Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	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. Reason: AIRE is a nuclear transcriptional regulator and multiple experimental and phylogenetic annotations support nuclear localization. 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:0045944 positive regulation of transcription by RNA polymerase II	IBA GO_REF:0000033	ACCEPT	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. Reason: AIRE positively regulates expression of tissue-restricted antigen and reporter genes; this Pol II transcription term is an appropriate core biological-process annotation. Supporting Evidence: PMID:11274163 we show that AIRE can activate the interferon beta minimal promoter in a transfection assay PMID:18292755 in vivo AIRE binds to and activates promoters containing low levels of H3K4me3
GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding	IBA GO_REF:0000033	ACCEPT	Summary: AIRE oligomers bind specific A/T-rich DNA motifs in vitro and are linked to promoter-level regulation of Pol II-transcribed genes. 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. 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	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
GO:0002509 central tolerance induction to self antigen	IBA GO_REF:0000033	ACCEPT	Summary: AIRE is crucial for central immunological tolerance and prevents autoimmunity by enabling thymic tissue-restricted antigen expression. Reason: Central tolerance induction is the defining biological role of AIRE in medullary thymic epithelial cells and is directly tied to AIRE disease mechanisms. Supporting Evidence: PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity. PMID:19302042 Aire plays an important role in T cell tolerance induction in the thymus
GO:0003682 chromatin binding	IBA GO_REF:0000033	ACCEPT	Summary: AIRE binds chromatin-associated histone H3 through PHD1 and engages promoters with low H3K4 trimethylation. Reason: AIRE binds histone H3 and chromatin at target promoters, so chromatin binding is an appropriate molecular-function annotation. Supporting Evidence: PMID:18292755 in vivo AIRE binds to and activates promoters containing low levels of H3K4me3 PMID:19446523 The structure reveals a detailed network of interactions between the protein and the amino-terminal residues of histone H3
GO:0006959 humoral immune response	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:9398840 This is the first report of a single-gene defect causing a systemic human autoimmune disease
GO:0042393 histone binding	IBA GO_REF:0000033	ACCEPT	Summary: AIRE PHD1 directly binds the N terminus of histone H3, preferentially recognizing non-methylated H3K4. Reason: Direct biochemical and structural work supports AIRE PHD1 binding to histone H3, especially H3K4me0. Supporting Evidence: PMID:19446523 The structure reveals a detailed network of interactions between the protein and the amino-terminal residues of histone H3 PMID:18292755 preferentially binds to non-methylated H3K4 (H3K4me0)
GO:0045060 negative thymic T cell selection	IBA GO_REF:0000033	ACCEPT	Summary: AIRE-dependent thymic antigen expression supports negative selection of autoreactive thymocytes, making this a core biological-process consequence. 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. Supporting Evidence: PMID:19446523 Mechanisms of central tolerance are mediated in part through the expression of a wide array of otherwise tissue-specific self-antigens PMID:19302042 The absence of Aire results in impaired clonal deletion of self-reactive thymocytes
GO:0097536 thymus epithelium morphogenesis	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: AIRE influences the mTEC differentiation program, but thymus epithelial morphogenesis is a developmental consequence rather than the core molecular function. Reason: AIRE affects mTEC differentiation and thymic epithelial programs, but morphogenesis is downstream/developmental relative to the core chromatin-transcription tolerance function. Supporting Evidence: PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
GO:2000410 regulation of thymocyte migration	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: AIRE regulation of thymic chemokine programs can alter thymocyte migration; this is a downstream thymic microenvironment role, not the core molecular function. Reason: This mouse-derived thymic microenvironment annotation is plausible, but it is a downstream consequence of AIRE transcriptional programs rather than the core function. Supporting Evidence: PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
GO:0002507 tolerance induction	IEA GO_REF:0000117	MODIFY	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. 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 replacements: central tolerance induction to self antigen peripheral T cell tolerance induction Supporting Evidence: PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity. PMID:19302042 Aire plays an important role in T cell tolerance induction in the thymus
