AHR encodes the aryl hydrocarbon receptor, a ligand-activated bHLH-PAS transcription factor that senses xenobiotic, dietary, microbiome-derived, and endogenous metabolites. In unstimulated cells AHR is mainly cytoplasmic in a chaperone-associated receptor complex; ligand binding promotes nuclear accumulation, heterodimerization with ARNT, binding to AHR/xenobiotic response elements, and regulation of RNA polymerase II target genes. AHR controls detoxification and xenobiotic-response programs such as CYP1A1 induction and also has context-dependent roles in immune regulation, intestinal epithelial responses, tumor immune escape, circadian cross-talk, development, and retinal biology.
Summary: nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
Summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
Reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
GO:0006357
regulation of transcription by RNA polymerase II
IBA
GO_REF:0000033
ACCEPT
Summary: regulation of transcription by RNA polymerase II is consistent with AHR acting as a ligand-activated transcription factor that regulates RNA polymerase II target genes after nuclear AHR:ARNT complex formation.
Reason: Transcriptional regulation is the central biological output of activated AHR. The term is broad in some cases, but the direction and process are supported by ligand-induced target gene activation and by cofactor/transactivation-domain evidence.
the acidic Q-rich region bound to components of the general transcription machinery
GO:0000976
transcription cis-regulatory region binding
IBA
GO_REF:0000033
ACCEPT
Summary: transcription cis-regulatory region binding is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
Reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
Summary: aryl hydrocarbon receptor complex is an appropriate AHR complex annotation. AHR forms cytosolic chaperone-associated complexes before activation and nuclear AHR:ARNT complexes after ligand-induced activation.
Reason: AHR complex membership is central to the receptor activation cycle. The receptor is maintained in a cytosolic HSP90/XAP2/p23 complex before activation and forms an AHR:ARNT DNA-bound complex in the nucleus after ligand activation.
Summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
Reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
Summary: nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
Summary: cytoplasm localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
GO:0006355
regulation of DNA-templated transcription
IEA
GO_REF:0000002
ACCEPT
Summary: regulation of DNA-templated transcription is consistent with AHR acting as a ligand-activated transcription factor that regulates RNA polymerase II target genes after nuclear AHR:ARNT complex formation.
Reason: Transcriptional regulation is the central biological output of activated AHR. The term is broad in some cases, but the direction and process are supported by ligand-induced target gene activation and by cofactor/transactivation-domain evidence.
Summary: xenobiotic metabolic process is a core AHR pathway outcome. AHR binds xenobiotic ligands such as TCDD/dioxin-related compounds and induces detoxification and response genes.
Reason: AHR does not enzymatically metabolize xenobiotics itself, but GO biological-process annotations correctly capture its upstream receptor/transcription-factor role in xenobiotic response and metabolism programs.
Summary: response to xenobiotic stimulus is a core AHR pathway outcome. AHR binds xenobiotic ligands such as TCDD/dioxin-related compounds and induces detoxification and response genes.
Reason: AHR does not enzymatically metabolize xenobiotics itself, but GO biological-process annotations correctly capture its upstream receptor/transcription-factor role in xenobiotic response and metabolism programs.
Summary: AHR signaling is an intracellular ligand-receptor pathway that couples xenobiotic, dietary, microbiome-derived, and endogenous metabolites to transcriptional responses.
Reason: The term is broad but correct for AHR. AHR activation by ligand causes nuclear translocation and transcriptional regulation of target genes including xenobiotic-response genes and immunometabolic targets.
IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid.
GO:0045893
positive regulation of DNA-templated transcription
IEA
GO_REF:0000117
ACCEPT
Summary: positive regulation of DNA-templated transcription is consistent with AHR acting as a ligand-activated transcription factor that regulates RNA polymerase II target genes after nuclear AHR:ARNT complex formation.
Reason: Transcriptional regulation is the central biological output of activated AHR. The term is broad in some cases, but the direction and process are supported by ligand-induced target gene activation and by cofactor/transactivation-domain evidence.
Summary: AHR dimerization is real, but the generic protein dimerization activity term should be replaced by the more informative heterodimerization term.
Reason: The biologically relevant dimer for activated AHR is AHR:ARNT. Existing human evidence specifically supports heterodimerization, so the generic dimerization annotation should be refined.
GO:0051239
regulation of multicellular organismal process
IEA
GO_REF:0000117
MARK AS OVER ANNOTATED
Summary: regulation of multicellular organismal process is biologically connected to AHR pleiotropy but is too broad or indirect for a core AHR annotation.
Reason: AHR affects development, cell cycle, apoptosis, and organism-level phenotypes through transcriptional programs, but these high-level process annotations risk implying a direct pathway role that is not supported by the specific evidence used here.
This review addresses novel findings relating to AHR functions that have resulted from experimental approaches markedly outside traditional receptor analyses.
GO:1904613
cellular response to 2,3,7,8-tetrachlorodibenzodioxine
IEA
GO_REF:0000117
ACCEPT
Summary: cellular response to 2,3,7,8-tetrachlorodibenzodioxine is a core AHR pathway outcome. AHR binds xenobiotic ligands such as TCDD/dioxin-related compounds and induces detoxification and response genes.
Reason: AHR does not enzymatically metabolize xenobiotics itself, but GO biological-process annotations correctly capture its upstream receptor/transcription-factor role in xenobiotic response and metabolism programs.
The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
GO:1990837
sequence-specific double-stranded DNA binding
IEA
GO_REF:0000117
ACCEPT
Summary: sequence-specific double-stranded DNA binding is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
Reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
IPI
PMID:10395741
Interactions of nuclear receptor coactivator/corepressor pro...
MODIFY
Summary: The original IPI evidence documents AHR/ARNT and coactivator/corepressor interactions, but protein binding is uninformative.
Reason: Replace the generic term with specific AHR heterodimerization and transcription cofactor-binding activities, which capture the relevant molecular interactions.
IPI
PMID:16257957
Regulation of transactivation function of the aryl hydrocarb...
MARK AS OVER ANNOTATED
Summary: This generic protein binding annotation reflects a viral EBNA3 interaction that modulates AHR transactivation, but it is not informative for the normal AHR core function.
Reason: The interaction may be experimentally real, but generic protein binding from a virus-specific perturbation should not be used as a functional summary of AHR.
IPI
PMID:28514442
Architecture of the human interactome defines protein commun...
MODIFY
Summary: The protein binding annotation reflects AHR interactions with ARNT/related bHLH-PAS partners, but the generic term should be refined.
Reason: AHR:ARNT or related heterodimerization is the informative activity supported by the interaction evidence. The review therefore proposes protein heterodimerization activity rather than generic protein binding.
Summary: The protein binding annotation reflects AHR interactions with ARNT/related bHLH-PAS partners, but the generic term should be refined.
Reason: AHR:ARNT or related heterodimerization is the informative activity supported by the interaction evidence. The review therefore proposes protein heterodimerization activity rather than generic protein binding.
IPI
PMID:9704006
Transcriptionally active heterodimer formation of an Arnt-li...
MODIFY
Summary: The protein binding annotation reflects AHR interactions with ARNT/related bHLH-PAS partners, but the generic term should be refined.
Reason: AHR:ARNT or related heterodimerization is the informative activity supported by the interaction evidence. The review therefore proposes protein heterodimerization activity rather than generic protein binding.
Summary: nucleoplasm localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
Summary: cytosol localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
Summary: xenobiotic metabolic process is a core AHR pathway outcome. AHR binds xenobiotic ligands such as TCDD/dioxin-related compounds and induces detoxification and response genes.
Reason: AHR does not enzymatically metabolize xenobiotics itself, but GO biological-process annotations correctly capture its upstream receptor/transcription-factor role in xenobiotic response and metabolism programs.
EXP
PMID:11259606
The hsp90 chaperone complex regulates intracellular localiza...
ACCEPT
Summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
Reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
Summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
Reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
Summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
Reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
EXP
PMID:34521881
The role of DNA-binding and ARNT dimerization on the nucleo-...
ACCEPT
Summary: cytoplasm localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
GO:0050728
negative regulation of inflammatory response
IDA
PMID:29454749
Microbiota-Derived Indole Metabolites Promote Human and Muri...
KEEP AS NON CORE
Summary: negative regulation of inflammatory response is supported as a downstream immunological context of AHR activation, especially through microbial or tryptophan-derived ligands.
Reason: AHR has substantial immune biology, but these process terms are cell-type- and disease-context-dependent outputs of AHR signaling rather than the core molecular function of the gene product.
Administration of indole metabolites showed prominent induction of IL-10R1 on cultured intestinal epithelia that was explained by activation of the aryl hydrocarbon receptor.
AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
IDA
PMID:34521881
The role of DNA-binding and ARNT dimerization on the nucleo-...
ACCEPT
Summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
Reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
IPI
PMID:34521881
The role of DNA-binding and ARNT dimerization on the nucleo-...
MODIFY
Summary: The protein binding annotation reflects AHR interactions with ARNT/related bHLH-PAS partners, but the generic term should be refined.
Reason: AHR:ARNT or related heterodimerization is the informative activity supported by the interaction evidence. The review therefore proposes protein heterodimerization activity rather than generic protein binding.
IDA
PMID:34521881
The role of DNA-binding and ARNT dimerization on the nucleo-...
ACCEPT
Summary: nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
IDA
PMID:34521881
The role of DNA-binding and ARNT dimerization on the nucleo-...
ACCEPT
Summary: response to xenobiotic stimulus is a core AHR pathway outcome. AHR binds xenobiotic ligands such as TCDD/dioxin-related compounds and induces detoxification and response genes.
Reason: AHR does not enzymatically metabolize xenobiotics itself, but GO biological-process annotations correctly capture its upstream receptor/transcription-factor role in xenobiotic response and metabolism programs.
IDA
PMID:34521881
The role of DNA-binding and ARNT dimerization on the nucleo-...
ACCEPT
Summary: nuclear aryl hydrocarbon receptor complex is an appropriate AHR complex annotation. AHR forms cytosolic chaperone-associated complexes before activation and nuclear AHR:ARNT complexes after ligand-induced activation.
Reason: AHR complex membership is central to the receptor activation cycle. The receptor is maintained in a cytosolic HSP90/XAP2/p23 complex before activation and forms an AHR:ARNT DNA-bound complex in the nucleus after ligand activation.
GO:0045944
positive regulation of transcription by RNA polymerase II
IDA
PMID:34521881
The role of DNA-binding and ARNT dimerization on the nucleo-...
ACCEPT
Summary: positive regulation of transcription by RNA polymerase II is consistent with AHR acting as a ligand-activated transcription factor that regulates RNA polymerase II target genes after nuclear AHR:ARNT complex formation.
Reason: Transcriptional regulation is the central biological output of activated AHR. The term is broad in some cases, but the direction and process are supported by ligand-induced target gene activation and by cofactor/transactivation-domain evidence.
The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
GO:1990837
sequence-specific double-stranded DNA binding
IDA
PMID:34521881
The role of DNA-binding and ARNT dimerization on the nucleo-...
ACCEPT
Summary: sequence-specific double-stranded DNA binding is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
Reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
IPI
PMID:15641800
Induced alpha-helix structure in the aryl hydrocarbon recept...
ACCEPT
Summary: TFIID-class transcription factor complex binding is supported by AHR transactivation-domain interactions with general transcription machinery and coactivators/coregulators.
Reason: These binding annotations are more informative than generic protein binding and connect directly to AHR transcriptional regulation. They should be retained as molecular-function annotations supporting the core transactivation mechanism.
These results confirmed functional and physical interactions of AhR/Arnt with ERAP 140 and SMRT in breast cancer cells.
GO:0071219
cellular response to molecule of bacterial origin
IDA
PMID:29454749
Microbiota-Derived Indole Metabolites Promote Human and Muri...
KEEP AS NON CORE
Summary: AHR responds to microbiota-derived indole metabolites and bacterial-origin molecules in intestinal epithelial/immune contexts.
Reason: This is a well supported physiological context for AHR signaling, but it is ligand/source-specific and should not displace the core receptor/transcription-factor function.
Administration of indole metabolites showed prominent induction of IL-10R1 on cultured intestinal epithelia that was explained by activation of the aryl hydrocarbon receptor.
IDA
PMID:28602820
Structural Basis for Aryl Hydrocarbon Receptor-Mediated Gene...
ACCEPT
Summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
Reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
IDA
PMID:28602820
Structural Basis for Aryl Hydrocarbon Receptor-Mediated Gene...
ACCEPT
Summary: nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
IDA
PMID:32866000
Endogenous Indole Pyruvate Pathway for Tryptophan Metabolism...
ACCEPT
Summary: nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
IPI
PMID:9079689
Characterization of a subset of the basic-helix-loop-helix-P...
ACCEPT
Summary: RNA polymerase II-specific DNA-binding transcription factor binding is supported by AHR transactivation-domain interactions with general transcription machinery and coactivators/coregulators.
Reason: These binding annotations are more informative than generic protein binding and connect directly to AHR transcriptional regulation. They should be retained as molecular-function annotations supporting the core transactivation mechanism.
IDA
PMID:32866000
Endogenous Indole Pyruvate Pathway for Tryptophan Metabolism...
ACCEPT
Summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
Reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
GO:0006357
regulation of transcription by RNA polymerase II
IDA
PMID:32818467
IL4I1 Is a Metabolic Immune Checkpoint that Activates the AH...
ACCEPT
Summary: regulation of transcription by RNA polymerase II is consistent with AHR acting as a ligand-activated transcription factor that regulates RNA polymerase II target genes after nuclear AHR:ARNT complex formation.
Reason: Transcriptional regulation is the central biological output of activated AHR. The term is broad in some cases, but the direction and process are supported by ligand-induced target gene activation and by cofactor/transactivation-domain evidence.
IDA
PMID:32818467
IL4I1 Is a Metabolic Immune Checkpoint that Activates the AH...
KEEP AS NON CORE
Summary: regulation of adaptive immune response is supported as a downstream immunological context of AHR activation, especially through microbial or tryptophan-derived ligands.
Reason: AHR has substantial immune biology, but these process terms are cell-type- and disease-context-dependent outputs of AHR signaling rather than the core molecular function of the gene product.
Administration of indole metabolites showed prominent induction of IL-10R1 on cultured intestinal epithelia that was explained by activation of the aryl hydrocarbon receptor.
AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
GO:0002841
negative regulation of T cell mediated immune response to tumor cell
IDA
PMID:32818467
IL4I1 Is a Metabolic Immune Checkpoint that Activates the AH...
KEEP AS NON CORE
Summary: negative regulation of T cell mediated immune response to tumor cell is supported as a downstream immunological context of AHR activation, especially through microbial or tryptophan-derived ligands.
Reason: AHR has substantial immune biology, but these process terms are cell-type- and disease-context-dependent outputs of AHR signaling rather than the core molecular function of the gene product.
Administration of indole metabolites showed prominent induction of IL-10R1 on cultured intestinal epithelia that was explained by activation of the aryl hydrocarbon receptor.
AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
IDA
PMID:32818467
IL4I1 Is a Metabolic Immune Checkpoint that Activates the AH...
ACCEPT
Summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
Reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
IDA
PMID:32818467
IL4I1 Is a Metabolic Immune Checkpoint that Activates the AH...
ACCEPT
Summary: nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
IDA
PMID:32818467
IL4I1 Is a Metabolic Immune Checkpoint that Activates the AH...
ACCEPT
Summary: cytoplasm localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
GO:0045944
positive regulation of transcription by RNA polymerase II
IDA
PMID:32818467
IL4I1 Is a Metabolic Immune Checkpoint that Activates the AH...
ACCEPT
Summary: positive regulation of transcription by RNA polymerase II is consistent with AHR acting as a ligand-activated transcription factor that regulates RNA polymerase II target genes after nuclear AHR:ARNT complex formation.
