latter qualification is preserved at the source-specific, non-core scope of the existing GO:0000977 annotations. This replacement refines an existing broad assertion; it does not add a NEW annotation or claim additional biological coverage from an ancestor term. Native promoter choice is not assigned to this assay. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR000770 SUPPORTS TRANSFER The AIRE/SAND sequence-family mapping supports broad DNA-binding capacity; recombinant human competition assays support the proposed specificity. InterPro:IPR008087 SUPPORTS TRANSFER The AIRE/SAND sequence-family mapping supports broad DNA-binding capacity; recombinant human competition assays support the proposed specificity. Proposed replacements: sequence-specific DNA binding Supporting Evidence: PMID:11533054 AIRE dimers and tetramers, but not the monomers, can bind to G-doublets with the ATTGGTTA motif and the TTATTA-box.
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: Multiple mappings agree with human nuclear localization. Reason: Mouse orthology, domain/family annotation and the UniProt nuclear location mapping converge on the broad nuclear compartment, independently established in human cell assays. No narrower nuclear substructure is imposed on every source. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR004865 SUPPORTS TRANSFER The identified AIRE family/domain mapping is independently corroborated by human localization. InterPro:IPR008087 SUPPORTS TRANSFER The identified AIRE family/domain mapping is independently corroborated by human localization. UniProtKB-SubCell:SL-0191 SUPPORTS TRANSFER UniProt subcellular-location vocabulary mapping agrees with direct human localization. UniProtKB:Q9Z0E3 SUPPORTS TRANSFER Mouse Aire identity is verified; direct human localization independently supports this broad compartment. The individual donor image was not inspected. ensembl:ENSMUSP00000114904 SUPPORTS TRANSFER Mouse Aire identity is verified; direct human localization independently supports this broad compartment. The individual donor image was not inspected. Supporting Evidence: PMID:11274163 At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies.
GO:0005737 cytoplasm	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: AIRE has a documented cytoplasmic, microtubule-associated pool. Reason: The combined mouse/family/location inference agrees with human localization experiments. Retain the broad cytoplasmic term for this observed pool without claiming it is the site of the central chromatin-regulatory function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: InterPro:IPR008087 SUPPORTS TRANSFER The identified AIRE family/domain mapping is independently corroborated by human localization. UniProtKB-SubCell:SL-0086 SUPPORTS TRANSFER UniProt subcellular-location vocabulary mapping agrees with direct human localization. UniProtKB:Q9Z0E3 SUPPORTS TRANSFER Mouse Aire identity is verified; direct human localization independently supports this broad compartment. The individual donor image was not inspected. ensembl:ENSMUSP00000114904 SUPPORTS TRANSFER Mouse Aire identity is verified; direct human localization independently supports this broad compartment. The individual donor image was not inspected. Supporting Evidence: PMID:11274163 At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies. PMID:14974083 Most of the mutations altered the nucleus-cytoplasm distribution of AIRE and disturbed its association with nuclear dots and cytoplasmic filaments.