GO:0003677 DNA binding	IEA GO_REF:0000002	MODIFY	Summary: The generic DNA-binding annotation is directionally correct but less informative than the existing sequence-specific transcription regulatory region binding term. Reason: Generic DNA binding is less informative than the existing RNA polymerase II transcription regulatory region sequence-specific DNA binding annotation. Proposed replacements: RNA polymerase II transcription regulatory region 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: 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. Reason: AIRE is a nuclear transcriptional regulator and multiple experimental and phylogenetic annotations support nuclear localization. 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 experimentally observed cytoplasmic and microtubule-associated localization, but this is secondary to its nuclear transcriptional regulatory function. Reason: Cytoplasmic/microtubule-associated AIRE localization is experimentally observed, but the primary biological role is nuclear chromatin and transcriptional regulation. 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	REMOVE	Summary: This annotation is an automated consequence of the InterPro translation-regulator mapping for AIRE and is not supported by the curated AIRE literature. 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. Supporting Evidence: PMID:11274163 we show that AIRE can activate the interferon beta minimal promoter in a transfection assay PMID:18292755 we show that AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger
GO:0006955 immune response	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	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. 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. 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	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:9398840 This is the first report of a single-gene defect causing a systemic human autoimmune disease
GO:0045182 translation regulator activity	IEA GO_REF:0000002	REMOVE	Summary: No direct translation-regulator molecular activity is supported for AIRE; the experimental evidence supports transcriptional and chromatin-regulatory activities instead. 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. Supporting Evidence: PMID:11274163 we show that AIRE can activate the interferon beta minimal promoter in a transfection assay PMID:18292755 we show that AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger
GO:0045944 positive regulation of transcription by RNA polymerase II	IEA GO_REF:0000117	ACCEPT	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. Reason: AIRE positively regulates expression of tissue-restricted antigen and reporter genes; this Pol II transcription term is an appropriate core biological-process annotation. Supporting Evidence: PMID:11274163 we show that AIRE can activate the interferon beta minimal promoter in a transfection assay PMID:18292755 in vivo AIRE binds to and activates promoters containing low levels of H3K4me3
GO:0005515 protein binding	IPI PMID:17474147 Systematic identification of SH3 domain-mediated human prote...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:17474147 a peptide target array composed of 1536 potential ligands
GO:0005515 protein binding	IPI PMID:18292755 The autoimmune regulator PHD finger binds to non-methylated ...	MARK AS OVER ANNOTATED	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. Reason: This interaction is better captured by the specific histone binding and chromatin binding annotations already present. Generic protein binding is over-annotation. Supporting Evidence: PMID:18292755 we show that AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger
GO:0005515 protein binding	IPI PMID:20085707 Aire's partners in the molecular control of immunological to...	MARK AS OVER ANNOTATED	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. Reason: The interaction screen identifies transcriptional, chromatin, nuclear transport, and RNA-processing partners; protein binding is too generic for the functional conclusion. Supporting Evidence: PMID:20085707 They fall into four major functional classes: nuclear transport, chromatin binding/structure, transcription and pre-mRNA processing.
GO:0005515 protein binding	IPI PMID:20185822 DAXX is a new AIRE-interacting protein.	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:20185822 led us to the discovery of a new AIRE-interacting protein called DAXX PMID:20185822 DAXX exerts a strong repressive role on the transcriptional activity of AIRE.
GO:0042802 identical protein binding	IPI PMID:15712268 Two novel mutations of the AIRE protein affecting its homodi...	KEEP AS NON CORE	Summary: AIRE homodimerization and higher-order oligomerization are experimentally supported and important for function, but they support rather than define the core transcriptional role. 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. Supporting Evidence: PMID:15712268 both mutations negatively affected the homodimerization properties of the AIRE protein
GO:0042802 identical protein binding	IPI PMID:20185822 DAXX is a new AIRE-interacting protein.	KEEP AS NON CORE	Summary: AIRE homodimerization and higher-order oligomerization are experimentally supported and important for function, but they support rather than define the core transcriptional role. 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. Supporting Evidence: PMID:15712268 both mutations negatively affected the homodimerization properties of the AIRE protein PMID:28540407 the mutant AIRE protein could not interact with the normal AIRE protein
GO:0042802 identical protein binding	IPI PMID:28540407 A new mutation site in the AIRE gene causes autoimmune polye...	KEEP AS NON CORE	Summary: AIRE homodimerization and higher-order oligomerization are experimentally supported and important for function, but they support rather than define the core transcriptional role. 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. Supporting Evidence: PMID:28540407 the mutant AIRE protein could not interact with the normal AIRE protein