Reason: Transcriptional regulation is the central biological output of activated AHR. The term is broad in some cases, but the direction and process are supported by ligand-induced target gene activation and by cofactor/transactivation-domain evidence.
the acidic Q-rich region bound to components of the general transcription machinery
GO:0000987
cis-regulatory region sequence-specific DNA binding
IDA
PMID:23275542
2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymer...
ACCEPT
Summary: cis-regulatory region sequence-specific DNA binding is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
Reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
Summary: chromatin localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
Summary: DNA-binding transcription factor activity, RNA polymerase II-specific is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
Reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
Summary: Homodimerization is transferred by similarity and may occur, but it is not the core activated AHR mechanism in human cells.
Reason: The main supported functional complex is the AHR:ARNT heterodimer. Homodimerization should not be treated as the central AHR molecular function.
IDA
PMID:28602820
Structural Basis for Aryl Hydrocarbon Receptor-Mediated Gene...
ACCEPT
Summary: DNA-binding transcription factor activity is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
Reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
IPI
PMID:28602820
Structural Basis for Aryl Hydrocarbon Receptor-Mediated Gene...
MODIFY
Summary: The protein binding annotation reflects AHR interactions with ARNT/related bHLH-PAS partners, but the generic term should be refined.
Reason: AHR:ARNT or related heterodimerization is the informative activity supported by the interaction evidence. The review therefore proposes protein heterodimerization activity rather than generic protein binding.
The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
GO:1990837
sequence-specific double-stranded DNA binding
IDA
PMID:28602820
Structural Basis for Aryl Hydrocarbon Receptor-Mediated Gene...
ACCEPT
Summary: sequence-specific double-stranded DNA binding is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
Reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
IDA
PMID:17329248
Phosphodiesterase 2A forms a complex with the co-chaperone X...
ACCEPT
Summary: nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
IDA
PMID:17329248
Phosphodiesterase 2A forms a complex with the co-chaperone X...
ACCEPT
Summary: cytosol localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
IDA
PMID:17329248
Phosphodiesterase 2A forms a complex with the co-chaperone X...
KEEP AS NON CORE
Summary: cellular response to cAMP reflects a specific regulatory input into AHR trafficking through the PDE2A/XAP2/cAMP pathway rather than a core evolved function.
Reason: The cited study supports cAMP/forskolin effects on AHR nuclear translocation, but these stimulus-response annotations are context-specific and secondary to the receptor/transcription-factor function.
IDA
PMID:17329248
Phosphodiesterase 2A forms a complex with the co-chaperone X...
KEEP AS NON CORE
Summary: cellular response to forskolin reflects a specific regulatory input into AHR trafficking through the PDE2A/XAP2/cAMP pathway rather than a core evolved function.
Reason: The cited study supports cAMP/forskolin effects on AHR nuclear translocation, but these stimulus-response annotations are context-specific and secondary to the receptor/transcription-factor function.
Binding of PDE2A to XAP2 inhibited TCDD- and cAMP-induced nuclear translocation of AhR in Hepa1c1c7 hepatocytes.
GO:1904613
cellular response to 2,3,7,8-tetrachlorodibenzodioxine
IDA
PMID:17329248
Phosphodiesterase 2A forms a complex with the co-chaperone X...
ACCEPT
Summary: cellular response to 2,3,7,8-tetrachlorodibenzodioxine is a core AHR pathway outcome. AHR binds xenobiotic ligands such as TCDD/dioxin-related compounds and induces detoxification and response genes.
Reason: AHR does not enzymatically metabolize xenobiotics itself, but GO biological-process annotations correctly capture its upstream receptor/transcription-factor role in xenobiotic response and metabolism programs.
IPI
PMID:15641800
Induced alpha-helix structure in the aryl hydrocarbon recept...
ACCEPT
Summary: transcription coactivator binding is supported by AHR transactivation-domain interactions with general transcription machinery and coactivators/coregulators.
Reason: These binding annotations are more informative than generic protein binding and connect directly to AHR transcriptional regulation. They should be retained as molecular-function annotations supporting the core transactivation mechanism.
IPI
PMID:15641800
Induced alpha-helix structure in the aryl hydrocarbon recept...
ACCEPT
Summary: TBP-class protein binding is supported by AHR transactivation-domain interactions with general transcription machinery and coactivators/coregulators.
Reason: These binding annotations are more informative than generic protein binding and connect directly to AHR transcriptional regulation. They should be retained as molecular-function annotations supporting the core transactivation mechanism.
IMP
PMID:15641800
Induced alpha-helix structure in the aryl hydrocarbon recept...
MODIFY
Summary: The evidence concerns AHR interactions with transcriptional machinery and complex formation, but the term protein-containing complex is too generic for curation.
Reason: AHR participates in defined receptor/transcription complexes. Replacing the generic complex term with aryl hydrocarbon receptor complex better captures the biology supported by the cited interaction and transcriptional evidence.
Summary: nucleoplasm localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
Summary: nucleoplasm localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
Summary: nucleoplasm localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
Summary: cytosol localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
Summary: cytosol localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
IDA
PMID:7961644
Dioxin binding activities of polymorphic forms of mouse and ...
ACCEPT
Summary: response to toxic substance is a core AHR pathway outcome. AHR binds xenobiotic ligands such as TCDD/dioxin-related compounds and induces detoxification and response genes.
Reason: AHR does not enzymatically metabolize xenobiotics itself, but GO biological-process annotations correctly capture its upstream receptor/transcription-factor role in xenobiotic response and metabolism programs.
The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
GO:0032922
circadian regulation of gene expression
ISS
GO_REF:0000024
KEEP AS NON CORE
Summary: Circadian regulation is a supported secondary AHR context through bHLH-PAS transcription-factor cross-talk, but not the primary function.
Reason: AHR can intersect circadian transcriptional regulation, but the principal conserved function remains ligand-activated AHR:ARNT transcriptional control of xenobiotic/endogenous-ligand response genes.
GO:0045892
negative regulation of DNA-templated transcription
ISS
GO_REF:0000024
KEEP AS NON CORE
Summary: Negative regulation of DNA-templated transcription is supported in specific AHR contexts such as circadian/cross-talk and repressor interactions, but it is not the primary AHR output.
Reason: The core AHR role is ligand-activated transcriptional regulation, usually represented by positive target-gene activation. Negative regulation occurs in specific contexts and should be retained as a secondary, context-dependent function.
This review addresses novel findings relating to AHR functions that have resulted from experimental approaches markedly outside traditional receptor analyses.
GO:0045893
positive regulation of DNA-templated transcription
ISS
GO_REF:0000024
ACCEPT
Summary: positive regulation of DNA-templated transcription is consistent with AHR acting as a ligand-activated transcription factor that regulates RNA polymerase II target genes after nuclear AHR:ARNT complex formation.
Reason: Transcriptional regulation is the central biological output of activated AHR. The term is broad in some cases, but the direction and process are supported by ligand-induced target gene activation and by cofactor/transactivation-domain evidence.
Summary: AHR binds AHR response elements/dioxin response elements with an E-box-like bHLH-PAS recognition mode, but the E-box binding term is less exact for AHR than cis-regulatory region sequence-specific DNA binding.
Reason: The transferred mouse annotation is directionally related but should be generalized to the better supported AHR response element/cis-regulatory sequence-specific DNA binding activity for human AHR.
IDA
PMID:23275542
2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymer...
ACCEPT
Summary: nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
GO:0000976
transcription cis-regulatory region binding
IDA
PMID:15681594
Constitutive activation and environmental chemical induction...
ACCEPT
Summary: transcription cis-regulatory region binding is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
Reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
IDA
PMID:15681594
Constitutive activation and environmental chemical induction...
MODIFY
Summary: AHR DNA binding is real, but the generic DNA binding term is less precise than the available cis-regulatory-region sequence-specific DNA-binding terms.
Reason: The evidence supports AHR binding to AHR response elements/xenobiotic response elements in regulatory DNA, not undifferentiated DNA binding. A more specific cis-regulatory sequence-specific DNA-binding term should be used.
AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
IDA
PMID:15681594
Constitutive activation and environmental chemical induction...
ACCEPT
Summary: nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
IDA
PMID:15681594
Constitutive activation and environmental chemical induction...
ACCEPT
Summary: cytoplasm localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
GO:0006357
regulation of transcription by RNA polymerase II
IDA
PMID:15681594
Constitutive activation and environmental chemical induction...
ACCEPT
Summary: regulation of transcription by RNA polymerase II is consistent with AHR acting as a ligand-activated transcription factor that regulates RNA polymerase II target genes after nuclear AHR:ARNT complex formation.
Reason: Transcriptional regulation is the central biological output of activated AHR. The term is broad in some cases, but the direction and process are supported by ligand-induced target gene activation and by cofactor/transactivation-domain evidence.
IDA
PMID:15681594
Constitutive activation and environmental chemical induction...
MODIFY
Summary: The B-cell study supports AHR-dependent transcriptional/gene-expression regulation, but the term regulation of gene expression is very broad.
Reason: AHR is a DNA-binding transcription factor. The more precise RNA polymerase II transcription-regulation term better represents the evidence than generic gene-expression regulation.
AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
IDA
PMID:15681594
Constitutive activation and environmental chemical induction...
KEEP AS NON CORE
Summary: regulation of B cell proliferation is supported as a downstream immunological context of AHR activation, especially through microbial or tryptophan-derived ligands.
Reason: AHR has substantial immune biology, but these process terms are cell-type- and disease-context-dependent outputs of AHR signaling rather than the core molecular function of the gene product.
Administration of indole metabolites showed prominent induction of IL-10R1 on cultured intestinal epithelia that was explained by activation of the aryl hydrocarbon receptor.
AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
TAS
PMID:8246913
Cloning and expression of a human Ah receptor cDNA.
MODIFY
Summary: AHR DNA binding is real, but the generic DNA binding term is less precise than the available cis-regulatory-region sequence-specific DNA-binding terms.
Reason: The evidence supports AHR binding to AHR response elements/xenobiotic response elements in regulatory DNA, not undifferentiated DNA binding. A more specific cis-regulatory sequence-specific DNA-binding term should be used.
AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
TAS
PMID:8246913
Cloning and expression of a human Ah receptor cDNA.
ACCEPT
Summary: nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
NAS
PMID:19538249
The aryl hydrocarbon receptor: a perspective on potential ro...
MARK AS OVER ANNOTATED
Summary: blood vessel development is biologically connected to AHR pleiotropy but is too broad or indirect for a core AHR annotation.
Reason: AHR affects development, cell cycle, apoptosis, and organism-level phenotypes through transcriptional programs, but these high-level process annotations risk implying a direct pathway role that is not supported by the specific evidence used here.
This review addresses novel findings relating to AHR functions that have resulted from experimental approaches markedly outside traditional receptor analyses.
TAS
PMID:19538249
The aryl hydrocarbon receptor: a perspective on potential ro...
MODIFY
Summary: AHR DNA binding is real, but the generic DNA binding term is less precise than the available cis-regulatory-region sequence-specific DNA-binding terms.
Reason: The evidence supports AHR binding to AHR response elements/xenobiotic response elements in regulatory DNA, not undifferentiated DNA binding. A more specific cis-regulatory sequence-specific DNA-binding term should be used.
AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
TAS
PMID:19538249
The aryl hydrocarbon receptor: a perspective on potential ro...
MODIFY
Summary: AHR is part of transcriptional regulatory complexes, but this broad cellular-component term is less informative than the existing AHR complex terms.
Reason: The relevant complex is the AHR receptor/transcription-factor complex, particularly ligand-activated AHR:ARNT. The more specific AHR complex terms should be used rather than the generic transcription regulator complex term.
TAS
PMID:19538249
The aryl hydrocarbon receptor: a perspective on potential ro...
ACCEPT
Summary: xenobiotic metabolic process is a core AHR pathway outcome. AHR binds xenobiotic ligands such as TCDD/dioxin-related compounds and induces detoxification and response genes.
Reason: AHR does not enzymatically metabolize xenobiotics itself, but GO biological-process annotations correctly capture its upstream receptor/transcription-factor role in xenobiotic response and metabolism programs.
TAS
PMID:19538249
The aryl hydrocarbon receptor: a perspective on potential ro...
ACCEPT
Summary: cytosolic aryl hydrocarbon receptor complex is an appropriate AHR complex annotation. AHR forms cytosolic chaperone-associated complexes before activation and nuclear AHR:ARNT complexes after ligand-induced activation.
Reason: AHR complex membership is central to the receptor activation cycle. The receptor is maintained in a cytosolic HSP90/XAP2/p23 complex before activation and forms an AHR:ARNT DNA-bound complex in the nucleus after ligand activation.
IPI
PMID:9079689
Characterization of a subset of the basic-helix-loop-helix-P...
MODIFY
Summary: The protein binding annotation reflects AHR interactions with ARNT/related bHLH-PAS partners, but the generic term should be refined.
Reason: AHR:ARNT or related heterodimerization is the informative activity supported by the interaction evidence. The review therefore proposes protein heterodimerization activity rather than generic protein binding.
IDA
PMID:9079689
Characterization of a subset of the basic-helix-loop-helix-P...
ACCEPT
Summary: Hsp90 binding is a well-supported part of inactive AHR cytosolic complex formation and receptor trafficking control.
Reason: AHR binding to the HSP90 chaperone complex is mechanistically important for receptor conformation, cytoplasmic retention, and ligand-dependent nuclear import. This is an informative molecular-function annotation.
NAS
PMID:9170146
Human Ah receptor (AHR) gene: localization to 7p15 and sugge...
ACCEPT
Summary: DNA-binding transcription factor activity is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
Reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
IDA
PMID:11782478
Differential activities of murine single minded 1 (SIM1) and...
ACCEPT
Summary: DNA-binding transcription factor activity is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
Reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
IDA
PMID:10395741
Interactions of nuclear receptor coactivator/corepressor pro...
ACCEPT
Summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
Reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
IDA
PMID:10395741
Interactions of nuclear receptor coactivator/corepressor pro...
ACCEPT
Summary: nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.
Reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
GO:0006355
regulation of DNA-templated transcription
IDA
PMID:10395741
Interactions of nuclear receptor coactivator/corepressor pro...
ACCEPT
Summary: regulation of DNA-templated transcription is consistent with AHR acting as a ligand-activated transcription factor that regulates RNA polymerase II target genes after nuclear AHR:ARNT complex formation.
Reason: Transcriptional regulation is the central biological output of activated AHR. The term is broad in some cases, but the direction and process are supported by ligand-induced target gene activation and by cofactor/transactivation-domain evidence.
TAS
PMID:12213388
Role of the aryl hydrocarbon receptor in cell cycle regulati...
MARK AS OVER ANNOTATED
Summary: apoptotic process is biologically connected to AHR pleiotropy but is too broad or indirect for a core AHR annotation.
Reason: AHR affects development, cell cycle, apoptosis, and organism-level phenotypes through transcriptional programs, but these high-level process annotations risk implying a direct pathway role that is not supported by the specific evidence used here.
This review addresses novel findings relating to AHR functions that have resulted from experimental approaches markedly outside traditional receptor analyses.
IDA
PMID:7961644
Dioxin binding activities of polymorphic forms of mouse and ...
ACCEPT
Summary: response to xenobiotic stimulus is a core AHR pathway outcome. AHR binds xenobiotic ligands such as TCDD/dioxin-related compounds and induces detoxification and response genes.
Reason: AHR does not enzymatically metabolize xenobiotics itself, but GO biological-process annotations correctly capture its upstream receptor/transcription-factor role in xenobiotic response and metabolism programs.
The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
Core Functions
Primary function. AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding to cytoplasmic AHR promotes nuclear accumulation, ARNT heterodimerization, binding to AHR response elements, and regulation of xenobiotic/endogenous-ligand response genes.
Activated AHR heterodimerizes with ARNT to form the nuclear DNA-binding transcription-factor complex. This heterodimeric state is required for efficient AHR response element binding and target-gene activation. Crystal structures of ligand-bound AHR:ARNT:DNA complexes show an unconventional assembly with intimate PAS-B to PAS-B association between AHR and ARNT, with the AHR PAS-B domain serving as the principal ligand-binding pocket.