GO:0006417 regulation of translation	IEA GO_REF:0000108	UNDECIDED	Summary: The recovered logical inference depends on a family MF whose functional basis remains unresolved. Reason: The GO_REF:0000108 source is GO:0045182, whose definition places it within regulation of translation. The local InterPro2GO snapshot (rules/arba/_interpro2go.txt, version 2025/09/01) explicitly assigns GO:0045182 to the AIRE entry IPR008087. The entry-to-term mapping is therefore recovered; its flat record contains no member-specific experiment or primary-evidence citation. GO:0045182 concerns regulation of polypeptide synthesis at the ribosome. The inspected AIRE transcription and pre-mRNA-processing studies establish different mechanisms, without testing or refuting a separate translation-regulatory capacity. A verified entry-level assignment alone does not resolve that biological scope. Retain UNDECIDED for the unresolved functional basis, not because the mapping file is inaccessible and not as deference to an experimental GOA row. Neither a demonstrated translation mechanism nor target-specific divergence from such a mechanism is established here. Propagation Review Root cause: UNRESOLVED Sources checked: GO:0045182 SOURCE WEAK OR INFERRED The source MF is explicitly assigned to IPR008087 in the local InterPro2GO file. GO:0045182 is part_of regulation of translation; the logical inference is traceable, while the AIRE functional basis of its input remains unresolved. Supporting Evidence: PMID:11274163 we show that AIRE can activate the interferon beta minimal promoter in a transfection assay
GO:0006955 immune response	IEA GO_REF:0000117	ACCEPT	Summary: Immune response is a broad description of AIRE-dependent immune regulation. Reason: The GO definition includes calibrated responses to internal threats, not only direct immune effector chemistry. AIRE-dependent self-antigen transcription and tolerance have that biological scope. Retain the broad automated process without inferring a particular antibody-producing mechanism; ARBA rule internals remain uninspected. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00026313 UNRESOLVED Exact rule predicates were not inspected; the annotation judgment uses independent human evidence. Supporting Evidence: PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
GO:0006959 humoral immune response	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: AIRE has a B-cell-context role in regulating humoral antibody responses. Reason: The local InterPro2GO snapshot explicitly maps IPR008087 to GO:0006959 at entry level; it does not provide member-specific experiments. Independent primary evidence in PMID:38260362 reports AIRE-AID interaction and B-cell antibody-diversification effects, including human-cell observations. The revised eLife reviewed-preprint version 2 (2026-09-21; DOI:10.7554/eLife.110530.2) and its positive public evidence assessment were inspected. This supports retention of the broad humoral-response annotation as a B-cell context, without making it the principal thymic core or retrospectively attributing the new mechanism to the original donor study. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: InterPro:IPR008087 SOURCE WEAK OR INFERRED The local version 2025/09/01 InterPro2GO record explicitly assigns GO:0006959 to IPR008087. This identifies the entry-level source; independent B-cell experiments support the target judgment without being retrospectively assigned as the historical mapping's evidence.
GO:0045182 translation regulator activity	IEA GO_REF:0000002	UNDECIDED	Summary: The translation-regulator mapping is recovered, but its biological support remains unresolved. Reason: The local InterPro2GO snapshot (rules/arba/_interpro2go.txt, version 2025/09/01) explicitly assigns GO:0045182 to the AIRE entry IPR008087. The entry-to-term mapping is therefore recovered; its flat record contains no member-specific experiment or primary-evidence citation. GO:0045182 concerns regulation of polypeptide synthesis at the ribosome. The inspected AIRE transcription and pre-mRNA-processing studies establish different mechanisms, without testing or refuting a separate translation-regulatory capacity. A verified entry-level assignment alone does not resolve that biological scope. Retain UNDECIDED for the unresolved functional basis, not because the mapping file is inaccessible and not as deference to an experimental GOA row. Neither a demonstrated translation mechanism nor target-specific divergence from such a mechanism is established here. Propagation Review Root cause: UNRESOLVED Sources checked: InterPro:IPR008087 SOURCE WEAK OR INFERRED The local version 2025/09/01 InterPro2GO record explicitly assigns GO:0045182 to IPR008087. The exact source mapping is recovered; the flat entry supplies no primary experimental citation that settles AIRE translation-regulatory activity. Supporting Evidence: PMID:11274163 we show that AIRE can activate the interferon beta minimal promoter in a transfection assay
GO:0045944 positive regulation of transcription by RNA polymerase II	IEA GO_REF:0000117	ACCEPT	Summary: Positive Pol II transcriptional regulation is directly established. Reason: The ARBA-derived process agrees with human reporter, promoter and target-gene assays. This biological judgment is independently grounded; the computational rule conditions were not reconstructed. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00027996 UNRESOLVED Exact rule predicates were not inspected; the annotation judgment uses independent human evidence. Supporting Evidence: PMID:11274163 we show that AIRE can activate the interferon beta minimal promoter in a transfection assay PMID:26084028 These missense PHD1 mutations suppressed gene expression driven by wild-type AIRE in a dominant-negative manner
GO:0005515 protein binding	IPI PMID:17474147 Systematic identification of SH3 domain-mediated human prote...	REMOVE	Summary: The NCK1 interaction annotation does not specify a molecular function. Reason: The GOA partner is NCK1 (P16333). PMID:17474147 describes SH3-domain peptide-array screening; its abstract does not identify which AIRE/NCK1 pair-level validations were performed. Remove the uninformative protein-binding term, without denying the interaction or treating the stated PLCG1 validation rate as AIRE-specific evidence. A bridging/adaptor function for AIRE is not established by this screen. Supporting Evidence: PMID:17474147 we attempted to simplify protein-protein interactions to the corresponding domain-ligand recognition and employed peptide arrays to identify such binding events.