GO:0002458 peripheral T cell tolerance induction	IEA GO_REF:0000107	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
GO:0016604 nuclear body	IEA GO_REF:0000107	ACCEPT	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. 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. 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:0032722 positive regulation of chemokine production	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Chemokine production is a downstream thymic epithelial program attributed largely by mouse orthology; keep as non-core for AIRE. Reason: Chemokine regulation is a downstream thymic epithelial effect and should be retained as non-core rather than elevated to AIRE core molecular function. Supporting Evidence: PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
GO:0042802 identical protein binding	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: AIRE homodimerization and higher-order oligomerization are experimentally supported and important for function, but they support rather than define the core transcriptional role. 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. Supporting Evidence: PMID:15712268 both mutations negatively affected the homodimerization properties of the AIRE protein
GO:0097536 thymus epithelium morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: AIRE influences the mTEC differentiation program, but thymus epithelial morphogenesis is a developmental consequence rather than the core molecular function. Reason: AIRE affects mTEC differentiation and thymic epithelial programs, but morphogenesis is downstream/developmental relative to the core chromatin-transcription tolerance function. Supporting Evidence: PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
GO:2000410 regulation of thymocyte migration	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: AIRE regulation of thymic chemokine programs can alter thymocyte migration; this is a downstream thymic microenvironment role, not the core molecular function. Reason: This mouse-derived thymic microenvironment annotation is plausible, but it is a downstream consequence of AIRE transcriptional programs rather than the core function. Supporting Evidence: PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
GO:0005634 nucleus	EXP PMID:14974083 APECED-causing mutations in AIRE reveal the functional domai...	ACCEPT	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. Reason: AIRE is a nuclear transcriptional regulator and multiple experimental and phylogenetic annotations support nuclear localization. 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:0005634 nucleus	EXP PMID:26084028 Dominant Mutations in the Autoimmune Regulator AIRE Are Asso...	ACCEPT	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. Reason: AIRE is a nuclear transcriptional regulator and multiple experimental and phylogenetic annotations support nuclear localization. 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:11274163 Subcellular localization of the autoimmune regulator protein...	KEEP AS NON CORE	Summary: AIRE has experimentally observed cytoplasmic and microtubule-associated localization, but this is secondary to its nuclear transcriptional regulatory function. Reason: Cytoplasmic/microtubule-associated AIRE localization is experimentally observed, but the primary biological role is nuclear chromatin and transcriptional regulation. 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:0005737 cytoplasm	EXP PMID:14974083 APECED-causing mutations in AIRE reveal the functional domai...	KEEP AS NON CORE	Summary: AIRE has experimentally observed cytoplasmic and microtubule-associated localization, but this is secondary to its nuclear transcriptional regulatory function. Reason: Cytoplasmic/microtubule-associated AIRE localization is experimentally observed, but the primary biological role is nuclear chromatin and transcriptional regulation. 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:0016604 nuclear body	ISS GO_REF:0000024	ACCEPT	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. 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. 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:0032722 positive regulation of chemokine production	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Chemokine production is a downstream thymic epithelial program attributed largely by mouse orthology; keep as non-core for AIRE. Reason: Chemokine regulation is a downstream thymic epithelial effect and should be retained as non-core rather than elevated to AIRE core molecular function. Supporting Evidence: PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
GO:0097536 thymus epithelium morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: AIRE influences the mTEC differentiation program, but thymus epithelial morphogenesis is a developmental consequence rather than the core molecular function. Reason: AIRE affects mTEC differentiation and thymic epithelial programs, but morphogenesis is downstream/developmental relative to the core chromatin-transcription tolerance function. Supporting Evidence: PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
GO:2000410 regulation of thymocyte migration	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: AIRE regulation of thymic chemokine programs can alter thymocyte migration; this is a downstream thymic microenvironment role, not the core molecular function. Reason: This mouse-derived thymic microenvironment annotation is plausible, but it is a downstream consequence of AIRE transcriptional programs rather than the core function. Supporting Evidence: PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