The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
Inactive AHR is maintained in a cytosolic chaperone-associated receptor complex. HSP90/p23/XAP2 interactions support ligand-binding conformation, cytoplasmic retention, and ligand-dependent nuclear import.
Differential activities of murine single minded 1 (SIM1) and SIM2 on a hypoxic response element. Cross-talk between basic helix-loop-helix/per-Arnt-Sim homology transcription factors.
2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase (TiPARP, ARTD14) is a mono-ADP-ribosyltransferase and repressor of aryl hydrocarbon receptor transactivation.
TIPARP directly interacts with and represses AHR, providing feedback regulation and evidence for AHR proteolytic degradation.
"TiPARP and AHR co-localized in the nucleus, directly interacted"
Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complex.
Crystal structures of AHR-ARNT-DNA complexes bound to six AHR ligands (tapinarof, FICZ, benzo[a]pyrene, beta-naphthoflavone, indigo, indirubin) reveal an unconventional assembly with intimate PAS-B to PAS-B association between AHR and ARNT.
The AHR PAS-B domain is the principal ligand-binding pocket, using eight conserved residues that dynamically rearrange to accommodate diverse ligands via hydrophobic and pi-pi interactions.
Ligand binding drives a structural transition of an AHR segment from chaperone engagement to ARNT-heterodimer stabilization, generating the transcriptionally competent AHR:ARNT DNA-bound complex.
The aryl hydrocarbon receptor: a rehabilitated target for therapeutic immune modulation.
AHR is a ligand-activated transcription factor that functions as a physiological regulator of both innate and adaptive immunity, modulated by diet, commensal flora, and metabolism in autoimmunity, cancer, and infection.
The AHR-activating drug tapinarof was approved for treatment of psoriasis, and AHR-targeting therapeutics are in clinical trials for inflammatory diseases, cancer, and infection, establishing AHR as a tractable therapeutic target.
Proteostasis PN ubiquitin proteasome system mapping set
file:human/AHR/AHR-notes.md
AHR manual review notes
Suggested Questions for Experts
Q: Does endogenous human AHR directly function as a CRL4/CUL4A-CUL4B substrate adaptor, or is the PN UPS placement better interpreted as broad complex/domain context plus AHR turnover rather than an AHR molecular function?
Q: Which immune and developmental AHR outputs should be treated as broadly physiological annotations versus ligand-, tissue-, or disease-specific non-core contexts?
Q: Now that AHR:ARNT:DNA structures define the PAS-B domain as the principal ligand-binding pocket and reveal a PAS-B/PAS-B heterodimer interface, should a ligand-binding molecular-function term (e.g., a small-molecule/xenobiotic sensor activity) be added to better capture AHR ligand recognition distinct from its DNA-binding and dimerization activities?
Suggested Experiments
Experiment: Reconstitute candidate DDB1-CUL4A/CUL4B-AHR/ARNT/TBL3 assemblies and test whether AHR directly recruits a defined substrate for ubiquitination, including CUL4 dependence, AHR mutant controls, and comparison with established DCAF substrate receptors.
Hypothesis: AHR should only receive GO:1990756 if it directly bridges a substrate to a CUL4 ubiquitin-ligase complex.
Type: in vitro ubiquitination and complex reconstitution
Experiment: Use endogenous-tagged AHR cells with proteasome inhibition, CUL4/DDB1 perturbation, and quantitative IP-MS/proximity labeling to distinguish AHR as a CUL4 substrate, a stable CRL4 complex component, or a substrate-recruiting adaptor.
Hypothesis: The PN AHR UPS projection may reflect regulated degradation of AHR rather than substrate-adaptor activity by AHR.
Type: endogenous proteomics and perturbation assay
Deep Research
Falcon
(AHR-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.FalconEdison Scientific Literature28 citations2 artifacts2026-06-07T04:12:03.546375
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Comprehensive research report: Human AHR (aryl hydrocarbon receptor; UniProt P35869) for functional annotation
1) Target verification (gene/protein identity)
The requested target AHR (UniProt P35869) is the human aryl hydrocarbon receptor, an evolutionarily conserved, ligand-activated basic helix–loop–helix/Per-ARNT-Sim (bHLH-PAS) transcription factor that senses diverse small molecules and converts those signals into context-dependent transcriptional programs. This identity is consistent across recent reviews and mechanistic papers that explicitly describe AHR as a bHLH-PAS transcription factor with bHLH, PAS-A, PAS-B (ligand-binding) and C-terminal transactivation regions; one review provides domain boundaries bHLH aa 33–87; PAS-A aa 111–273; PAS-B aa 275–386; TAD aa 490–805. (elson2023tumorsuppressivefunctionsof pages 2-4, bahman2024arylhydrocarbonreceptor pages 2-4)
2) Key concepts and definitions (current understanding)
Canonical AHR signaling is defined by a cytosol-to-nucleus activation cycle in which ligand binding triggers AHR nuclear translocation, heterodimerization with ARNT, binding to XRE/DRE DNA motifs, and transcriptional activation of a stereotyped gene set (“AHR gene battery”) including CYP1A1 (a canonical biomarker), CYP1A2, CYP1B1, AHRR, and TIPARP. (dawe2025thearylhydrocarbon pages 1-2, bahman2024arylhydrocarbonreceptor pages 2-4, elson2023tumorsuppressivefunctionsof pages 2-4)
Key sequence concepts used in the literature:
- XRE/DRE consensus: reported as 5′-TNGCGTG-3′ (also described with core GCGTG and examples including TTGCGTG). (polonio2025thearylhydrocarbon pages 4-6, bahman2024arylhydrocarbonreceptor pages 2-4, elson2023tumorsuppressivefunctionsof pages 2-4)
2.2 Ligand classes and “functional selectivity”
AHR is now viewed as a broad-spectrum small-molecule sensor activated by exogenous toxicants (e.g., dioxin-like compounds), dietary ligands, microbiome-derived indoles, and endogenous metabolites such as tryptophan pathway products; ligand affinity and metabolism shape signal duration (e.g., persistent activation by high-affinity ligands versus transient activation by rapidly metabolized ligands). (polonio2025thearylhydrocarbon pages 4-6, dawe2025thearylhydrocarbon pages 1-2, bahman2024arylhydrocarbonreceptor pages 2-4)
2.3 Non-canonical AHR signaling
Beyond XRE-driven transcription, AHR can:
- Engage transcription factor cross-talk (e.g., with NF-κB subunits RelA/RelB) and immunoregulatory mediators such as SOCS2, affecting inflammatory cytokine programs. (polonio2025thearylhydrocarbon pages 4-6)
- Function as part of a CUL4B-based E3 ubiquitin ligase complex (CUL4B^AHR) targeting proteins such as ER-α, AR, β-catenin, PPARγ for degradation, and can act as a cytoplasmic adaptor/scaffold linking SRC/JAK2 to kinase pathways (PI3K–AKT, MEK–ERK, YAP–ERK) in certain contexts. (xie2024uremictoxinsmediate pages 7-9)
3) Molecular mechanism, domains, and subcellular localization
3.1 Domain architecture and ligand recognition
AHR contains an N-terminal bHLH DNA-binding/dimerization domain followed by tandem PAS-A and PAS-B domains; PAS-B contains the principal ligand-binding pocket, while bHLH/PAS-A contribute critically to dimerization and DNA binding with ARNT. (diao2025structuralbasisfor pages 1-2, xie2024uremictoxinsmediate pages 7-9, bahman2024arylhydrocarbonreceptor pages 2-4)
3.2 Resting localization and cytosolic chaperone complex
In the unliganded state, AHR is predominantly cytoplasmic, held in a multiprotein chaperone complex that includes HSP90 (as a dimer), AIP/XAP2, and p23 (and can include SRC). This complex maintains AHR in a ligand-responsive state and constrains DNA-binding/nuclear trafficking until activation. (dawe2025thearylhydrocarbon pages 1-2, bahman2024arylhydrocarbonreceptor pages 2-4, elson2023tumorsuppressivefunctionsof pages 2-4)
3.3 Nuclear translocation, ARNT dimerization, and transcriptional output
Upon ligand binding (primarily at PAS-B), AHR undergoes conformational change with exposure of nuclear localization features, translocates to the nucleus, dimerizes with ARNT (HIF-1β), binds XRE/DRE motifs, recruits coactivators, and activates transcription. Canonical induced targets include CYP1A1/CYP1A2/CYP1B1, and immunoregulatory targets (context dependent) including IL-10 and IL-22 are also reported in mechanistic reviews. (polonio2025thearylhydrocarbon pages 4-6, xie2024uremictoxinsmediate pages 7-9, bahman2024arylhydrocarbonreceptor pages 2-4)
3.4 Negative feedback and pathway termination
Canonical negative feedback loops include:
- CYP1 enzymes that metabolize many AHR ligands (terminating signaling, but sometimes bioactivating procarcinogens).
- AHRR (aryl hydrocarbon receptor repressor), which competes for ARNT and dampens transcriptional activity.
- TIPARP/TiPARP, and proteasomal degradation of ligated AHR after dissociation from DNA. (dawe2025thearylhydrocarbon pages 1-2, polonio2025thearylhydrocarbon pages 4-6)
A schematic of this canonical cycle and its feedback mechanisms is shown in a figure from a recent skin-focused review. (dawe2025thearylhydrocarbon media 492c33b4)
4) Primary functional annotation: what AHR “does”
4.1 Primary function (functional core)
AHR’s best-supported primary function is as a ligand-activated transcription factor that couples chemical exposure (environmental, dietary, microbial, endogenous) to gene expression programs, with a conserved “detoxification” module that induces phase I xenobiotic-metabolizing enzymes (CYP1A1/1A2/1B1). (elson2023tumorsuppressivefunctionsof pages 2-4, bahman2024arylhydrocarbonreceptor pages 2-4)
In this context, AHR is not itself an enzyme; rather, it regulates enzymatic systems that metabolize xenobiotics and endogenous ligands. A key mechanistic example is that CYP1A1 can oxidize benzo[a]pyrene to carcinogenic metabolites (bioactivation) while also metabolizing certain endogenous/physiological ligands such as FICZ, shaping signaling dynamics. (dawe2025thearylhydrocarbon pages 1-2)
4.2 Key ligand categories (examples)
Exogenous/toxicological ligands: TCDD and polycyclic aromatic hydrocarbons (e.g., BaP) are prototypical AHR agonists used in mechanistic toxicology and risk assessment. (elson2023tumorsuppressivefunctionsof pages 2-4, bahman2024arylhydrocarbonreceptor pages 1-2)
Physiological/endogenous ligands: UV/tryptophan-derived FICZ, bilirubin, and kynurenine-pathway metabolites are described as endogenous AHR ligands that connect AHR to homeostatic immune/barrier functions. (dawe2025thearylhydrocarbon pages 1-2, bahman2024arylhydrocarbonreceptor pages 2-4)
Diet/microbiome-derived ligands: dietary indole precursors and microbiome metabolism of tryptophan generate AHR agonists (e.g., I3C-derived ligands and related indole species), contributing to mucosal and immune homeostasis. (polonio2025thearylhydrocarbon pages 4-6)
5) Pathways and biological processes (well-supported roles)
5.1 Xenobiotic sensing and metabolism
AHR is historically and mechanistically central to xenobiotic responses: ligand activation leads to AHR–ARNT binding at XREs and induction of CYP1 family enzymes and related detoxification modules. This canonical axis is foundational for understanding chemical toxicity and the biological effects of dioxin-like compounds. (elson2023tumorsuppressivefunctionsof pages 2-4, bahman2024arylhydrocarbonreceptor pages 1-2)
5.2 Barrier tissue homeostasis (skin as a clear example)
In barrier tissues such as skin, AHR integrates environmental inputs (including UV-associated ligands such as FICZ and microbiome-derived indoles) to promote barrier integrity and regulate inflammation, with the outcome depending strongly on ligand type, dose, and duration. (dawe2025thearylhydrocarbon pages 1-2)
5.3 Immunoregulation (innate/adaptive)
Recent immunology-focused reviews describe AHR as broadly expressed and functionally important in immune cells, where it regulates cytokine programs and tolerance/inflammation balance. Reported target outputs include cytokines such as IL-10, IL-17, and IL-22, and immunoregulatory modules such as CD39/CD73 (adenosinergic pathway) in certain settings. (bahman2024arylhydrocarbonreceptor pages 2-4, polonio2025thearylhydrocarbon pages 4-6)
A 2024 kidney-focused review frames AHR as a receptor for uremic toxins (endogenous ligands that accumulate with renal dysfunction) and describes both canonical transcriptional outputs (including CYP1 genes and immunoregulatory mediators) and non-canonical signaling, including CUL4B^AHR E3 ligase activity and cytoplasmic adaptor signaling that can engage kinase cascades. (xie2024uremictoxinsmediate pages 7-9)
6) Recent developments and latest research (emphasis on 2023–2024; include key 2025 structural advance)
6.1 2023–2024: improved mechanistic synthesis and expanded immunology context
Recent reviews consolidate: (i) the composition of the cytosolic chaperone complex (HSP90/AIP/p23), (ii) PAS-B-driven ligand binding and ARNT partnering, (iii) XRE/DRE consensus usage, and (iv) expanding immune-regulatory target repertoires that include cytokines and metabolic enzymes. (Publication dates: 2023-03; 2024-03; 2024-08) (elson2023tumorsuppressivefunctionsof pages 2-4, xie2024uremictoxinsmediate pages 7-9, bahman2024arylhydrocarbonreceptor pages 2-4)
A major structural advance solved AHR–ARNT–DNA complexes bound to six ligands (tapinarof, FICZ, BaP, BNF, indigo, indirubin), directly supporting structure-guided interpretation of ligand-dependent activation and informing rational development of AHR-targeting drugs. The study also reported strong homology between porcine and human AHR N-terminal regions (91% sequence identity; 66/71 interacting residues identical) in the crystallized constructs, supporting relevance to human AHR. (Publication date: 2025-02) (diao2025structuralbasisfor pages 1-2)
7) Current applications and real-world implementations
7.1 Toxicology and biomonitoring: CYP1A1 induction and XRE reporter assays
AHR biology is implemented widely in toxicology through:
- CYP1A1 induction as a canonical biomarker of AHR activation/exposure, repeatedly cited as a standard readout.
- XRE-driven reporter gene assays that operationalize AHR–ARNT binding to XREs to detect AHR agonists.
These implementations are grounded in the canonical mechanism (AHR–ARNT→XRE→CYP1A1) and are supported by mechanistic toxicology literature and reviews. (dawe2025thearylhydrocarbon pages 1-2, mosa2025identifyingarylhydrocarbona pages 29-34, elson2023tumorsuppressivefunctionsof pages 2-4)
Tapinarof 1% topical cream is a clinically implemented AHR agonist/modulator. In two phase 3 trials (PSOARING 1 and 2; n=683 adults), up to 40% of participants achieved PGA 0/1 at week 12 (vs up to 6% vehicle) and up to 47% achieved PASI-75 (vs up to 10% vehicle). A long-term extension (PSOARING 3) reported maintained response for ≥4 months after stopping treatment. Tapinarof was FDA-approved in May 2022 for adult plaque psoriasis (described as first-in-class AHR modulating drug). (dawe2025thearylhydrocarbon pages 7-9)
A related AHR modulator, benvitimod, is described as approved in China following phase 3 testing (with different formulation/dosing considerations noted). (dawe2025thearylhydrocarbon pages 7-9)
7.3 Therapeutics: new indications and oncology programs
Oncology AHR antagonism: IK-175 is an oral AHR inhibitor/antagonist in early clinical oncology development. A phase 1b HNSCC study combining IK-175 with nivolumab (NCT05472506) was withdrawn with actual enrollment 0. (NCT05472506 chunk 1)
8) Expert synthesis and interpretation (authoritative perspectives)
Recent authoritative reviews emphasize that AHR has transitioned from being viewed primarily as a “dioxin receptor” to a rehabilitated therapeutic target whose biology depends on ligand pharmacology (affinity, persistence, metabolism) and tissue context, motivating the concept of selective AHR modulators designed to capture beneficial barrier/immune effects while avoiding toxicological liabilities. (polonio2025thearylhydrocarbon pages 4-6, dawe2025thearylhydrocarbon pages 1-2)
9) Disease association evidence (database supplementation; interpret cautiously)
Open Targets reports disease-target association evidence linking AHR to atopic eczema and psoriasis, including clinical-stage evidence entries (including approval-stage items consistent with an approved AHR modulator in psoriasis). These database associations are supportive context but should be interpreted alongside primary clinical and mechanistic literature. (OpenTargets Search: -AHR)
The following table consolidates the most actionable functional-annotation facts, ligand examples, canonical targets, non-canonical modes, and real-world clinical/statistical highlights.