GO:0005515 protein binding	IPI PMID:18292755 The autoimmune regulator PHD finger binds to non-methylated ...	MODIFY	Summary: The annotated histone H3 interaction has a specific histone-reader function. Reason: The P68431 partner is histone H3, and the source directly measures human AIRE-PHD1 binding to H3 with preference for H3K4me0. Replace generic protein binding with histone binding, already represented independently in the annotation set. Proposed replacements: histone binding Supporting Evidence: PMID:18292755 we show that AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger (AIRE-PHD1) and preferentially binds to non-methylated H3K4 (H3K4me0).
GO:0005515 protein binding	IPI PMID:20085707 Aire's partners in the molecular control of immunological to...	REMOVE	Summary: DNA-PK association is real but generic protein binding is uninformative. Reason: PMID:20085707 identifies DNA protein kinase and associated transcription/processing partners. The PRKDC (P78527) association does not make AIRE a kinase or establish an independent specific adaptor MF. Remove only the generic binding annotation; retain the association and recruitment biology in the synthesis. Supporting Evidence: PMID:20085707 One set of Aire interactions centered on DNA protein kinase and a group of proteins it partners with to resolve DNA double-stranded breaks or promote transcriptional elongation.
GO:0005515 protein binding	IPI PMID:20185822 DAXX is a new AIRE-interacting protein.	REMOVE	Summary: DAXX interaction modulates AIRE transcription but generic binding lacks functional specificity. Reason: The Q9UER7 partner is DAXX. The source reports yeast two-hybrid, mammalian coimmunoprecipitation/colocalization and repression of AIRE transactivation by DAXX. DAXX is the multifunctional adaptor described in the abstract; that description is not evidence that AIRE itself has adaptor activity. Removing generic protein binding does not reject the measured interaction. Supporting Evidence: PMID:20185822 The interaction between AIRE and DAXX has been validated by in vivo coimmunoprecipitation analysis and colocalization study in mammalian cells.
GO:0042802 identical protein binding	IPI PMID:15712268 Two novel mutations of the AIRE protein affecting its homodi...	ACCEPT	Summary: AIRE self-association is integral to its transcriptional assembly. Reason: PMID:15712268 tests human disease-mutant constructs against wild-type AIRE in yeast two-hybrid assays, showing loss of interaction. The self-association property is independently corroborated by oligomer studies and CARD-dependent transcriptional condensates; it is a mechanistic core property, not an incidental binding event. Supporting Evidence: PMID:15712268 With the two-hybrid assay in the yeast system we found that constructs containing the two mutations fail to interact with the wild-type protein. PMID:39169234 Specifically, CTT binds coactivators CBP/p300, recruiting Aire to CBP/p300-rich enhancers and promoting CARD-mediated condensate assembly.