GO:0002458 peripheral T cell tolerance induction	ISS GO_REF:0000024	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
GO:0002509 central tolerance induction to self antigen	IMP PMID:26084028 Dominant Mutations in the Autoimmune Regulator AIRE Are Asso...	ACCEPT	Summary: AIRE is crucial for central immunological tolerance and prevents autoimmunity by enabling thymic tissue-restricted antigen expression. Reason: Central tolerance induction is the defining biological role of AIRE in medullary thymic epithelial cells and is directly tied to AIRE disease mechanisms. Supporting Evidence: PMID:26084028 The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity. PMID:19302042 Aire plays an important role in T cell tolerance induction in the thymus
GO:0045893 positive regulation of DNA-templated transcription	IMP PMID:26084028 Dominant Mutations in the Autoimmune Regulator AIRE Are Asso...	MODIFY	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. 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 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
GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding	IDA PMID:11533054 The autoimmune regulator (AIRE) is a DNA-binding protein.	ACCEPT	Summary: AIRE oligomers bind specific A/T-rich DNA motifs in vitro and are linked to promoter-level regulation of Pol II-transcribed genes. 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. 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 promotes expression of tissue-restricted antigen genes and activates reporter or target gene expression; the Pol II transcription-regulation annotation is well supported. Reason: AIRE positively regulates expression of tissue-restricted antigen and reporter genes; this Pol II transcription term is an appropriate core biological-process annotation. Supporting Evidence: PMID:11274163 we show that AIRE can activate the interferon beta minimal promoter in a transfection assay PMID:18292755 in vivo AIRE binds to and activates promoters containing low levels of H3K4me3
GO:0003682 chromatin binding	IDA PMID:18292755 The autoimmune regulator PHD finger binds to non-methylated ...	ACCEPT	Summary: AIRE binds chromatin-associated histone H3 through PHD1 and engages promoters with low H3K4 trimethylation. Reason: AIRE binds histone H3 and chromatin at target promoters, so chromatin binding is an appropriate molecular-function annotation. Supporting Evidence: PMID:18292755 in vivo AIRE binds to and activates promoters containing low levels of H3K4me3 PMID:19446523 The structure reveals a detailed network of interactions between the protein and the amino-terminal residues of histone H3
GO:0006355 regulation of DNA-templated transcription	IDA PMID:18292755 The autoimmune regulator PHD finger binds to non-methylated ...	MODIFY	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. 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 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
GO:0008270 zinc ion binding	IDA PMID:19446523 Structure and site-specific recognition of histone H3 by the...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:19446523 two Zn finger-containing plant homeodomain (PHD) finger motifs and a SAND
GO:0042393 histone binding	IDA PMID:18292755 The autoimmune regulator PHD finger binds to non-methylated ...	ACCEPT	Summary: AIRE PHD1 directly binds the N terminus of histone H3, preferentially recognizing non-methylated H3K4. Reason: Direct biochemical and structural work supports AIRE PHD1 binding to histone H3, especially H3K4me0. Supporting Evidence: PMID:18292755 we show that AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger PMID:18292755 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: AIRE PHD1 directly binds the N terminus of histone H3, preferentially recognizing non-methylated H3K4. Reason: Direct biochemical and structural work supports AIRE PHD1 binding to histone H3, especially H3K4me0. Supporting Evidence: PMID:19446523 The structure reveals a detailed network of interactions between the protein and the amino-terminal residues of histone H3 PMID:18292755 preferentially binds to non-methylated H3K4 (H3K4me0)
GO:0045893 positive regulation of DNA-templated transcription	IDA PMID:18292755 The autoimmune regulator PHD finger binds to non-methylated ...	MODIFY	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. 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 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
GO:0005634 nucleus	TAS PMID:9398839 Positional cloning of the APECED gene.	ACCEPT	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. Reason: AIRE is a nuclear transcriptional regulator and multiple experimental and phylogenetic annotations support nuclear localization. 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...	MARK AS OVER ANNOTATED	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. 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. 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: 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. Reason: AIRE is a nuclear transcriptional regulator and multiple experimental and phylogenetic annotations support nuclear localization. Supporting Evidence: PMID:9398840 encoding for a putative nuclear protein featuring two PHD-type zinc-finger motifs, suggesting its involvement in transcriptional regulation.