Aspect
Compact summary
Identity / verification
Human AHR / aryl hydrocarbon receptor, UniProt P35869; ligand-activated bHLH-PAS transcription factor. Domain organization reported as bHLH (DNA binding/dimerization), PAS-A (heterodimer stability), PAS-B (principal ligand-binding pocket), and C-terminal transactivation domain; one review gives boundaries bHLH aa 33–87, PAS-A aa 111–273, PAS-B aa 275–386, TAD aa 490–805. This matches the requested human AHR protein/domain context (bahman2024arylhydrocarbonreceptor pages 1-2, bahman2024arylhydrocarbonreceptor pages 2-4, elson2023tumorsuppressivefunctionsof pages 2-4, sahoo2025exploringtherole pages 2-4).
Resting state / localization
Inactive AHR is mainly cytosolic in a multiprotein complex with HSP90 (dimer), AIP/XAP2, p23, and c-SRC/SRC; HSP90 helps maintain ligand-responsive conformation and masks/exposes trafficking/DNA-binding functions until activation (dawe2025thearylhydrocarbon pages 1-2, diao2025structuralbasisfor pages 1-2, bahman2024arylhydrocarbonreceptor pages 2-4, elson2023tumorsuppressivefunctionsof pages 2-4, dawe2025thearylhydrocarbon media 492c33b4).
Canonical activation steps
Ligand binds PAS-B → conformational change → AIP dissociation / NLS exposure → nuclear import (importin-β / transportin pathways reported) → heterodimerization with ARNT (HIF-1β) → binding to XRE/DRE motifs (consensus reported as 5'-TNGCGTG-3', also core GCGTG/TTGCGTG) → transcription of the “AHR gene battery”; negative feedback via AHRR, TIPARP/TiPARP, CYP1-mediated ligand metabolism, and proteasomal degradation (dawe2025thearylhydrocarbon pages 1-2, xie2024uremictoxinsmediate pages 7-9, polonio2025thearylhydrocarbon pages 4-6, bahman2024arylhydrocarbonreceptor pages 2-4, elson2023tumorsuppressivefunctionsof pages 2-4, dawe2025thearylhydrocarbon media 492c33b4).
Structural advance
2025 structural work solved AHR-ARNT-DNA complexes with 6 ligands (tapinarof, FICZ, benzo[a]pyrene, β-naphthoflavone, indigo, indirubin) and described a ligand-driven transition from chaperone engagement to ARNT-stabilized active complex; porcine and human N-terminal halves showed 91% sequence identity and 66/71 interacting residues identical (diao2025structuralbasisfor pages 1-2).
Key exogenous ligands
Classic xenobiotic/toxic ligands include TCDD, benzo[a]pyrene (BaP), β-naphthoflavone (BNF); therapeutic/experimental agonists include tapinarof and indirubin/indigo. High-affinity ligands such as TCDD can produce prolonged signaling (diao2025structuralbasisfor pages 1-2, polonio2025thearylhydrocarbon pages 4-6, elson2023tumorsuppressivefunctionsof pages 2-4).
Key endogenous / physiological ligands
Endogenous and host-/microbiome-derived agonists include FICZ (UV/tryptophan photoproduct), kynurenine (Kyn), kynurenic acid (KYNA), bilirubin, dietary indole precursors such as indole-3-carbinol (I3C) and metabolites such as DIM/ICZ/TEACOPs, plus microbial indole pathways linking AHR to barrier and immune homeostasis (dawe2025thearylhydrocarbon pages 1-2, polonio2025thearylhydrocarbon pages 4-6, bahman2024arylhydrocarbonreceptor pages 2-4).
Primary canonical target genes
Strongly recurrent transcriptional targets: CYP1A1, CYP1A2, CYP1B1 (canonical biomarkers of activation), plus AHRR and TIPARP/TiPARP; additional reported targets include NQO1, TDO2, IDO1, IL10, IL17, IL22, CD39, CD73, and some ABC transporters, depending on cell context (dawe2025thearylhydrocarbon pages 1-2, polonio2025thearylhydrocarbon pages 4-6, bahman2024arylhydrocarbonreceptor pages 2-4, elson2023tumorsuppressivefunctionsof pages 2-4).
Core biological function
Best-supported primary function is as a small-molecule sensor and transcriptional regulator coupling exposure to environmental, dietary, microbial, and endogenous metabolites to xenobiotic metabolism, especially induction of phase I enzymes that metabolize ligands and other substrates; this also creates feedback and, in some cases, bioactivation of procarcinogens (e.g., BaP → BPDE) (dawe2025thearylhydrocarbon pages 1-2, bahman2024arylhydrocarbonreceptor pages 1-2, elson2023tumorsuppressivefunctionsof pages 2-4).
Barrier / immune roles
AHR has well-supported roles in skin and gut barrier maintenance and immune regulation, especially through tryptophan/microbiome ligands and cytokine programs such as IL-22 and IL-10; reviews emphasize strong activity in barrier tissues (skin, gut, lung) and immune cells including Th17/ILC3-associated programs (dawe2025thearylhydrocarbon pages 1-2, diao2025structuralbasisfor pages 1-2, bahman2024arylhydrocarbonreceptor pages 1-2, bahman2024arylhydrocarbonreceptor pages 2-4).
Activated AHR can assemble a CUL4B-based E3 ubiquitin ligase (CUL4B^AHR) that promotes degradation of ER-α, AR, β-catenin, PPARγ; cytoplasmic ligand-AHR can also act as an adaptor/scaffold linking SRC/JAK2 to PI3K-AKT, MEK-ERK, and YAP-ERK signaling. A dose-dependent switch between transcriptional and E3-ligase functions has been reported for some ligands (e.g., indoxyl sulfate) (xie2024uremictoxinsmediate pages 7-9).
Real-world application: approved dermatology drug
Tapinarof 1% cream is a topical AHR agonist/modulator. Two phase 3 psoriasis trials (PSOARING 1 and 2) enrolled 683 adults; by week 12, up to 40% achieved PGA 0/1 versus up to 6% vehicle, and up to 47% achieved PASI-75 versus up to 10% vehicle. FDA approval: May 2022 for adult plaque psoriasis; described as the first-in-class AHR-modulating drug. Long-term extension (PSOARING 3) reported maintained response for at least 4 months off treatment (dawe2025thearylhydrocarbon pages 7-9, polonio2025thearylhydrocarbon pages 9-11, dawe2025thearylhydrocarbon pages 1-2).
Additional dermatology implementation
Benvitimod (tapinarof-related AHR modulator) is noted as approved in China after phase 3 testing, with different formulation/dosing from tapinarof (dawe2025thearylhydrocarbon pages 7-9).
Ongoing / new indication trial for tapinarof
NCT06661213: topical tapinarof for cutaneous lupus erythematosus; Early Phase 1, open-label, enrolling by invitation; estimated enrollment 10, started 2025-04-03; evaluates Week-16 CLA/CLASI activity outcomes (NCT06661213 chunk 1).
Oncology antagonist program
IK-175 is an oral AHR antagonist/inhibitor in oncology development. NCT04200963 (phase 1a/b, single agent and with nivolumab in advanced/metastatic solid tumors and urothelial carcinoma) is listed as completed with enrollment 78 in trial-search results; broader review literature cites IK-175 as part of early-stage oncology programs (polonio2025thearylhydrocarbon pages 16-18).
Withdrawn IK-175 study
NCT05472506: IK-175 + nivolumab for primary PD-1-resistant metastatic/recurrent HNSCC; Phase 1b, randomized dose-expansion, but withdrawn by sponsor decision with actual enrollment 0 and no results reported (NCT05472506 chunk 1).
Broader development landscape
A 2025 drug-discovery review notes BAY2416964 and IK-175 in oncology and states ~20 additional trials of AHR modulation (endogenous, dietary, synthetic ligands), underscoring active translational exploitation of AHR as a therapeutic node (polonio2025thearylhydrocarbon pages 16-18).
Table: This table condenses verified functional annotation for human AHR (UniProt P35869), covering domain architecture, canonical and non-canonical signaling, major ligand classes, target genes, and current translational applications. It also captures key quantitative clinical figures for tapinarof and IK-175 that are useful for rapid reference.
Key figure: canonical pathway schematic
A pathway schematic illustrating the canonical cytosolic chaperone complex, ligand-triggered nuclear translocation, ARNT dimerization, XRE binding, and major feedback loops (AHRR/CYP1/TiPARP) is available here. (dawe2025thearylhydrocarbon media 492c33b4)
URLs and publication dates (selected high-priority sources used)
Bahman F, et al. Frontiers in Immunology (2024-08). https://doi.org/10.3389/fimmu.2024.1421346 (bahman2024arylhydrocarbonreceptor pages 1-2)
Dawe HR, Di Meglio P. International Journal of Molecular Sciences (2025-02). https://doi.org/10.3390/ijms26041618 (dawe2025thearylhydrocarbon pages 1-2)
(elson2023tumorsuppressivefunctionsof pages 2-4): Daniel J. Elson and Siva K. Kolluri. Tumor-suppressive functions of the aryl hydrocarbon receptor (ahr) and ahr as a therapeutic target in cancer. Biology, 12:526, Mar 2023. URL: https://doi.org/10.3390/biology12040526, doi:10.3390/biology12040526. This article has 37 citations.
(bahman2024arylhydrocarbonreceptor pages 2-4): Fatemah Bahman, Khubaib Choudhry, Fatema Al-Rashed, Fahd Al-Mulla, Sardar Sindhu, and Rasheed Ahmad. Aryl hydrocarbon receptor: current perspectives on key signaling partners and immunoregulatory role in inflammatory diseases. Frontiers in Immunology, Aug 2024. URL: https://doi.org/10.3389/fimmu.2024.1421346, doi:10.3389/fimmu.2024.1421346. This article has 83 citations and is from a peer-reviewed journal.
(dawe2025thearylhydrocarbon pages 1-2): Hannah R. Dawe and Paola Di Meglio. The aryl hydrocarbon receptor (ahr): peacekeeper of the skin. International Journal of Molecular Sciences, 26:1618, Feb 2025. URL: https://doi.org/10.3390/ijms26041618, doi:10.3390/ijms26041618. This article has 27 citations.
(polonio2025thearylhydrocarbon pages 4-6): Carolina M. Polonio, Kimberly A. McHale, David H. Sherr, David Rubenstein, and Francisco J. Quintana. The aryl hydrocarbon receptor: a rehabilitated target for therapeutic immune modulation. Nature reviews. Drug discovery, 24:610-630, Apr 2025. URL: https://doi.org/10.1038/s41573-025-01172-x, doi:10.1038/s41573-025-01172-x. This article has 73 citations.
(xie2024uremictoxinsmediate pages 7-9): Hongyan Xie, Ninghao Yang, Chen Yu, and Limin Lu. Uremic toxins mediate kidney diseases: the role of aryl hydrocarbon receptor. Cellular & Molecular Biology Letters, Mar 2024. URL: https://doi.org/10.1186/s11658-024-00550-4, doi:10.1186/s11658-024-00550-4. This article has 30 citations and is from a peer-reviewed journal.
(diao2025structuralbasisfor pages 1-2): Xiaotong Diao, Qinghong Shang, Mengqi Guo, Yubin Huang, Meina Zhang, Xiaoyu Chen, Yinping Liang, Xiangnan Sun, Fan Zhou, Jingjing Zhuang, Shuang-Jiang Liu, Christoph F. A. Vogel, Fraydoon Rastinejad, and Dalei Wu. Structural basis for the ligand-dependent activation of heterodimeric ahr-arnt complex. Nature Communications, Feb 2025. URL: https://doi.org/10.1038/s41467-025-56574-7, doi:10.1038/s41467-025-56574-7. This article has 44 citations and is from a highest quality peer-reviewed journal.
(dawe2025thearylhydrocarbon media 492c33b4): Hannah R. Dawe and Paola Di Meglio. The aryl hydrocarbon receptor (ahr): peacekeeper of the skin. International Journal of Molecular Sciences, 26:1618, Feb 2025. URL: https://doi.org/10.3390/ijms26041618, doi:10.3390/ijms26041618. This article has 27 citations.
(bahman2024arylhydrocarbonreceptor pages 1-2): Fatemah Bahman, Khubaib Choudhry, Fatema Al-Rashed, Fahd Al-Mulla, Sardar Sindhu, and Rasheed Ahmad. Aryl hydrocarbon receptor: current perspectives on key signaling partners and immunoregulatory role in inflammatory diseases. Frontiers in Immunology, Aug 2024. URL: https://doi.org/10.3389/fimmu.2024.1421346, doi:10.3389/fimmu.2024.1421346. This article has 83 citations and is from a peer-reviewed journal.
(dawe2025thearylhydrocarbon pages 7-9): Hannah R. Dawe and Paola Di Meglio. The aryl hydrocarbon receptor (ahr): peacekeeper of the skin. International Journal of Molecular Sciences, 26:1618, Feb 2025. URL: https://doi.org/10.3390/ijms26041618, doi:10.3390/ijms26041618. This article has 27 citations.
(NCT06661213 chunk 1): Paras Vakharia. Tapinarof for Cutaneous Lupus Erythematosus. Northwestern University. 2025. ClinicalTrials.gov Identifier: NCT06661213
(NCT05472506 chunk 1): Oral AHR Antagonist in Combination With Nivolumab in Patients With PD-1 Resistant Metastatic or Recurrent Head and Neck Cancer. Ikena Oncology. 2023. ClinicalTrials.gov Identifier: NCT05472506
(OpenTargets Search: -AHR): Open Targets Query (-AHR, 30 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(sahoo2025exploringtherole pages 2-4): Manisha Sahoo, Luna Samanta, and Raghunath Satpathy. Exploring the role of toxic and therapeutic compounds in aryl hydrocarbon receptor (ahr) modulation: insights from molecular modeling study. Discover Chemistry, Jun 2025. URL: https://doi.org/10.1007/s44371-025-00221-z, doi:10.1007/s44371-025-00221-z. This article has 1 citations.
(polonio2025thearylhydrocarbon pages 9-11): Carolina M. Polonio, Kimberly A. McHale, David H. Sherr, David Rubenstein, and Francisco J. Quintana. The aryl hydrocarbon receptor: a rehabilitated target for therapeutic immune modulation. Nature reviews. Drug discovery, 24:610-630, Apr 2025. URL: https://doi.org/10.1038/s41573-025-01172-x, doi:10.1038/s41573-025-01172-x. This article has 73 citations.
(polonio2025thearylhydrocarbon pages 16-18): Carolina M. Polonio, Kimberly A. McHale, David H. Sherr, David Rubenstein, and Francisco J. Quintana. The aryl hydrocarbon receptor: a rehabilitated target for therapeutic immune modulation. Nature reviews. Drug discovery, 24:610-630, Apr 2025. URL: https://doi.org/10.1038/s41573-025-01172-x, doi:10.1038/s41573-025-01172-x. This article has 73 citations.
Falcon deep research was attempted with just deep-research-falcon human AHR --fallback perplexity-lite. Falcon timed out after 600 seconds and the configured perplexity-lite fallback failed with a quota error, so no provider deep-research file was created. This review therefore uses the fetched UniProt/GOA files, cached publications, and the Proteostasis PN projection/mapping reports.