GO:0042802 identical protein binding	IPI PMID:20185822 DAXX is a new AIRE-interacting protein.	ACCEPT	Summary: AIRE homomerization supports its functional transcriptional assembly. Reason: The GOA assertion records AIRE-AIRE interaction from PMID:20185822; the abstract foregrounds DAXX and does not expose the exact self-interaction panel. Retain curator attribution because self-association is independently measured in human AIRE studies and is mechanistically required for functional condensate assembly. Do not substitute the DAXX-AIRE interaction as proof of identical-protein binding. Supporting Evidence: PMID:15712268 With the two-hybrid assay in the yeast system we found that constructs containing the two mutations fail to interact with the wild-type protein. PMID:39169234 Specifically, CTT binds coactivators CBP/p300, recruiting Aire to CBP/p300-rich enhancers and promoting CARD-mediated condensate assembly.
GO:0042802 identical protein binding	IPI PMID:28540407 A new mutation site in the AIRE gene causes autoimmune polye...	ACCEPT	Summary: The human Q69P variant perturbs AIRE self-association. Reason: The cited yeast two-hybrid experiment compares mutant and normal AIRE and reports loss of their interaction. This provides source-specific support for the self-association property, with independent evidence linking CARD-mediated assembly to transcription. The disease assay does not define one invariant oligomer stoichiometry in human thymus. Supporting Evidence: PMID:28540407 the mutant AIRE protein could not interact with the normal AIRE protein. PMID:39169234 Specifically, CTT binds coactivators CBP/p300, recruiting Aire to CBP/p300-rich enhancers and promoting CARD-mediated condensate assembly.
GO:0002458 peripheral T cell tolerance induction	IEA GO_REF:0000107	UNDECIDED	Summary: Peripheral tolerogenic cells are established; the protein-specific donor mechanism remains unresolved. Reason: Mouse Q9Z0E3/Aire is the ortholog source; the MGI graph attaches this term to IDA J:208220, whose exact bibliographic mapping was not recovered. Independently, PMID:23993652 demonstrates tolerogenic mouse extrathymic Aire-expressing cells using an Aire-promoter-driven antigen transgene, and identifies human AIRE-positive lymph-node cells. This establishes the cell population and tolerance outcome, but the inspected experiments do not isolate the requirement for AIRE protein in the peripheral antigen-expression step. The gene-level participation and exact donor evidence remain unresolved; this is not evidence against peripheral AIRE function. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q9Z0E3 UNRESOLVED Peripheral process donor is mouse Aire; MGI IDA J:208220 bibliographic mapping remains unresolved. PMID:23993652 independently establishes the tolerogenic cell population, not an isolated protein requirement. ensembl:ENSMUSP00000114904 UNRESOLVED Peripheral process donor is mouse Aire; MGI IDA J:208220 bibliographic mapping remains unresolved. PMID:23993652 independently establishes the tolerogenic cell population, not an isolated protein requirement.
GO:0016604 nuclear body	IEA GO_REF:0000107	ACCEPT	Summary: Nuclear bodies are a functional AIRE localization. Reason: The mouse orthology transfer is corroborated by human nuclear-dot imaging and later human thymic epithelial cell condensates linked to transcription. The source term does not require every observed punctum to be transcriptionally active. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9Z0E3 SUPPORTS TRANSFER Mouse nuclear-body evidence maps to PMID:19015306 and is corroborated by direct human imaging. ensembl:ENSMUSP00000114904 SUPPORTS TRANSFER Mouse nuclear-body evidence maps to PMID:19015306 and is corroborated by direct human imaging. Supporting Evidence: PMID:11274163 At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies. PMID:39169234 Specifically, CTT binds coactivators CBP/p300, recruiting Aire to CBP/p300-rich enhancers and promoting CARD-mediated condensate assembly.
GO:0032722 positive regulation of chemokine production	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: AIRE positively regulates thymic chemokine production. Reason: The mouse donor PMID:19923453 includes chemokine expression/protein measurements and AIRE gain-of-expression effects. This is positive regulation by the transcriptional regulator, not chemokine activity of AIRE itself. Retain as a thymic context of the broader transcriptional function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9Z0E3 SUPPORTS TRANSFER Mouse chemokine-regulation source maps to IMP PMID:19923453. ensembl:ENSMUSP00000114904 SUPPORTS TRANSFER Mouse chemokine-regulation source maps to IMP PMID:19923453.