Core Functions

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:

histone binding

Directly Involved In:

positive regulation of transcription by RNA polymerase II central tolerance induction to self antigen

Cellular Locations:

nucleus nuclear body

Supporting Evidence:

PMID:18292755
we show that AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger
PMID:18292755
preferentially binds to non-methylated H3K4 (H3K4me0)
PMID:18292755
in vivo AIRE binds to and activates promoters containing low levels of H3K4me3
file:human/AIRE/AIRE-deep-research-manual.md
AIRE's core molecular features are chromatin engagement, histone H3 recognition, DNA binding, transcriptional activation, and oligomerization.
PMID:19302042
Aire plays an important role in T cell tolerance induction in the thymus
PMID:19302042
Transcriptional regulation by Aire is unusual in being very broad, context-dependent, probabilistic, and noisy.

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:

RNA polymerase II transcription regulatory region sequence-specific DNA binding

Directly Involved In:

positive regulation of transcription by RNA polymerase II negative thymic T cell selection

Cellular Locations:

nucleus

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.
PMID:26084028
The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity.
PMID:19302042
The absence of Aire results in impaired clonal deletion of self-reactive thymocytes
PMID:19302042
Transcriptional regulation by Aire is unusual in being very broad, context-dependent, probabilistic, and noisy.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:11274163

Subcellular localization of the autoimmune regulator protein. characterization of nuclear targeting and transcriptional activation domain.

PMID:11533054

The autoimmune regulator (AIRE) is a DNA-binding protein.

PMID:14974083

APECED-causing mutations in AIRE reveal the functional domains of the protein.

PMID:15712268

Two novel mutations of the AIRE protein affecting its homodimerization properties.

PMID:17474147

Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening.

PMID:18292755

The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression.

PMID:19302042

Aire.

PMID:19446523

Structure and site-specific recognition of histone H3 by the PHD finger of human autoimmune regulator.

PMID:20085707

Aire's partners in the molecular control of immunological tolerance.

PMID:20185822

DAXX is a new AIRE-interacting protein.

PMID:26084028

Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases.

PMID:28540407

A new mutation site in the AIRE gene causes autoimmune polyendocrine syndrome type 1.

PMID:9398839

Positional cloning of the APECED gene.

PMID:9398840

An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains.

file:human/AIRE/AIRE-notes.md

AIRE PN batch curation notes

file:human/AIRE/AIRE-deep-research-manual.md

AIRE manual deep research fallback

file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv

Proteostasis PN projected annotations report

Suggested Experiments

Experiment: 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.

Hypothesis: AIRE lacks intrinsic ubiquitin E3 ligase activity despite its PN UPS RING-variant/PHD placement.