AHR is primarily a ligand-activated bHLH-PAS receptor/transcription factor. Ligand binding is directly supported by the human/mouse AHR mutagenesis study showing that the cDNA-encoded protein binds TCDD specifically PMID:7961644.
Activated AHR forms the AHR:ARNT transcription-factor complex and binds regulatory DNA. Structural work describes AHR and ARNT as a heterodimeric bHLH-PAS transcription factor and reports the DNA-bound AHR:ARNT structure [PMID:28602820 "AHR is activated by xenobiotics, notably dioxin"; PMID:28602820 "structural basis of AHR assembly and DNA interaction"].
AHR trafficking is part of the core activation cycle: inactive AHR is predominantly cytoplasmic, ligand binding stabilizes nuclear accumulation, and DNA/ARNT interaction is not required for the trafficking step itself PMID:34521881.
HSP90/p23/XAP2 binding is a real mechanistic part of the cytosolic AHR complex and should be retained as informative, unlike generic protein binding annotations PMID:11259606.
AHR has many downstream immune and disease-context roles. IL4I1-derived tryptophan catabolites activate AHR and suppress anti-tumor immunity, but these are context-dependent outputs rather than separate core molecular functions PMID:32818467.
The Proteostasis PN projection proposes GO:1990756 ubiquitin-like ligase-substrate adaptor activity for AHR from Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate adaptor, status new_to_goa [file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv "AHR GO:1990756 ubiquitin-like ligase-substrate adaptor activity new_to_goa"].
Conservatively, I did not accept the PN AHR projection. The specific AHR/ARNT/TBL3 subtype is no_mapping in the UPS mapping YAML, while the parent Cul4A/Cul4B substrate-adaptor group is flagged for manual gene-level review before any gene-review change [file:projects/PROTEOSTASIS/mappings/ubiquitin_proteasome_system.yaml "Cul4A/Cul4B substrate adaptor|AHR / ARNT / TBL3 complex|PAS"; file:projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv "manual_gene_level_review_required_before_gene_review_change"]. Local evidence supports AHR proteasomal degradation and transcriptional regulation, but not direct AHR substrate-recruiting adaptor activity for a CUL4 ligase.
Falcon deep research findings (2026-06-07)
A newly generated Falcon (Edison) deep research report was reviewed and synthesized against the existing COMPLETE review. The report is consistent with the existing review and adds mostly newer primary/review literature plus mechanistic and translational detail. Key findings, emphasizing what is NEW relative to the current review:
Molecular function / structural mechanism (NEW primary reference): Crystal structures of AHR-ARNT-DNA complexes were solved with six distinct ligands (tapinarof, FICZ, benzo[a]pyrene, β-naphthoflavone, indigo, indirubin), revealing an unconventional assembly with intimate PAS-B–PAS-B association between AHR and ARNT; AHR's PAS-B domain uses eight conserved residues that dynamically rearrange to bind ligands via hydrophobic and π–π interactions, and a segment of AHR transitions from chaperone engagement to ARNT-heterodimer stabilization to form the transcriptionally competent complex PMID:39900897. This directly strengthens the existing nuclear-receptor-activity, heterodimerization, and DNA-binding annotations and pinpoints PAS-B as the principal ligand-binding pocket. According to PubMed, doi:10.1038/s41467-025-56574-7.
Biological process / immunology (NEW review reference): A 2025 Nature Reviews Drug Discovery review consolidates AHR as a physiological regulator of innate and adaptive immunity, modulated by diet, commensal flora, and metabolism in autoimmunity, cancer, and infection; reported context-dependent transcriptional outputs include cytokines such as IL-10, IL-17, and IL-22 and immunoregulatory modules (e.g., CD39/CD73 adenosinergic pathway) PMID:40247142. This supports (does not change) the existing KEEP_AS_NON_CORE immune-process annotations. According to PubMed, doi:10.1038/s41573-025-01172-x.
Cellular localization / activation cycle: Falcon reaffirms the resting cytosolic chaperone complex (HSP90 dimer, AIP/XAP2, p23, sometimes SRC) and ligand-triggered nuclear translocation, ARNT dimerization, XRE/DRE binding (consensus 5'-TNGCGTG-3', core GCGTG), and the canonical "AHR gene battery" (CYP1A1/1A2/1B1, AHRR, TIPARP). All already captured in the review; AHRR is a feedback repressor mentioned but not annotation-changing here. (Dawe & Di Meglio 2025, doi:10.3390/ijms26041618; Bahman et al. 2024, doi:10.3389/fimmu.2024.1421346)
Non-canonical signaling (consistent with existing notes, not annotation-changing): Falcon describes activated AHR assembling a CUL4B-based E3 ubiquitin ligase (CUL4B^AHR) targeting ER-α, AR, β-catenin, PPARγ, and acting as a cytoplasmic adaptor/scaffold linking SRC/JAK2 to PI3K-AKT, MEK-ERK, YAP-ERK. This matches the previously documented Proteostasis PN E3-adaptor question and is retained as an open question rather than an accepted annotation (review-only, kidney-focused review: Xie et al. 2024, doi:10.1186/s11658-024-00550-4).
Disease links / translational (context, not annotation-changing): Tapinarof (a topical AHR agonist) was FDA-approved (May 2022) for plaque psoriasis and is in trials for additional indications; benvitimod is approved in China; AHR antagonists (e.g., IK-175, BAY2416964) are in oncology development. Open Targets links AHR to atopic eczema and psoriasis. These are pharmacological/clinical and do not alter the GO core-function annotations PMID:40247142.
Provenance note: the two Nature-family papers above (Diao et al. 2025; Polonio et al. 2025) were resolved to PMIDs and exact titles via the PubMed MCP (DOI→PMID conversion). Other Falcon citations (Dawe 2025, Bahman 2024, Xie 2024, Elson & Kolluri 2023, Sahoo 2025, Mosa 2025) and ClinicalTrials.gov / Open Targets entries are recorded here as supporting context only and were not added to the YAML.
Pn Notes
(AHR-pn-notes.md)
AHR PN Consistency Notes
Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
Description: AHR encodes the aryl hydrocarbon receptor, a ligand-activated bHLH-PAS transcription factor that senses xenobiotic, dietary, microbiome-derived, and endogenous metabolites. In unstimulated cells AHR is mainly cytoplasmic in a chaperone-associated receptor complex; ligand binding promotes nuclear accumulation, heterodimerization with ARNT, binding to AHR/xenobiotic response elements, and regulation of RNA polymerase II target genes. AHR controls detoxification and xenobiotic-response programs such as CYP1A1 induction and also has context-dependent roles in immune regulation, intestinal epithelial responses, tumor immune escape, circadian cross-talk, development, and retinal biology.
Consistency: Large but well-managed divergence. PN frames AHR as a CUL4 substrate adaptor in the UPS branch. Deep research (falcon) and review establish AHR's canonical identity as a ligand-activated bHLH-PAS nuclear receptor / RNA Pol II transcription factor (HSP90/XAP2/p23 cytosolic complex → ARNT heterodimer → XRE binding). The review/notes explicitly did NOT accept the PN GO:1990756 projection: AHR's own subtype/type are no_mapping, and the parent group is flagged manual_gene_level_review_required_before_gene_review_change. Notes acknowledge CUL4B^AHR E3 activity from the literature (Xie 2024 review; ER-α/AR/β-catenin targets) but retain it as an open question, not an annotation. Internally consistent; PN UPS role deliberately not propagated.
PN story / NEW pressure: PN asserts an MF (GO:1990756, verified real/non-obsolete) absent from GOA. AHR-as-CUL4-adaptor is supported only by a subset of (largely review/secondary) literature and is mechanistically contested vs. AHR being itself a CUL4 substrate. Verdict: over-reaches as a gene-level GO assertion now — correctly deferred (suggested_question + suggested_experiment to test direct substrate-bridging vs AHR turnover). The genuine AHR core functions (nuclear receptor activity, heterodimerization, sequence-specific DNA binding, Hsp90 binding) are already richly annotated.
Evidence alignment: No overlap between PN refs (PMID:17392787, 28416634 — uncached, not used) and the review's evidence base (PMID:34521881, 28602820, 7961644, 11259606, 15641800, 32818467, etc.). The review builds the canonical TF case independently; the PN UPS citations are neither verified nor relied upon. Divergent reference sets, reconciled by treating the UPS role as unverified.
Verdict: PN UPS/CUL4-adaptor projection (GO:1990756) over-reaches; correctly NOT propagated to AHR (left as open question). Core TF/nuclear-receptor function fully captured. Recommended edits: none to YAML. [MAP]: keep AHR/ARNT/TBL3 and PAS subtypes no_mapping; gate the Cul4A/Cul4B substrate-adaptor group GO:1990756 behind per-gene review (AHR is the cautionary case). [REF]: optionally fetch/verify PN PMID:17392787 & 28416634 to substantiate or retire the AHR UPS placement.
PN placement:Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate adaptor|AHR / ARNT / TBL3 complex|PAS ; PN-node mapping: subtype(PAS)/type(AHR/ARNT/TBL3) no_mapping; group (Cul4A/Cul4B substrate adaptor) mapped GO:1990756 ubiquitin-like ligase-substrate adaptor activity (new_to_goa); class (E3 ligases) context_only too_broad GO:0061630; branch no_mapping. PN references: PMID:17392787, 28416634 (titles not in dossier; not cached locally).
Consistency: Large but well-managed divergence. PN frames AHR as a CUL4 substrate adaptor in the UPS branch. Deep research (falcon) and review establish AHR's canonical identity as a ligand-activated bHLH-PAS nuclear receptor / RNA Pol II transcription factor (HSP90/XAP2/p23 cytosolic complex → ARNT heterodimer → XRE binding). The review/notes explicitly did NOT accept the PN GO:1990756 projection: AHR's own subtype/type are no_mapping, and the parent group is flagged manual_gene_level_review_required_before_gene_review_change. Notes acknowledge CUL4B^AHR E3 activity from the literature (Xie 2024 review; ER-α/AR/β-catenin targets) but retain it as an open question, not an annotation. Internally consistent; PN UPS role deliberately not propagated.
PN story / NEW pressure: PN asserts an MF (GO:1990756, verified real/non-obsolete) absent from GOA. AHR-as-CUL4-adaptor is supported only by a subset of (largely review/secondary) literature and is mechanistically contested vs. AHR being itself a CUL4 substrate. Verdict: over-reaches as a gene-level GO assertion now — correctly deferred (suggested_question + suggested_experiment to test direct substrate-bridging vs AHR turnover). The genuine AHR core functions (nuclear receptor activity, heterodimerization, sequence-specific DNA binding, Hsp90 binding) are already richly annotated.
Mapping strategy: Gene does not change the node. The Cul4A/Cul4B substrate-adaptor group→GO:1990756 mapping is too liberal for AHR; AHR's leaf nodes are appropriately no_mapping, and the review upholds that. This is a stronger "do not propagate" case than broader-term rejections (TOMM20/HSPA8/RAB7A) because the asserted MF is a different biological role from AHR's primary function.
Evidence alignment: No overlap between PN refs (PMID:17392787, 28416634 — uncached, not used) and the review's evidence base (PMID:34521881, 28602820, 7961644, 11259606, 15641800, 32818467, etc.). The review builds the canonical TF case independently; the PN UPS citations are neither verified nor relied upon. Divergent reference sets, reconciled by treating the UPS role as unverified.
Verdict: PN UPS/CUL4-adaptor projection (GO:1990756) over-reaches; correctly NOT propagated to AHR (left as open question). Core TF/nuclear-receptor function fully captured. Recommended edits: none to YAML. [MAP]: keep AHR/ARNT/TBL3 and PAS subtypes no_mapping; gate the Cul4A/Cul4B substrate-adaptor group GO:1990756 behind per-gene review (AHR is the cautionary case). [REF]: optionally fetch/verify PN PMID:17392787 & 28416634 to substantiate or retire the AHR UPS placement.
PN Dossier Context
review_batch: proteostasis-batch-2026-06-03
review_yaml: genes/human/AHR/AHR-ai-review.yaml
PN workbook rows: 1
PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul4A/Cul4B substrate adaptor | AHR / ARNT / TBL3 complex | PAS
UniProt: P35869
In branches: UPS
Signature domains: (none)
Auxiliary domains: IPR000014
PN references (titles):
17392787
28416634
PN-node mapping records (path + ancestors):
[subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate adaptor|AHR / ARNT / TBL3 complex|PAS
status=no_mapping scope= GO=[]
rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
[type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate adaptor|AHR / ARNT / TBL3 complex
status=no_mapping scope= GO=[]
rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
[group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate adaptor
status=mapped scope=ok_for_propagation_to_go GO=[GO:1990756 ubiquitin-like ligase-substrate adaptor activity]
rationale: This PN group captures substrate receptors/adaptors for cullin/UBL ligase systems. The shared GO molecular-function target is ubiquitin-like ligase-substrate adaptor 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.
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: P35869
gene_symbol: AHR
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: AHR encodes the aryl hydrocarbon receptor, a ligand-activated bHLH-PAS transcription factor that senses xenobiotic, dietary, microbiome-derived, and endogenous metabolites. In unstimulated cells AHR is mainly cytoplasmic in a chaperone-associated receptor complex; ligand binding promotes nuclear accumulation, heterodimerization with ARNT, binding to AHR/xenobiotic response elements, and regulation of RNA polymerase II target genes. AHR controls detoxification and xenobiotic-response programs such as CYP1A1 induction and also has context-dependent roles in immune regulation, intestinal epithelial responses, tumor immune escape, circadian cross-talk, development, and retinal biology.
existing_annotations:
- term:
id: GO:0005634
label: nucleus
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: 'nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0004879
label: nuclear receptor activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: enables
review:
summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
action: ACCEPT
reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: regulation of transcription by RNA polymerase II is consistent with AHR acting as a ligand-activated transcription factor that regulates RNA polymerase II target genes after nuclear AHR:ARNT complex formation.
action: ACCEPT
reason: Transcriptional regulation is the central biological output of activated AHR. The term is broad in some cases, but the direction and process are supported by ligand-induced target gene activation and by cofactor/transactivation-domain evidence.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:10395741
supporting_text: These results confirmed functional and physical interactions of AhR/Arnt with ERAP 140 and SMRT in breast cancer cells.
- reference_id: PMID:15641800
supporting_text: the acidic Q-rich region bound to components of the general transcription machinery
- term:
id: GO:0000976
label: transcription cis-regulatory region binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: enables
review:
summary: transcription cis-regulatory region binding is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
action: ACCEPT
reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:15681594
supporting_text: AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
- term:
id: GO:0034751
label: aryl hydrocarbon receptor complex
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: part_of
review:
summary: aryl hydrocarbon receptor complex is an appropriate AHR complex annotation. AHR forms cytosolic chaperone-associated complexes before activation and nuclear AHR:ARNT complexes after ligand-induced activation.
action: ACCEPT
reason: AHR complex membership is central to the receptor activation cycle. The receptor is maintained in a cytosolic HSP90/XAP2/p23 complex before activation and forms an AHR:ARNT DNA-bound complex in the nucleus after ligand activation.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:11259606
supporting_text: The molecular chaperone complex hsp90-p23 interacts with the dioxin receptor
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0004879
label: nuclear receptor activity
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: enables
review:
summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
action: ACCEPT
reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005634
label: nucleus
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: 'nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: 'cytoplasm localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0006355
label: regulation of DNA-templated transcription
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
summary: regulation of DNA-templated transcription is consistent with AHR acting as a ligand-activated transcription factor that regulates RNA polymerase II target genes after nuclear AHR:ARNT complex formation.
action: ACCEPT
reason: Transcriptional regulation is the central biological output of activated AHR. The term is broad in some cases, but the direction and process are supported by ligand-induced target gene activation and by cofactor/transactivation-domain evidence.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:10395741
supporting_text: These results confirmed functional and physical interactions of AhR/Arnt with ERAP 140 and SMRT in breast cancer cells.