GO:0042802 identical protein binding	IEA GO_REF:0000120	ACCEPT	Summary: AIRE self-association is supported beyond the automatic mappings. Reason: The combined ARBA and mouse/Ensembl sources are consistent with direct human interaction and mutant assays. The ARBA rule was not inspected; independent human self-association and CARD-dependent transcriptional assembly justify the biological action without assuming identical oligomer stoichiometry across systems. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00027930 UNRESOLVED Exact rule predicates were not inspected; the annotation judgment uses independent human evidence. UniProtKB:Q9Z0E3 SUPPORTS TRANSFER Mouse self-association mapping is independently corroborated by human AIRE interaction studies; the exact mouse assay was not reconstituted here. ensembl:ENSMUSP00000114904 SUPPORTS TRANSFER Mouse self-association mapping is independently corroborated by human AIRE interaction studies; the exact mouse assay was not reconstituted here. Supporting Evidence: PMID:15712268 With the two-hybrid assay in the yeast system we found that constructs containing the two mutations fail to interact with the wild-type protein. PMID:39169234 Specifically, CTT binds coactivators CBP/p300, recruiting Aire to CBP/p300-rich enhancers and promoting CARD-mediated condensate assembly.
GO:0097536 thymus epithelium morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Aire contributes to the medullary epithelial differentiation program. Reason: Mouse donor PMID:19015306 combines Aire-locus genetics with analysis of medullary epithelial organization and differentiation, including altered cell morphology and reduced terminal differentiation markers. This supports the existing developmental process in a thymic epithelial context. Retain it as non-core alongside the primary chromatin/transcription mechanism; do not recast the phenotype as a direct structural constituent activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9Z0E3 SUPPORTS TRANSFER Mouse epithelial-development source maps to IMP PMID:19015306. ensembl:ENSMUSP00000114904 SUPPORTS TRANSFER Mouse epithelial-development source maps to IMP PMID:19015306.
GO:2000410 regulation of thymocyte migration	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: AIRE-dependent thymic chemokines regulate thymocyte migration. Reason: Mouse donor PMID:19923453 reports reduced CCR4/CCR7 ligands and delayed CD4-positive thymocyte emigration in Aire-deficient animals, with chemokine and migration effects in gain-of-expression experiments. The regulator changes the thymic environment; it is not a motility motor in the migrating thymocyte. This existing regulatory process is defensible and context-specific. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9Z0E3 SUPPORTS TRANSFER Mouse migration-regulation source maps to IMP PMID:19923453. ensembl:ENSMUSP00000114904 SUPPORTS TRANSFER Mouse migration-regulation source maps to IMP PMID:19923453.
GO:0005634 nucleus	EXP PMID:14974083 APECED-causing mutations in AIRE reveal the functional domai...	ACCEPT	Summary: The human variant study supports nuclear localization. Reason: PMID:14974083 directly studies localization and identifies mutation-dependent disturbance of nuclear dots and nucleus-cytoplasm distribution. Retain the existing broad nuclear annotation; mutant redistribution does not negate the wild-type nuclear pool. Supporting Evidence: PMID:14974083 Most of the mutations altered the nucleus-cytoplasm distribution of AIRE and disturbed its association with nuclear dots and cytoplasmic filaments.
GO:0005634 nucleus	EXP PMID:26084028 Dominant Mutations in the Autoimmune Regulator AIRE Are Asso...	ACCEPT	Summary: Nuclear localization is coherent with the human AIRE functional study. Reason: The experimental annotation is retained at curator scope. PMID:26084028 establishes dominant PHD1 effects on AIRE-dependent expression, while its cached abstract does not show the exact localization image. Nuclear AIRE is independently measured in PMID:11274163; lack of that image in the abstract is not negative localization evidence. Supporting Evidence: PMID:11274163 At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies. PMID:26084028 These missense PHD1 mutations suppressed gene expression driven by wild-type AIRE in a dominant-negative manner
GO:0005737 cytoplasm	EXP PMID:11274163 Subcellular localization of the autoimmune regulator protein...	KEEP AS NON CORE	Summary: Human AIRE is observed on cytoplasmic microtubular structures. Reason: This source explicitly reports the cytoskeletal pool along with nuclear dots. Its presence is retained as a secondary location, without asserting that it is artifactual or that transcription occurs there. Supporting Evidence: PMID:11274163 At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies.