Type: in vitro ubiquitination assay and cellular ubiquitinomics

Deep Research

Manual

(AIRE-deep-research-manual.md)

AIRE manual deep research fallback Manual

AIRE manual deep research fallback

Provenance

Falcon deep research was attempted with:

just deep-research-falcon human AIRE --fallback perplexity-lite

Falcon timed out after 600 seconds. The configured perplexity-lite fallback then failed with a Perplexity API 401 quota error, so no provider-generated deep research file was created. This manual fallback summarizes the cached publications, UniProt-derived context, and PN projection report used for the review.

Functional Synthesis

AIRE is a thymic self-tolerance regulator. Human disease genetics and mechanistic studies support AIRE as a nuclear transcriptional/chromatin regulator rather than a general immune effector. Dominant PHD1 mutations suppress gene expression driven by wild-type AIRE and are associated with organ-specific autoimmunity PMID:26084028. The broader disease role is thymic T cell tolerance induction and autoimmunity prevention [PMID:19302042 "Aire plays an important role in T cell tolerance induction in the thymus"; PMID:26084028 "The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity."].

AIRE's core molecular features are chromatin engagement, histone H3 recognition, DNA binding, transcriptional activation, and oligomerization. PHD1 selectively binds histone H3 and preferentially recognizes non-methylated H3K4 [PMID:18292755 "AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger"; PMID:18292755 "preferentially binds to non-methylated H3K4 (H3K4me0)"]. Structural work confirms an extensive AIRE PHD1-H3 interface PMID:19446523. AIRE oligomers bind A/T-rich DNA motifs PMID:11533054 and activate promoter/reporter expression [PMID:11274163 "AIRE can activate the interferon beta minimal promoter in a transfection assay"; PMID:18292755 "in vivo AIRE binds to and activates promoters containing low levels of H3K4me3"].

Cellular localization is primarily nuclear, with nuclear dot/nuclear-body-like localization and some cytoplasmic or microtubule-associated signal [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."].

PN Projection Assessment

The Proteostasis PN projection report assigns AIRE a candidate GO:0061630 ubiquitin protein ligase activity annotation from the path Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING variant|PHD|other [file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv]. This was not added as a new GO annotation. The projection is based on a UPS domain/family bucket, while the direct AIRE literature supports a PHD histone-reader/transcriptional regulator. The current evidence does not demonstrate direct ubiquitin transfer or intrinsic E3 ligase activity for AIRE.

GO Review Implications

Accept histone binding, chromatin binding, sequence-specific transcription regulatory region DNA binding, positive regulation of RNA polymerase II transcription, nuclear/nuclear-body localization, central tolerance induction, and negative thymic T cell selection.
Keep cytoplasmic localization, oligomerization, peripheral tolerance, thymic epithelial morphogenesis, thymocyte migration, chemokine-production regulation, and zinc ion binding as non-core or supporting features.
Mark generic protein binding, immune response, and humoral immune response as over-annotated where they obscure the more specific AIRE mechanism.
Remove automated translation-regulator annotations because the available evidence supports transcription/chromatin regulation rather than translation regulation.
Do not add GO:0061630 ubiquitin protein ligase activity without direct biochemical or cellular ubiquitination evidence.

📚 Additional Documentation

Notes

(AIRE-notes.md)

AIRE notes

2026-06-03 PN batch review

AIRE was fetched fresh for the human Proteostasis PN batch. Falcon deep research was attempted with just deep-research-falcon human AIRE --fallback perplexity-lite; Falcon timed out after 600 seconds and the perplexity-lite fallback failed with a Perplexity API 401 quota error. No provider-generated deep research file was created, so the GOA review was completed from the seeded human GOA, cached publications, UniProt, the PN projection report, and the manual fallback summary in AIRE-deep-research-manual.md.