- reference_id: PMID:15641800
supporting_text: the acidic Q-rich region bound to components of the general transcription machinery
- term:
id: GO:0006805
label: xenobiotic metabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
summary: xenobiotic metabolic process is a core AHR pathway outcome. AHR binds xenobiotic ligands such as TCDD/dioxin-related compounds and induces detoxification and response genes.
action: ACCEPT
reason: AHR does not enzymatically metabolize xenobiotics itself, but GO biological-process annotations correctly capture its upstream receptor/transcription-factor role in xenobiotic response and metabolism programs.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- term:
id: GO:0009410
label: response to xenobiotic stimulus
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: involved_in
review:
summary: response to xenobiotic stimulus is a core AHR pathway outcome. AHR binds xenobiotic ligands such as TCDD/dioxin-related compounds and induces detoxification and response genes.
action: ACCEPT
reason: AHR does not enzymatically metabolize xenobiotics itself, but GO biological-process annotations correctly capture its upstream receptor/transcription-factor role in xenobiotic response and metabolism programs.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- term:
id: GO:0030522
label: intracellular receptor signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000108
qualifier: involved_in
review:
summary: AHR signaling is an intracellular ligand-receptor pathway that couples xenobiotic, dietary, microbiome-derived, and endogenous metabolites to transcriptional responses.
action: ACCEPT
reason: The term is broad but correct for AHR. AHR activation by ligand causes nuclear translocation and transcriptional regulation of target genes including xenobiotic-response genes and immunometabolic targets.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:32818467
supporting_text: IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid.
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: involved_in
review:
summary: positive regulation of DNA-templated transcription is consistent with AHR acting as a ligand-activated transcription factor that regulates RNA polymerase II target genes after nuclear AHR:ARNT complex formation.
action: ACCEPT
reason: Transcriptional regulation is the central biological output of activated AHR. The term is broad in some cases, but the direction and process are supported by ligand-induced target gene activation and by cofactor/transactivation-domain evidence.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:10395741
supporting_text: These results confirmed functional and physical interactions of AhR/Arnt with ERAP 140 and SMRT in breast cancer cells.
- reference_id: PMID:15641800
supporting_text: the acidic Q-rich region bound to components of the general transcription machinery
- term:
id: GO:0046983
label: protein dimerization activity
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: AHR dimerization is real, but the generic protein dimerization activity term should be replaced by the more informative heterodimerization term.
action: MODIFY
reason: The biologically relevant dimer for activated AHR is AHR:ARNT. Existing human evidence specifically supports heterodimerization, so the generic dimerization annotation should be refined.
proposed_replacement_terms:
- id: GO:0046982
label: protein heterodimerization activity
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0051239
label: regulation of multicellular organismal process
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: involved_in
review:
summary: regulation of multicellular organismal process is biologically connected to AHR pleiotropy but is too broad or indirect for a core AHR annotation.
action: MARK_AS_OVER_ANNOTATED
reason: AHR affects development, cell cycle, apoptosis, and organism-level phenotypes through transcriptional programs, but these high-level process annotations risk implying a direct pathway role that is not supported by the specific evidence used here.
supported_by:
- reference_id: PMID:12213388
supporting_text: This review addresses novel findings relating to AHR functions that have resulted from experimental approaches markedly outside traditional receptor analyses.
- term:
id: GO:1904613
label: cellular response to 2,3,7,8-tetrachlorodibenzodioxine
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: involved_in
review:
summary: cellular response to 2,3,7,8-tetrachlorodibenzodioxine is a core AHR pathway outcome. AHR binds xenobiotic ligands such as TCDD/dioxin-related compounds and induces detoxification and response genes.
action: ACCEPT
reason: AHR does not enzymatically metabolize xenobiotics itself, but GO biological-process annotations correctly capture its upstream receptor/transcription-factor role in xenobiotic response and metabolism programs.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- term:
id: GO:1990837
label: sequence-specific double-stranded DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: enables
review:
summary: sequence-specific double-stranded DNA binding is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
action: ACCEPT
reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:15681594
supporting_text: AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:10395741
qualifier: enables
review:
summary: The original IPI evidence documents AHR/ARNT and coactivator/corepressor interactions, but protein binding is uninformative.
action: MODIFY
reason: Replace the generic term with specific AHR heterodimerization and transcription cofactor-binding activities, which capture the relevant molecular interactions.
proposed_replacement_terms:
- id: GO:0046982
label: protein heterodimerization activity
- id: GO:0001094
label: TFIID-class transcription factor complex binding
- id: GO:0001223
label: transcription coactivator binding
supported_by:
- reference_id: PMID:10395741
supporting_text: These results confirmed functional and physical interactions of AhR/Arnt with ERAP 140 and SMRT in breast cancer cells.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16257957
qualifier: enables
review:
summary: This generic protein binding annotation reflects a viral EBNA3 interaction that modulates AHR transactivation, but it is not informative for the normal AHR core function.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction may be experimentally real, but generic protein binding from a virus-specific perturbation should not be used as a functional summary of AHR.
supported_by:
- reference_id: PMID:16257957
supporting_text: Regulation of transactivation function of the aryl hydrocarbon receptor by the Epstein-Barr virus-encoded EBNA-3 protein.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:28514442
qualifier: enables
review:
summary: The protein binding annotation reflects AHR interactions with ARNT/related bHLH-PAS partners, but the generic term should be refined.
action: MODIFY
reason: AHR:ARNT or related heterodimerization is the informative activity supported by the interaction evidence. The review therefore proposes protein heterodimerization activity rather than generic protein binding.
proposed_replacement_terms:
- id: GO:0046982
label: protein heterodimerization activity
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:33961781
qualifier: enables
review:
summary: The protein binding annotation reflects AHR interactions with ARNT/related bHLH-PAS partners, but the generic term should be refined.
action: MODIFY
reason: AHR:ARNT or related heterodimerization is the informative activity supported by the interaction evidence. The review therefore proposes protein heterodimerization activity rather than generic protein binding.
proposed_replacement_terms:
- id: GO:0046982
label: protein heterodimerization activity
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:9704006
qualifier: enables
review:
summary: The protein binding annotation reflects AHR interactions with ARNT/related bHLH-PAS partners, but the generic term should be refined.
action: MODIFY
reason: AHR:ARNT or related heterodimerization is the informative activity supported by the interaction evidence. The review therefore proposes protein heterodimerization activity rather than generic protein binding.
proposed_replacement_terms:
- id: GO:0046982
label: protein heterodimerization activity
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: IDA
original_reference_id: GO_REF:0000052
qualifier: located_in
review:
summary: 'nucleoplasm localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005829
label: cytosol
evidence_type: IDA
original_reference_id: GO_REF:0000052
qualifier: located_in
review:
summary: 'cytosol localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0006805
label: xenobiotic metabolic process
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8937144
qualifier: involved_in
review:
summary: xenobiotic metabolic process is a core AHR pathway outcome. AHR binds xenobiotic ligands such as TCDD/dioxin-related compounds and induces detoxification and response genes.
action: ACCEPT
reason: AHR does not enzymatically metabolize xenobiotics itself, but GO biological-process annotations correctly capture its upstream receptor/transcription-factor role in xenobiotic response and metabolism programs.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- term:
id: GO:0004879
label: nuclear receptor activity
evidence_type: EXP
original_reference_id: PMID:11259606
qualifier: enables
review:
summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
action: ACCEPT
reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0004879
label: nuclear receptor activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8936849
qualifier: enables
review:
summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
action: ACCEPT
reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0004879
label: nuclear receptor activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8937191
qualifier: enables
review:
summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
action: ACCEPT
reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005737
label: cytoplasm
evidence_type: EXP
original_reference_id: PMID:34521881
qualifier: located_in
review:
summary: 'cytoplasm localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0050728
label: negative regulation of inflammatory response
evidence_type: IDA
original_reference_id: PMID:29454749
qualifier: involved_in
review:
summary: negative regulation of inflammatory response is supported as a downstream immunological context of AHR activation, especially through microbial or tryptophan-derived ligands.
action: KEEP_AS_NON_CORE
reason: AHR has substantial immune biology, but these process terms are cell-type- and disease-context-dependent outputs of AHR signaling rather than the core molecular function of the gene product.
supported_by:
- reference_id: PMID:32818467
supporting_text: IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid.
- reference_id: PMID:29454749
supporting_text: Administration of indole metabolites showed prominent induction of IL-10R1 on cultured intestinal epithelia that was explained by activation of the aryl hydrocarbon receptor.
- reference_id: PMID:15681594
supporting_text: AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
- term:
id: GO:0004879
label: nuclear receptor activity
evidence_type: IDA
original_reference_id: PMID:34521881
qualifier: contributes_to
review:
summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
action: ACCEPT
reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:34521881
qualifier: enables
review:
summary: The protein binding annotation reflects AHR interactions with ARNT/related bHLH-PAS partners, but the generic term should be refined.
action: MODIFY
reason: AHR:ARNT or related heterodimerization is the informative activity supported by the interaction evidence. The review therefore proposes protein heterodimerization activity rather than generic protein binding.
proposed_replacement_terms:
- id: GO:0046982
label: protein heterodimerization activity
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:34521881
qualifier: is_active_in
review:
summary: 'nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0009410
label: response to xenobiotic stimulus
evidence_type: IDA
original_reference_id: PMID:34521881
qualifier: involved_in
review:
summary: response to xenobiotic stimulus is a core AHR pathway outcome. AHR binds xenobiotic ligands such as TCDD/dioxin-related compounds and induces detoxification and response genes.
action: ACCEPT
reason: AHR does not enzymatically metabolize xenobiotics itself, but GO biological-process annotations correctly capture its upstream receptor/transcription-factor role in xenobiotic response and metabolism programs.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- term:
id: GO:0034753
label: nuclear aryl hydrocarbon receptor complex
evidence_type: IDA
original_reference_id: PMID:34521881
qualifier: is_active_in
review:
summary: nuclear aryl hydrocarbon receptor complex is an appropriate AHR complex annotation. AHR forms cytosolic chaperone-associated complexes before activation and nuclear AHR:ARNT complexes after ligand-induced activation.
action: ACCEPT
reason: AHR complex membership is central to the receptor activation cycle. The receptor is maintained in a cytosolic HSP90/XAP2/p23 complex before activation and forms an AHR:ARNT DNA-bound complex in the nucleus after ligand activation.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:11259606
supporting_text: The molecular chaperone complex hsp90-p23 interacts with the dioxin receptor
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:34521881
qualifier: involved_in
review:
summary: positive regulation of transcription by RNA polymerase II is consistent with AHR acting as a ligand-activated transcription factor that regulates RNA polymerase II target genes after nuclear AHR:ARNT complex formation.
action: ACCEPT
reason: Transcriptional regulation is the central biological output of activated AHR. The term is broad in some cases, but the direction and process are supported by ligand-induced target gene activation and by cofactor/transactivation-domain evidence.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:10395741
supporting_text: These results confirmed functional and physical interactions of AhR/Arnt with ERAP 140 and SMRT in breast cancer cells.
- reference_id: PMID:15641800
supporting_text: the acidic Q-rich region bound to components of the general transcription machinery
- term:
id: GO:0046982
label: protein heterodimerization activity
evidence_type: IDA
original_reference_id: PMID:34521881
qualifier: enables
review:
summary: AHR heterodimerization, especially with ARNT, is essential for DNA binding and transcriptional activation.
action: ACCEPT
reason: The AHR:ARNT heterodimer is a core mechanistic state of activated AHR. Structural and mutational evidence supports this term directly.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- term:
id: GO:1990837
label: sequence-specific double-stranded DNA binding
evidence_type: IDA
original_reference_id: PMID:34521881
qualifier: enables
review:
summary: sequence-specific double-stranded DNA binding is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
action: ACCEPT
reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:15681594
supporting_text: AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
- term:
id: GO:0001094
label: TFIID-class transcription factor complex binding
evidence_type: IPI
original_reference_id: PMID:15641800
qualifier: enables
review:
summary: TFIID-class transcription factor complex binding is supported by AHR transactivation-domain interactions with general transcription machinery and coactivators/coregulators.
action: ACCEPT
reason: These binding annotations are more informative than generic protein binding and connect directly to AHR transcriptional regulation. They should be retained as molecular-function annotations supporting the core transactivation mechanism.
supported_by:
- reference_id: PMID:15641800
supporting_text: the acidic Q-rich region bound to components of the general transcription machinery
- reference_id: PMID:10395741
supporting_text: These results confirmed functional and physical interactions of AhR/Arnt with ERAP 140 and SMRT in breast cancer cells.
- term:
id: GO:0071219
label: cellular response to molecule of bacterial origin
evidence_type: IDA
original_reference_id: PMID:29454749
qualifier: involved_in
review:
summary: AHR responds to microbiota-derived indole metabolites and bacterial-origin molecules in intestinal epithelial/immune contexts.
action: KEEP_AS_NON_CORE
reason: This is a well supported physiological context for AHR signaling, but it is ligand/source-specific and should not displace the core receptor/transcription-factor function.
supported_by:
- reference_id: PMID:29454749
supporting_text: Administration of indole metabolites showed prominent induction of IL-10R1 on cultured intestinal epithelia that was explained by activation of the aryl hydrocarbon receptor.
- term:
id: GO:0004879
label: nuclear receptor activity
evidence_type: IDA
original_reference_id: PMID:28602820
qualifier: enables
review:
summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
action: ACCEPT
reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:28602820
qualifier: is_active_in
review:
summary: 'nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:32866000
qualifier: is_active_in
review:
summary: 'nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0061629
label: RNA polymerase II-specific DNA-binding transcription factor binding
evidence_type: IPI
original_reference_id: PMID:9079689
qualifier: enables
review:
summary: RNA polymerase II-specific DNA-binding transcription factor binding is supported by AHR transactivation-domain interactions with general transcription machinery and coactivators/coregulators.
action: ACCEPT
reason: These binding annotations are more informative than generic protein binding and connect directly to AHR transcriptional regulation. They should be retained as molecular-function annotations supporting the core transactivation mechanism.
supported_by:
- reference_id: PMID:15641800
supporting_text: the acidic Q-rich region bound to components of the general transcription machinery
- reference_id: PMID:10395741
supporting_text: These results confirmed functional and physical interactions of AhR/Arnt with ERAP 140 and SMRT in breast cancer cells.
- term:
id: GO:0004879
label: nuclear receptor activity
evidence_type: IDA
original_reference_id: PMID:32866000
qualifier: enables
review:
summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
action: ACCEPT
reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:32818467
qualifier: involved_in
review:
summary: regulation of transcription by RNA polymerase II is consistent with AHR acting as a ligand-activated transcription factor that regulates RNA polymerase II target genes after nuclear AHR:ARNT complex formation.
action: ACCEPT
reason: Transcriptional regulation is the central biological output of activated AHR. The term is broad in some cases, but the direction and process are supported by ligand-induced target gene activation and by cofactor/transactivation-domain evidence.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:10395741
supporting_text: These results confirmed functional and physical interactions of AhR/Arnt with ERAP 140 and SMRT in breast cancer cells.
- reference_id: PMID:15641800
supporting_text: the acidic Q-rich region bound to components of the general transcription machinery
- term:
id: GO:0002819
label: regulation of adaptive immune response
evidence_type: IDA
original_reference_id: PMID:32818467
qualifier: involved_in
review:
summary: regulation of adaptive immune response is supported as a downstream immunological context of AHR activation, especially through microbial or tryptophan-derived ligands.
action: KEEP_AS_NON_CORE
reason: AHR has substantial immune biology, but these process terms are cell-type- and disease-context-dependent outputs of AHR signaling rather than the core molecular function of the gene product.
supported_by:
- reference_id: PMID:32818467
supporting_text: IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid.
- reference_id: PMID:29454749
supporting_text: Administration of indole metabolites showed prominent induction of IL-10R1 on cultured intestinal epithelia that was explained by activation of the aryl hydrocarbon receptor.