GO:0005737 cytoplasm	EXP PMID:14974083 APECED-causing mutations in AIRE reveal the functional domai...	KEEP AS NON CORE	Summary: AIRE variant imaging documents nuclear and cytoplasmic distribution. Reason: The source reports changes in cytoplasmic filaments and nuclear dots across mutations. The broad cytoplasmic localization is supported; physiological regulation of that pool is distinct from the core nuclear transcriptional mechanism. Supporting Evidence: PMID:14974083 Most of the mutations altered the nucleus-cytoplasm distribution of AIRE and disturbed its association with nuclear dots and cytoplasmic filaments.
GO:0016604 nuclear body	ISS GO_REF:0000024	ACCEPT	Summary: The mouse nuclear-body transfer is independently corroborated in human cells. Reason: The mouse graph includes IDA J:141379 (PMID:19015306). Human nuclear-dot imaging and functional nuclear condensates support the same broad location; neither absence of a cached mouse full text nor variability among puncta establishes mislocalization. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9Z0E3 SUPPORTS TRANSFER Mouse nuclear-body IDA J:141379 maps to PMID:19015306, with independent human localization support. Supporting Evidence: PMID:11274163 At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies.
GO:0032722 positive regulation of chemokine production	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: AIRE positively regulates thymic chemokine production. Reason: The mouse donor PMID:19923453 includes chemokine expression/protein measurements and AIRE gain-of-expression effects. This is positive regulation by the transcriptional regulator, not chemokine activity of AIRE itself. Retain as a thymic context of the broader transcriptional function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9Z0E3 SUPPORTS TRANSFER Mouse chemokine-regulation source maps to IMP PMID:19923453.
GO:0097536 thymus epithelium morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Aire contributes to the medullary epithelial differentiation program. Reason: Mouse donor PMID:19015306 combines Aire-locus genetics with analysis of medullary epithelial organization and differentiation, including altered cell morphology and reduced terminal differentiation markers. This supports the existing developmental process in a thymic epithelial context. Retain it as non-core alongside the primary chromatin/transcription mechanism; do not recast the phenotype as a direct structural constituent activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9Z0E3 SUPPORTS TRANSFER Mouse epithelial-development source maps to IMP PMID:19015306.
GO:2000410 regulation of thymocyte migration	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: AIRE-dependent thymic chemokines regulate thymocyte migration. Reason: Mouse donor PMID:19923453 reports reduced CCR4/CCR7 ligands and delayed CD4-positive thymocyte emigration in Aire-deficient animals, with chemokine and migration effects in gain-of-expression experiments. The regulator changes the thymic environment; it is not a motility motor in the migrating thymocyte. This existing regulatory process is defensible and context-specific. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9Z0E3 SUPPORTS TRANSFER Mouse migration-regulation source maps to IMP PMID:19923453.
GO:0002458 peripheral T cell tolerance induction	ISS GO_REF:0000024	UNDECIDED	Summary: Peripheral tolerogenic cells are established; the protein-specific donor mechanism remains unresolved. Reason: Mouse Q9Z0E3/Aire is the ortholog source; the MGI graph attaches this term to IDA J:208220, whose exact bibliographic mapping was not recovered. Independently, PMID:23993652 demonstrates tolerogenic mouse extrathymic Aire-expressing cells using an Aire-promoter-driven antigen transgene, and identifies human AIRE-positive lymph-node cells. This establishes the cell population and tolerance outcome, but the inspected experiments do not isolate the requirement for AIRE protein in the peripheral antigen-expression step. The gene-level participation and exact donor evidence remain unresolved; this is not evidence against peripheral AIRE function. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q9Z0E3 UNRESOLVED Mouse peripheral process IDA J:208220 remains bibliographically unresolved; independent PMID:23993652 has cell-population/transgene scope.