Core biology: AIRE is best supported as a nuclear chromatin-associated transcriptional regulator for thymic self-tolerance. It promotes central tolerance and prevents autoimmunity PMID:26084028. Mechanistically, AIRE binds histone H3 through PHD1 and preferentially recognizes H3K4me0 [PMID:18292755 "AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger"; PMID:18292755 "preferentially binds to non-methylated H3K4 (H3K4me0)"], with structural support for the H3-binding interface PMID:19446523. AIRE also binds A/T-rich DNA motifs as oligomers PMID:11533054 and activates transcription in reporter/promoter contexts [PMID:11274163 "AIRE can activate the interferon beta minimal promoter in a transfection assay"; PMID:18292755 "in vivo AIRE binds to and activates promoters containing low levels of H3K4me3"].

PN projection: the PN report projects GO:0061630 ubiquitin protein ligase activity for AIRE from Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING variant|PHD|other [file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv]. I did not add this as a NEW annotation. The projection is a domain/family-bucket inference and the current AIRE evidence supports PHD histone-reader/chromatin/transcription functions, not catalytic ubiquitin transfer. AIRE's PHD domain is experimentally characterized as a histone-recognition zinc finger rather than an E3 ligase catalytic module PMID:19446523. I added a suggested question/experiment to test whether any direct E3 activity exists, but the current conservative curation decision is no GO ubiquitin ligase annotation.

Annotation decisions: broad protein binding entries were marked over-annotated because the useful biology is captured by histone binding, chromatin binding, DAXX/PRKDC/transcription-complex interactions, or oligomerization rather than generic binding. Automated translation regulator annotations were removed as unsupported. Broad immune/humoral immune response terms were marked over-annotated; specific tolerance, negative selection, chemokine/thymocyte migration, and thymus epithelial terms were kept according to evidence strength and core-vs-non-core status.

Pn Notes

(AIRE-pn-notes.md)

AIRE PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: O43918
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-03 (PR 1358)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/AIRE/AIRE-ai-review.yaml
AIGR review HTML: present - genes/human/AIRE/AIRE-ai-review.html
Gene notes: present - genes/human/AIRE/AIRE-notes.md
GOA TSV: present - genes/human/AIRE/AIRE-goa.tsv
UniProt record: present - genes/human/AIRE/AIRE-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/AIRE.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/AIRE.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/AIRE/AIRE-deep-research-manual.md

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 21; KEEP_AS_NON_CORE: 19; MARK_AS_OVER_ANNOTATED: 8; MODIFY: 5; REMOVE: 2

PN Consistency Summary

Consistency: Major contradiction between PN annotation and review. PN classifies AIRE as a catalytic E3 ligase (RING-variant/PHD) and projects GO:0061630 as a new GOA annotation. The review and notes treat AIRE strictly as a nuclear chromatin reader / Pol II transcriptional activator (PHD1 = H3K4me0 histone reader, PMID:18292755, 19446523) and explicitly decline to add GO:0061630, adding instead a suggested experiment to test for absent E3 activity. Deep research (manual) and review are internally consistent; the PN node is the outlier.
PN story / NEW pressure: PN asserts an E3-ligase MF not in GOA. GO:0061630 is a real term, but for AIRE this is a domain-bucket inference (PHD≈RING fold) not supported by the cached AIRE evidence, which characterizes the PHD as a histone-recognition module, not a catalytic ligase. Verdict: over-reaches as currently projected; treat as candidate requiring direct ubiquitin-transfer evidence, not an automatic ADD. (Some non-cached mouse literature reports AIRE E2-binding/E3-like activity — flag for full-text check before any REMOVE/ADD verdict; reviewer's conservative non-adoption is defensible.)
Evidence alignment: Divergent. PN cites PMIDs 14734522 and 15150263 (not in the review's reference list); review is built on the chromatin/transcription corpus (PMID:11533054, 18292755, 19446523, 26084028). No PMID overlap — the PN E3 case rests on references the review never adjudicated.
Verdict: PN E3-ligase placement/projection over-reaches for AIRE; review correctly withholds GO:0061630 pending direct evidence.