- reference_id: PMID:15681594
supporting_text: AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
- term:
id: GO:0002841
label: negative regulation of T cell mediated immune response to tumor cell
evidence_type: IDA
original_reference_id: PMID:32818467
qualifier: involved_in
review:
summary: negative regulation of T cell mediated immune response to tumor cell is supported as a downstream immunological context of AHR activation, especially through microbial or tryptophan-derived ligands.
action: KEEP_AS_NON_CORE
reason: AHR has substantial immune biology, but these process terms are cell-type- and disease-context-dependent outputs of AHR signaling rather than the core molecular function of the gene product.
supported_by:
- reference_id: PMID:32818467
supporting_text: IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid.
- reference_id: PMID:29454749
supporting_text: Administration of indole metabolites showed prominent induction of IL-10R1 on cultured intestinal epithelia that was explained by activation of the aryl hydrocarbon receptor.
- reference_id: PMID:15681594
supporting_text: AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
- term:
id: GO:0004879
label: nuclear receptor activity
evidence_type: IDA
original_reference_id: PMID:32818467
qualifier: enables
review:
summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
action: ACCEPT
reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:32818467
qualifier: located_in
review:
summary: 'nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:32818467
qualifier: located_in
review:
summary: 'cytoplasm localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:32818467
qualifier: involved_in
review:
summary: positive regulation of transcription by RNA polymerase II is consistent with AHR acting as a ligand-activated transcription factor that regulates RNA polymerase II target genes after nuclear AHR:ARNT complex formation.
action: ACCEPT
reason: Transcriptional regulation is the central biological output of activated AHR. The term is broad in some cases, but the direction and process are supported by ligand-induced target gene activation and by cofactor/transactivation-domain evidence.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:10395741
supporting_text: These results confirmed functional and physical interactions of AhR/Arnt with ERAP 140 and SMRT in breast cancer cells.
- reference_id: PMID:15641800
supporting_text: the acidic Q-rich region bound to components of the general transcription machinery
- term:
id: GO:0000987
label: cis-regulatory region sequence-specific DNA binding
evidence_type: IDA
original_reference_id: PMID:23275542
qualifier: enables
review:
summary: cis-regulatory region sequence-specific DNA binding is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
action: ACCEPT
reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:15681594
supporting_text: AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
- term:
id: GO:0000785
label: chromatin
evidence_type: ISA
original_reference_id: GO_REF:0000113
qualifier: located_in
review:
summary: 'chromatin localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase II-specific
evidence_type: ISA
original_reference_id: GO_REF:0000113
qualifier: enables
review:
summary: DNA-binding transcription factor activity, RNA polymerase II-specific is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
action: ACCEPT
reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:15681594
supporting_text: AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
- term:
id: GO:0042803
label: protein homodimerization activity
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: enables
review:
summary: Homodimerization is transferred by similarity and may occur, but it is not the core activated AHR mechanism in human cells.
action: KEEP_AS_NON_CORE
reason: The main supported functional complex is the AHR:ARNT heterodimer. Homodimerization should not be treated as the central AHR molecular function.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IDA
original_reference_id: PMID:28602820
qualifier: enables
review:
summary: DNA-binding transcription factor activity is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
action: ACCEPT
reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:15681594
supporting_text: AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:28602820
qualifier: enables
review:
summary: The protein binding annotation reflects AHR interactions with ARNT/related bHLH-PAS partners, but the generic term should be refined.
action: MODIFY
reason: AHR:ARNT or related heterodimerization is the informative activity supported by the interaction evidence. The review therefore proposes protein heterodimerization activity rather than generic protein binding.
proposed_replacement_terms:
- id: GO:0046982
label: protein heterodimerization activity
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0046982
label: protein heterodimerization activity
evidence_type: IDA
original_reference_id: PMID:28602820
qualifier: enables
review:
summary: AHR heterodimerization, especially with ARNT, is essential for DNA binding and transcriptional activation.
action: ACCEPT
reason: The AHR:ARNT heterodimer is a core mechanistic state of activated AHR. Structural and mutational evidence supports this term directly.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- term:
id: GO:1990837
label: sequence-specific double-stranded DNA binding
evidence_type: IDA
original_reference_id: PMID:28602820
qualifier: enables
review:
summary: sequence-specific double-stranded DNA binding is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
action: ACCEPT
reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:15681594
supporting_text: AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:17329248
qualifier: located_in
review:
summary: 'nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005829
label: cytosol
evidence_type: IDA
original_reference_id: PMID:17329248
qualifier: located_in
review:
summary: 'cytosol localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0071320
label: cellular response to cAMP
evidence_type: IDA
original_reference_id: PMID:17329248
qualifier: involved_in
review:
summary: cellular response to cAMP reflects a specific regulatory input into AHR trafficking through the PDE2A/XAP2/cAMP pathway rather than a core evolved function.
action: KEEP_AS_NON_CORE
reason: The cited study supports cAMP/forskolin effects on AHR nuclear translocation, but these stimulus-response annotations are context-specific and secondary to the receptor/transcription-factor function.
supported_by:
- reference_id: PMID:17329248
supporting_text: Binding of PDE2A to XAP2 inhibited TCDD- and cAMP-induced nuclear translocation of AhR in Hepa1c1c7 hepatocytes.
- term:
id: GO:1904322
label: cellular response to forskolin
evidence_type: IDA
original_reference_id: PMID:17329248
qualifier: involved_in
review:
summary: cellular response to forskolin reflects a specific regulatory input into AHR trafficking through the PDE2A/XAP2/cAMP pathway rather than a core evolved function.
action: KEEP_AS_NON_CORE
reason: The cited study supports cAMP/forskolin effects on AHR nuclear translocation, but these stimulus-response annotations are context-specific and secondary to the receptor/transcription-factor function.
supported_by:
- reference_id: PMID:17329248
supporting_text: Binding of PDE2A to XAP2 inhibited TCDD- and cAMP-induced nuclear translocation of AhR in Hepa1c1c7 hepatocytes.
- term:
id: GO:1904613
label: cellular response to 2,3,7,8-tetrachlorodibenzodioxine
evidence_type: IDA
original_reference_id: PMID:17329248
qualifier: involved_in
review:
summary: cellular response to 2,3,7,8-tetrachlorodibenzodioxine is a core AHR pathway outcome. AHR binds xenobiotic ligands such as TCDD/dioxin-related compounds and induces detoxification and response genes.
action: ACCEPT
reason: AHR does not enzymatically metabolize xenobiotics itself, but GO biological-process annotations correctly capture its upstream receptor/transcription-factor role in xenobiotic response and metabolism programs.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- term:
id: GO:0001223
label: transcription coactivator binding
evidence_type: IPI
original_reference_id: PMID:15641800
qualifier: enables
review:
summary: transcription coactivator binding is supported by AHR transactivation-domain interactions with general transcription machinery and coactivators/coregulators.
action: ACCEPT
reason: These binding annotations are more informative than generic protein binding and connect directly to AHR transcriptional regulation. They should be retained as molecular-function annotations supporting the core transactivation mechanism.
supported_by:
- reference_id: PMID:15641800
supporting_text: the acidic Q-rich region bound to components of the general transcription machinery
- reference_id: PMID:10395741
supporting_text: These results confirmed functional and physical interactions of AhR/Arnt with ERAP 140 and SMRT in breast cancer cells.
- term:
id: GO:0017025
label: TBP-class protein binding
evidence_type: IPI
original_reference_id: PMID:15641800
qualifier: enables
review:
summary: TBP-class protein binding is supported by AHR transactivation-domain interactions with general transcription machinery and coactivators/coregulators.
action: ACCEPT
reason: These binding annotations are more informative than generic protein binding and connect directly to AHR transcriptional regulation. They should be retained as molecular-function annotations supporting the core transactivation mechanism.
supported_by:
- reference_id: PMID:15641800
supporting_text: the acidic Q-rich region bound to components of the general transcription machinery
- reference_id: PMID:10395741
supporting_text: These results confirmed functional and physical interactions of AhR/Arnt with ERAP 140 and SMRT in breast cancer cells.
- term:
id: GO:0032991
label: protein-containing complex
evidence_type: IMP
original_reference_id: PMID:15641800
qualifier: part_of
review:
summary: The evidence concerns AHR interactions with transcriptional machinery and complex formation, but the term protein-containing complex is too generic for curation.
action: MODIFY
reason: AHR participates in defined receptor/transcription complexes. Replacing the generic complex term with aryl hydrocarbon receptor complex better captures the biology supported by the cited interaction and transcriptional evidence.
proposed_replacement_terms:
- id: GO:0034751
label: aryl hydrocarbon receptor complex
supported_by:
- reference_id: PMID:10395741
supporting_text: These results confirmed functional and physical interactions of AhR/Arnt with ERAP 140 and SMRT in breast cancer cells.
- reference_id: PMID:15641800
supporting_text: the acidic Q-rich region bound to components of the general transcription machinery
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8937169
qualifier: located_in
review:
summary: 'nucleoplasm localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8937177
qualifier: located_in
review:
summary: 'nucleoplasm localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8937191
qualifier: located_in
review:
summary: 'nucleoplasm localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8936849
qualifier: located_in
review:
summary: 'cytosol localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8937169
qualifier: located_in
review:
summary: 'cytosol localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0009636
label: response to toxic substance
evidence_type: IDA
original_reference_id: PMID:7961644
qualifier: involved_in
review:
summary: response to toxic substance is a core AHR pathway outcome. AHR binds xenobiotic ligands such as TCDD/dioxin-related compounds and induces detoxification and response genes.
action: ACCEPT
reason: AHR does not enzymatically metabolize xenobiotics itself, but GO biological-process annotations correctly capture its upstream receptor/transcription-factor role in xenobiotic response and metabolism programs.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- term:
id: GO:0032922
label: circadian regulation of gene expression
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: involved_in
review:
summary: Circadian regulation is a supported secondary AHR context through bHLH-PAS transcription-factor cross-talk, but not the primary function.
action: KEEP_AS_NON_CORE
reason: AHR can intersect circadian transcriptional regulation, but the principal conserved function remains ligand-activated AHR:ARNT transcriptional control of xenobiotic/endogenous-ligand response genes.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0045892
label: negative regulation of DNA-templated transcription
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: involved_in
review:
summary: Negative regulation of DNA-templated transcription is supported in specific AHR contexts such as circadian/cross-talk and repressor interactions, but it is not the primary AHR output.
action: KEEP_AS_NON_CORE
reason: The core AHR role is ligand-activated transcriptional regulation, usually represented by positive target-gene activation. Negative regulation occurs in specific contexts and should be retained as a secondary, context-dependent function.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:12213388
supporting_text: This review addresses novel findings relating to AHR functions that have resulted from experimental approaches markedly outside traditional receptor analyses.
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: involved_in
review:
summary: positive regulation of DNA-templated transcription is consistent with AHR acting as a ligand-activated transcription factor that regulates RNA polymerase II target genes after nuclear AHR:ARNT complex formation.
action: ACCEPT
reason: Transcriptional regulation is the central biological output of activated AHR. The term is broad in some cases, but the direction and process are supported by ligand-induced target gene activation and by cofactor/transactivation-domain evidence.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:10395741
supporting_text: These results confirmed functional and physical interactions of AhR/Arnt with ERAP 140 and SMRT in breast cancer cells.
- reference_id: PMID:15641800
supporting_text: the acidic Q-rich region bound to components of the general transcription machinery
- term:
id: GO:0070888
label: E-box binding
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: enables
review:
summary: AHR binds AHR response elements/dioxin response elements with an E-box-like bHLH-PAS recognition mode, but the E-box binding term is less exact for AHR than cis-regulatory region sequence-specific DNA binding.
action: MODIFY
reason: The transferred mouse annotation is directionally related but should be generalized to the better supported AHR response element/cis-regulatory sequence-specific DNA binding activity for human AHR.
proposed_replacement_terms:
- id: GO:0000987
label: cis-regulatory region sequence-specific DNA binding
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:23275542
qualifier: located_in
review:
summary: 'nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0000976
label: transcription cis-regulatory region binding
evidence_type: IDA
original_reference_id: PMID:15681594
qualifier: enables
review:
summary: transcription cis-regulatory region binding is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
action: ACCEPT
reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:15681594
supporting_text: AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
- term:
id: GO:0003677
label: DNA binding
evidence_type: IDA
original_reference_id: PMID:15681594
qualifier: enables
review:
summary: AHR DNA binding is real, but the generic DNA binding term is less precise than the available cis-regulatory-region sequence-specific DNA-binding terms.
action: MODIFY
reason: The evidence supports AHR binding to AHR response elements/xenobiotic response elements in regulatory DNA, not undifferentiated DNA binding. A more specific cis-regulatory sequence-specific DNA-binding term should be used.
proposed_replacement_terms:
- id: GO:0000987
label: cis-regulatory region sequence-specific DNA binding
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:15681594
supporting_text: AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:15681594
qualifier: located_in
review:
summary: 'nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:15681594
qualifier: located_in
review:
summary: 'cytoplasm localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:15681594
qualifier: involved_in
review:
summary: regulation of transcription by RNA polymerase II is consistent with AHR acting as a ligand-activated transcription factor that regulates RNA polymerase II target genes after nuclear AHR:ARNT complex formation.
action: ACCEPT
reason: Transcriptional regulation is the central biological output of activated AHR. The term is broad in some cases, but the direction and process are supported by ligand-induced target gene activation and by cofactor/transactivation-domain evidence.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:10395741
supporting_text: These results confirmed functional and physical interactions of AhR/Arnt with ERAP 140 and SMRT in breast cancer cells.
- reference_id: PMID:15641800
supporting_text: the acidic Q-rich region bound to components of the general transcription machinery
- term:
id: GO:0010468
label: regulation of gene expression
evidence_type: IDA
original_reference_id: PMID:15681594
qualifier: involved_in
review:
summary: The B-cell study supports AHR-dependent transcriptional/gene-expression regulation, but the term regulation of gene expression is very broad.
action: MODIFY
reason: AHR is a DNA-binding transcription factor. The more precise RNA polymerase II transcription-regulation term better represents the evidence than generic gene-expression regulation.
proposed_replacement_terms:
- id: GO:0006357
label: regulation of transcription by RNA polymerase II
supported_by:
- reference_id: PMID:15681594
supporting_text: AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
- term:
id: GO:0030888
label: regulation of B cell proliferation
evidence_type: IDA
original_reference_id: PMID:15681594
qualifier: involved_in
review:
summary: regulation of B cell proliferation is supported as a downstream immunological context of AHR activation, especially through microbial or tryptophan-derived ligands.
action: KEEP_AS_NON_CORE
reason: AHR has substantial immune biology, but these process terms are cell-type- and disease-context-dependent outputs of AHR signaling rather than the core molecular function of the gene product.
supported_by:
- reference_id: PMID:32818467
supporting_text: IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid.
- reference_id: PMID:29454749
supporting_text: Administration of indole metabolites showed prominent induction of IL-10R1 on cultured intestinal epithelia that was explained by activation of the aryl hydrocarbon receptor.
- reference_id: PMID:15681594
supporting_text: AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
- term:
id: GO:0003677
label: DNA binding
evidence_type: TAS
original_reference_id: PMID:8246913
qualifier: enables
review:
summary: AHR DNA binding is real, but the generic DNA binding term is less precise than the available cis-regulatory-region sequence-specific DNA-binding terms.
action: MODIFY
reason: The evidence supports AHR binding to AHR response elements/xenobiotic response elements in regulatory DNA, not undifferentiated DNA binding. A more specific cis-regulatory sequence-specific DNA-binding term should be used.
proposed_replacement_terms:
- id: GO:0000987
label: cis-regulatory region sequence-specific DNA binding
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:15681594
supporting_text: AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
- term:
id: GO:0005634
label: nucleus
evidence_type: TAS
original_reference_id: PMID:8246913
qualifier: located_in
review:
summary: 'nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0001568
label: blood vessel development
evidence_type: NAS
original_reference_id: PMID:19538249
qualifier: involved_in
review:
summary: blood vessel development is biologically connected to AHR pleiotropy but is too broad or indirect for a core AHR annotation.
action: MARK_AS_OVER_ANNOTATED
reason: AHR affects development, cell cycle, apoptosis, and organism-level phenotypes through transcriptional programs, but these high-level process annotations risk implying a direct pathway role that is not supported by the specific evidence used here.
supported_by:
- reference_id: PMID:12213388
supporting_text: This review addresses novel findings relating to AHR functions that have resulted from experimental approaches markedly outside traditional receptor analyses.