GO:0002509 central tolerance induction to self antigen	IMP PMID:26084028 Dominant Mutations in the Autoimmune Regulator AIRE Are Asso...	ACCEPT	Summary: Human AIRE mutations impair central self-tolerance. Reason: The study identifies dominant PHD1 variants and shows suppression of wild-type-dependent target-gene expression. Together with the established self-antigen program, this supports the existing central tolerance annotation without equating every clinical autoimmune phenotype with a separate direct AIRE process. Supporting Evidence: PMID:26084028 These missense PHD1 mutations suppressed gene expression driven by wild-type AIRE in a dominant-negative manner PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
GO:0045893 positive regulation of DNA-templated transcription	IMP PMID:26084028 Dominant Mutations in the Autoimmune Regulator AIRE Are Asso...	MODIFY	Summary: Human variant assays support positive regulation of Pol II target transcription. Reason: The source measures expression driven by wild-type AIRE and its suppression by PHD1 variants. The corresponding Pol II transcription-regulation term is the informative specific process, corroborated by promoter and chromatin assays. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:26084028 These missense PHD1 mutations suppressed gene expression driven by wild-type AIRE in a dominant-negative manner PMID:18292755 in vivo AIRE binds to and activates promoters containing low levels of H3K4me3 in human embryonic kidney 293 cells.
GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding	IDA PMID:11533054 The autoimmune regulator (AIRE) is a DNA-binding protein.	KEEP AS NON CORE	Summary: Recombinant human AIRE binds regulatory DNA motifs in vitro. Reason: PMID:11533054 used refolded recombinant human AIRE and synthetic EGR consensus, mutant competitor and selected ATTGGTTA/TTATTA oligonucleotides. Positive motif discrimination is real, and consensus regulatory DNA provides a defensible biochemical scope for the curated term. Retain this binding capacity as non-core: these assays do not identify the physiological AIRE target promoters or establish that sequence recognition drives thymic targeting. PMID:15649436 independently maps motif-binding regions; chromatin recruitment studies and the newer enhancer-condensate model establish additional targeting mechanisms, not a negative replication of the original EMSA. Supporting Evidence: PMID:11533054 AIRE dimers and tetramers, but not the monomers, can bind to G-doublets with the ATTGGTTA motif and the TTATTA-box.
GO:0045944 positive regulation of transcription by RNA polymerase II	IMP PMID:11274163 Subcellular localization of the autoimmune regulator protein...	ACCEPT	Summary: AIRE activates a Pol II promoter reporter. Reason: PMID:11274163 directly demonstrates activation of the interferon-beta minimal promoter in transfected cells and tests domains involved in localization and activity. This supports transcriptional regulation, with reporter-system scope rather than a claim that interferon-beta is the universal physiological target. Supporting Evidence: PMID:11274163 we show that AIRE can activate the interferon beta minimal promoter in a transfection assay
GO:0003682 chromatin binding	IDA PMID:18292755 The autoimmune regulator PHD finger binds to non-methylated ...	ACCEPT	Summary: AIRE PHD1 participates in chromatin association. Reason: The source combines direct H3 binding with cellular promoter occupancy and activation at low-H3K4me3 loci. This establishes chromatin association without requiring direct DNA sequence recognition. Supporting Evidence: PMID:18292755 in vivo AIRE binds to and activates promoters containing low levels of H3K4me3 in human embryonic kidney 293 cells. PMID:18292755 we show that AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger (AIRE-PHD1) and preferentially binds to non-methylated H3K4 (H3K4me0).