Full Consistency Review

UniProt: O43918 · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE
PN placement: Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING variant|PHD|other ; PN-node mapping: PHD/RING-variant subtype+type no_mapping; group (RING variant) mapped→GO:0061630 (ubiquitin protein ligase activity, propagate); class context_only (too_broad). Projection: GO:0061630 new_to_goa.
Consistency: Major contradiction between PN annotation and review. PN classifies AIRE as a catalytic E3 ligase (RING-variant/PHD) and projects GO:0061630 as a new GOA annotation. The review and notes treat AIRE strictly as a nuclear chromatin reader / Pol II transcriptional activator (PHD1 = H3K4me0 histone reader, PMID:18292755, 19446523) and explicitly decline to add GO:0061630, adding instead a suggested experiment to test for absent E3 activity. Deep research (manual) and review are internally consistent; the PN node is the outlier.
PN story / NEW pressure: PN asserts an E3-ligase MF not in GOA. GO:0061630 is a real term, but for AIRE this is a domain-bucket inference (PHD≈RING fold) not supported by the cached AIRE evidence, which characterizes the PHD as a histone-recognition module, not a catalytic ligase. Verdict: over-reaches as currently projected; treat as candidate requiring direct ubiquitin-transfer evidence, not an automatic ADD. (Some non-cached mouse literature reports AIRE E2-binding/E3-like activity — flag for full-text check before any REMOVE/ADD verdict; reviewer's conservative non-adoption is defensible.)
Mapping strategy: The RING-variant group→GO:0061630 propagation is biologically safe for canonical RING E3s but mis-fires on the PHD/"other" subtype that AIRE occupies. The subtype is already no_mapping; the issue is the parent group propagating catalytic activity down to a histone-reader PHD. Mapping should not project GO:0061630 onto PHD-only members lacking ligase evidence.
Evidence alignment: Divergent. PN cites PMIDs 14734522 and 15150263 (not in the review's reference list); review is built on the chromatin/transcription corpus (PMID:11533054, 18292755, 19446523, 26084028). No PMID overlap — the PN E3 case rests on references the review never adjudicated.
Verdict: PN E3-ligase placement/projection over-reaches for AIRE; review correctly withholds GO:0061630 pending direct evidence.
Recommended edits: [MAP] Mark AIRE (and other PHD-"other" members) as a gene-level exception to the RING-variant→GO:0061630 propagation, or downgrade that subtree to context_only, since PHD-reader members are not demonstrated catalytic E3s. [REF] Adjudicate PMID:14734522 and PMID:15150263 (the PN E3 references) — fetch full text and record a reference_review before any E3 verdict.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-03
review_yaml: genes/human/AIRE/AIRE-ai-review.yaml
PN workbook rows: 1

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | RING variant | PHD | other

UniProt: O43918
In branches: UPS
Signature domains: IPR001965
Auxiliary domains: (none)
PN references (titles):
- 14734522
- 15150263
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING variant|PHD|other
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING variant|PHD
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING variant
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This PN group is a catalytic ubiquitin E3 ligase bucket. The shared GO molecular-function target is ubiquitin protein ligase activity.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
  status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

GO:0061630 ubiquitin protein ligase activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING variant

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

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

AIRE

Gene Description

Existing Annotations Review

Core Functions

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.

AIRE oligomerizes and binds A/T-rich transcription regulatory DNA motifs, supporting promoter-level transcriptional regulation needed for thymic negative selection and self-tolerance.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Manual

AIRE manual deep research fallback

Provenance

Functional Synthesis

PN Projection Assessment

GO Review Implications

📚 Additional Documentation

Notes

AIRE notes

2026-06-03 PN batch review

Pn Notes

AIRE PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | RING variant | PHD | other

Projected GO annotations (1)

Note

📄 View Raw YAML