GO:0006355 regulation of DNA-templated transcription	IDA PMID:18292755 The autoimmune regulator PHD finger binds to non-methylated ...	MODIFY	Summary: The measured transcriptional effect is positive and Pol II-associated. Reason: PMID:18292755 measures AIRE-dependent activation of selected human target genes and promoter association. Refine the unsigned DNA-templated transcription regulation term to positive regulation of transcription by RNA polymerase II. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:18292755 in vivo AIRE binds to and activates promoters containing low levels of H3K4me3 in human embryonic kidney 293 cells.
GO:0008270 zinc ion binding	IDA PMID:19446523 Structure and site-specific recognition of histone H3 by the...	ACCEPT	Summary: Structural zinc supports the core histone-reader domain. Reason: The human PHD1-H3 structure contains two zinc sites stabilizing the PHD fold. Zinc binding is integral to this core chromatin-reader architecture, rather than an unrelated pleiotropic activity. It does not imply a zinc-dependent catalytic reaction. Supporting Evidence: PMID:19446523 Here we report the three-dimensional solution structure of the first PHD finger of human AIRE bound to a histone H3 peptide.
GO:0042393 histone binding	IDA PMID:18292755 The autoimmune regulator PHD finger binds to non-methylated ...	ACCEPT	Summary: Human AIRE-PHD1 directly binds histone H3K4me0. Reason: Biochemical and biophysical assays demonstrate direct histone-tail recognition and methylation-sensitive affinity. This is a central molecular activity of AIRE. Supporting Evidence: PMID:18292755 we show that AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger (AIRE-PHD1) and preferentially binds to non-methylated H3K4 (H3K4me0).
GO:0042393 histone binding	IDA PMID:19446523 Structure and site-specific recognition of histone H3 by the...	ACCEPT	Summary: The human AIRE-PHD1-H3 complex defines specific histone contacts. Reason: Solution structural and binding experiments directly establish the H3-recognition interface of human PHD1. This supports the histone-reader activity independently of a particular native promoter-targeting model. Supporting Evidence: PMID:19446523 Here we report the three-dimensional solution structure of the first PHD finger of human AIRE bound to a histone H3 peptide.
GO:0045893 positive regulation of DNA-templated transcription	IDA PMID:18292755 The autoimmune regulator PHD finger binds to non-methylated ...	MODIFY	Summary: AIRE activates Pol II-transcribed target genes. Reason: The original experiments demonstrate positive transcriptional regulation in human cells. The Pol II-specific term captures the measured function more precisely than the broader positive DNA-templated transcription term. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:18292755 in vivo AIRE binds to and activates promoters containing low levels of H3K4me3 in human embryonic kidney 293 cells.
GO:0005634 nucleus	TAS PMID:9398839 Positional cloning of the APECED gene.	ACCEPT	Summary: The historical nuclear assignment is corroborated by later direct assays. Reason: PMID:9398839 identifies the human disease gene and transcription-factor-like motifs. Its abstract does not itself provide a localization image; later human nuclear-dot and chromatin experiments independently establish the compartment. Retain the traceable historical annotation without describing prediction as microscopy. Supporting Evidence: PMID:11274163 At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies.
GO:0006955 immune response	TAS PMID:9398840 An autoimmune disease, APECED, caused by mutations in a nove...	ACCEPT	Summary: AIRE participates in immune regulation through self-tolerance. Reason: The historical human genetic discovery establishes an immune disease connection, while subsequent human functional studies resolve the transcriptional tolerance mechanism. The broad immune-response term is compatible with calibrated immunity to internal threats and does not require AIRE to be an antibody or an immune effector enzyme. Supporting Evidence: PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
GO:0005634 nucleus	NAS PMID:9398840 An autoimmune disease, APECED, caused by mutations in a nove...	ACCEPT	Summary: The predicted nuclear protein was subsequently localized experimentally. Reason: The original source explicitly describes a putative nuclear protein. Direct human localization and chromatin studies independently confirm the nuclear compartment, so retain the NAS annotation with the historical prediction scope made explicit. Supporting Evidence: PMID:11274163 At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies.

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