- term:
id: GO:0003677
label: DNA binding
evidence_type: TAS
original_reference_id: PMID:19538249
qualifier: enables
review:
summary: AHR DNA binding is real, but the generic DNA binding term is less precise than the available cis-regulatory-region sequence-specific DNA-binding terms.
action: MODIFY
reason: The evidence supports AHR binding to AHR response elements/xenobiotic response elements in regulatory DNA, not undifferentiated DNA binding. A more specific cis-regulatory sequence-specific DNA-binding term should be used.
proposed_replacement_terms:
- id: GO:0000987
label: cis-regulatory region sequence-specific DNA binding
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:15681594
supporting_text: AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
- term:
id: GO:0005667
label: transcription regulator complex
evidence_type: TAS
original_reference_id: PMID:19538249
qualifier: part_of
review:
summary: AHR is part of transcriptional regulatory complexes, but this broad cellular-component term is less informative than the existing AHR complex terms.
action: MODIFY
reason: The relevant complex is the AHR receptor/transcription-factor complex, particularly ligand-activated AHR:ARNT. The more specific AHR complex terms should be used rather than the generic transcription regulator complex term.
proposed_replacement_terms:
- id: GO:0034751
label: aryl hydrocarbon receptor complex
supported_by:
- reference_id: PMID:10395741
supporting_text: These results confirmed functional and physical interactions of AhR/Arnt with ERAP 140 and SMRT in breast cancer cells.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0006805
label: xenobiotic metabolic process
evidence_type: TAS
original_reference_id: PMID:19538249
qualifier: involved_in
review:
summary: xenobiotic metabolic process is a core AHR pathway outcome. AHR binds xenobiotic ligands such as TCDD/dioxin-related compounds and induces detoxification and response genes.
action: ACCEPT
reason: AHR does not enzymatically metabolize xenobiotics itself, but GO biological-process annotations correctly capture its upstream receptor/transcription-factor role in xenobiotic response and metabolism programs.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- term:
id: GO:0034752
label: cytosolic aryl hydrocarbon receptor complex
evidence_type: TAS
original_reference_id: PMID:19538249
qualifier: part_of
review:
summary: cytosolic aryl hydrocarbon receptor complex is an appropriate AHR complex annotation. AHR forms cytosolic chaperone-associated complexes before activation and nuclear AHR:ARNT complexes after ligand-induced activation.
action: ACCEPT
reason: AHR complex membership is central to the receptor activation cycle. The receptor is maintained in a cytosolic HSP90/XAP2/p23 complex before activation and forms an AHR:ARNT DNA-bound complex in the nucleus after ligand activation.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:11259606
supporting_text: The molecular chaperone complex hsp90-p23 interacts with the dioxin receptor
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:9079689
qualifier: enables
review:
summary: The protein binding annotation reflects AHR interactions with ARNT/related bHLH-PAS partners, but the generic term should be refined.
action: MODIFY
reason: AHR:ARNT or related heterodimerization is the informative activity supported by the interaction evidence. The review therefore proposes protein heterodimerization activity rather than generic protein binding.
proposed_replacement_terms:
- id: GO:0046982
label: protein heterodimerization activity
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0051879
label: Hsp90 protein binding
evidence_type: IDA
original_reference_id: PMID:9079689
qualifier: enables
review:
summary: Hsp90 binding is a well-supported part of inactive AHR cytosolic complex formation and receptor trafficking control.
action: ACCEPT
reason: AHR binding to the HSP90 chaperone complex is mechanistically important for receptor conformation, cytoplasmic retention, and ligand-dependent nuclear import. This is an informative molecular-function annotation.
supported_by:
- reference_id: PMID:11259606
supporting_text: The molecular chaperone complex hsp90-p23 interacts with the dioxin receptor
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: NAS
original_reference_id: PMID:9170146
qualifier: enables
review:
summary: DNA-binding transcription factor activity is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
action: ACCEPT
reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:15681594
supporting_text: AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IDA
original_reference_id: PMID:11782478
qualifier: enables
review:
summary: DNA-binding transcription factor activity is supported by the DNA-bound AHR:ARNT transcription-factor complex and by functional assays showing loss of AHR-mediated gene activation when DNA-binding or dimerization interfaces are disrupted.
action: ACCEPT
reason: AHR directly binds cis-regulatory response elements as a heterodimer with ARNT and regulates RNA polymerase II target genes. These DNA-binding/transcription-factor activity terms describe the core activated AHR mechanism.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:15681594
supporting_text: AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation.
- term:
id: GO:0004879
label: nuclear receptor activity
evidence_type: IDA
original_reference_id: PMID:10395741
qualifier: enables
review:
summary: AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding, nuclear translocation, ARNT heterodimerization, and target-gene activation are all well supported.
action: ACCEPT
reason: Although AHR is a bHLH-PAS receptor rather than a classical steroid-receptor-family member, GO nuclear receptor activity appropriately captures its ligand-activated receptor function in the nucleus. This is a core molecular function.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:10395741
qualifier: located_in
review:
summary: 'nucleus localization is consistent with AHR biology: inactive AHR is predominantly cytoplasmic/cytosolic in a chaperone complex and ligand activation drives nuclear/nucleoplasmic accumulation and chromatin-associated transcriptional activity.'
action: ACCEPT
reason: These cellular-component annotations reflect the normal ligand-dependent trafficking cycle of AHR rather than separate functions. The 2021 live-cell analysis directly supports cytoplasmic localization and nuclear translocation; chromatin/nuclear annotations are consistent with the DNA-bound AHR:ARNT transcription-factor complex.
supported_by:
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- term:
id: GO:0006355
label: regulation of DNA-templated transcription
evidence_type: IDA
original_reference_id: PMID:10395741
qualifier: involved_in
review:
summary: regulation of DNA-templated transcription is consistent with AHR acting as a ligand-activated transcription factor that regulates RNA polymerase II target genes after nuclear AHR:ARNT complex formation.
action: ACCEPT
reason: Transcriptional regulation is the central biological output of activated AHR. The term is broad in some cases, but the direction and process are supported by ligand-induced target gene activation and by cofactor/transactivation-domain evidence.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:10395741
supporting_text: These results confirmed functional and physical interactions of AhR/Arnt with ERAP 140 and SMRT in breast cancer cells.
- reference_id: PMID:15641800
supporting_text: the acidic Q-rich region bound to components of the general transcription machinery
- term:
id: GO:0006915
label: apoptotic process
evidence_type: TAS
original_reference_id: PMID:12213388
qualifier: involved_in
review:
summary: apoptotic process is biologically connected to AHR pleiotropy but is too broad or indirect for a core AHR annotation.
action: MARK_AS_OVER_ANNOTATED
reason: AHR affects development, cell cycle, apoptosis, and organism-level phenotypes through transcriptional programs, but these high-level process annotations risk implying a direct pathway role that is not supported by the specific evidence used here.
supported_by:
- reference_id: PMID:12213388
supporting_text: This review addresses novel findings relating to AHR functions that have resulted from experimental approaches markedly outside traditional receptor analyses.
- term:
id: GO:0009410
label: response to xenobiotic stimulus
evidence_type: IDA
original_reference_id: PMID:7961644
qualifier: involved_in
review:
summary: response to xenobiotic stimulus is a core AHR pathway outcome. AHR binds xenobiotic ligands such as TCDD/dioxin-related compounds and induces detoxification and response genes.
action: ACCEPT
reason: AHR does not enzymatically metabolize xenobiotics itself, but GO biological-process annotations correctly capture its upstream receptor/transcription-factor role in xenobiotic response and metabolism programs.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
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:0000052
title: Gene Ontology annotation based on curation of immunofluorescence data
findings: []
- id: GO_REF:0000108
title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links
findings: []
- id: GO_REF:0000113
title: Gene Ontology annotation of human sequence-specific DNA binding transcription factors (DbTFs) based on the TFClass database
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:10395741
title: Interactions of nuclear receptor coactivator/corepressor proteins with the aryl hydrocarbon receptor complex.
findings:
- statement: AHR/ARNT physically and functionally interacts with transcriptional coactivator/corepressor proteins.
supporting_text: functional and physical interactions of AhR/Arnt with ERAP 140 and SMRT
- id: PMID:11259606
title: The hsp90 chaperone complex regulates intracellular localization of the dioxin receptor.
findings:
- statement: HSP90-p23/XAP2 controls AHR cytoplasmic retention and ligand-dependent nuclear import.
supporting_text: hsp90 molecular chaperone complex in regulation of the intracellular localization of the dioxin receptor
- id: PMID:11782478
title: Differential activities of murine single minded 1 (SIM1) and SIM2 on a hypoxic response element. Cross-talk between basic helix-loop-helix/per-Arnt-Sim homology transcription factors.
findings: []
- id: PMID:12213388
title: Role of the aryl hydrocarbon receptor in cell cycle regulation.
findings: []
- id: PMID:15641800
title: Induced alpha-helix structure in the aryl hydrocarbon receptor transactivation domain modulates protein-protein interactions.
findings: []
- id: PMID:15681594
title: Constitutive activation and environmental chemical induction of the aryl hydrocarbon receptor/transcription factor in activated human B lymphocytes.
findings: []
- id: PMID:16257957
title: Regulation of transactivation function of the aryl hydrocarbon receptor by the Epstein-Barr virus-encoded EBNA-3 protein.
findings: []
- id: PMID:17329248
title: Phosphodiesterase 2A forms a complex with the co-chaperone XAP2 and regulates nuclear translocation of the aryl hydrocarbon receptor.
findings: []
- id: PMID:19538249
title: 'The aryl hydrocarbon receptor: a perspective on potential roles in the immune system.'
findings: []
- id: PMID:23275542
title: 2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase (TiPARP, ARTD14) is a mono-ADP-ribosyltransferase and repressor of aryl hydrocarbon receptor transactivation.
findings:
- statement: TIPARP directly interacts with and represses AHR, providing feedback regulation and evidence for AHR proteolytic degradation.
supporting_text: TiPARP and AHR co-localized in the nucleus, directly interacted
- id: PMID:28514442
title: Architecture of the human interactome defines protein communities and disease networks.
findings: []
- id: PMID:28602820
title: Structural Basis for Aryl Hydrocarbon Receptor-Mediated Gene Activation.
findings:
- statement: The AHR:ARNT bHLH-PAS complex binds target DNA and its interfaces are required for gene activation.
supporting_text: structural basis of AHR assembly and DNA interaction
- id: PMID:29454749
title: Microbiota-Derived Indole Metabolites Promote Human and Murine Intestinal Homeostasis through Regulation of Interleukin-10 Receptor.
findings: []
- id: PMID:32818467
title: IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression.
findings:
- statement: Tryptophan-catabolite activation of AHR promotes tumor progression and suppresses adaptive immunity.
supporting_text: IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid
- id: PMID:32866000
title: Endogenous Indole Pyruvate Pathway for Tryptophan Metabolism Mediated by IL4I1.
findings: []
- id: PMID:33961781
title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
findings: []
- id: PMID:34521881
title: The role of DNA-binding and ARNT dimerization on the nucleo-cytoplasmic translocation of the aryl hydrocarbon receptor.
findings:
- statement: AHR is predominantly cytoplasmic and ligand activation stabilizes nuclear accumulation independent of ARNT or DNA binding.
supporting_text: predominantly located in the cytoplasm, while activation depends on its nuclear translocation
- id: PMID:39900897
title: Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complex.
full_text_unavailable: true
findings:
- statement: Crystal structures of AHR-ARNT-DNA complexes bound to six AHR ligands (tapinarof, FICZ, benzo[a]pyrene, beta-naphthoflavone, indigo, indirubin) reveal an unconventional assembly with intimate PAS-B to PAS-B association between AHR and ARNT.
- statement: The AHR PAS-B domain is the principal ligand-binding pocket, using eight conserved residues that dynamically rearrange to accommodate diverse ligands via hydrophobic and pi-pi interactions.
- statement: Ligand binding drives a structural transition of an AHR segment from chaperone engagement to ARNT-heterodimer stabilization, generating the transcriptionally competent AHR:ARNT DNA-bound complex.
- id: PMID:40247142
title: 'The aryl hydrocarbon receptor: a rehabilitated target for therapeutic immune modulation.'
full_text_unavailable: true
findings:
- statement: AHR is a ligand-activated transcription factor that functions as a physiological regulator of both innate and adaptive immunity, modulated by diet, commensal flora, and metabolism in autoimmunity, cancer, and infection.
- statement: The AHR-activating drug tapinarof was approved for treatment of psoriasis, and AHR-targeting therapeutics are in clinical trials for inflammatory diseases, cancer, and infection, establishing AHR as a tractable therapeutic target.
- id: PMID:7961644
title: Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors.
findings:
- statement: Human AHR ligand binding is directly supported by expression and mutagenesis assays.
supporting_text: the cDNA-encoded protein binds the ligand specifically
- id: PMID:8246913
title: Cloning and expression of a human Ah receptor cDNA.
findings: []
- id: PMID:9079689
title: Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway.
findings: []
- id: PMID:9170146
title: 'Human Ah receptor (AHR) gene: localization to 7p15 and suggestive correlation of polymorphism with CYP1A1 inducibility.'
findings: []
- id: PMID:9704006
title: Transcriptionally active heterodimer formation of an Arnt-like PAS protein, Arnt3, with HIF-1a, HLF, and clock.
findings: []
- id: Reactome:R-HSA-8936849
title: AHR:2xHSP90:AIP:PTGES3 binds TCDD
findings: []
- id: Reactome:R-HSA-8937144
title: Aryl hydrocarbon receptor signalling
findings: []
- id: Reactome:R-HSA-8937169
title: AHR:TCDD:2xHSP90AB1:AIP:PTGES3 translocates from cytosol to nucleoplasm
findings: []
- id: Reactome:R-HSA-8937177
title: AHR:TCDD binds ARNT
findings: []
- id: Reactome:R-HSA-8937191
title: AHR:TCDD:2xHSP90AB1:AIP:PTGES3 dissociates
findings: []
- id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv
title: Proteostasis PN projected candidate additions
findings: []
- id: file:projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv
title: Proteostasis PN mapping scrutiny report
findings: []
- id: file:projects/PROTEOSTASIS/mappings/ubiquitin_proteasome_system.yaml
title: Proteostasis PN ubiquitin proteasome system mapping set
findings: []
- id: file:human/AHR/AHR-notes.md
title: AHR manual review notes
findings: []
core_functions:
- molecular_function:
id: GO:0004879
label: nuclear receptor activity
directly_involved_in:
- id: GO:0006357
label: regulation of transcription by RNA polymerase II
- id: GO:0006805
label: xenobiotic metabolic process
- id: GO:0009410
label: response to xenobiotic stimulus
locations:
- id: GO:0005737
label: cytoplasm
- id: GO:0005634
label: nucleus
in_complex:
id: GO:0034751
label: aryl hydrocarbon receptor complex
description: Primary function. AHR is a ligand-activated intracellular receptor/transcription factor. Ligand binding to cytoplasmic AHR promotes nuclear accumulation, ARNT heterodimerization, binding to AHR response elements, and regulation of xenobiotic/endogenous-ligand response genes.
supported_by:
- reference_id: PMID:7961644
supporting_text: This result provides the first direct evidence that the cDNA-encoded protein binds the ligand specifically.
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- molecular_function:
id: GO:0046982
label: protein heterodimerization activity
directly_involved_in:
- id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
locations:
- id: GO:0005654
label: nucleoplasm
in_complex:
id: GO:0034753
label: nuclear aryl hydrocarbon receptor complex
description: Activated AHR heterodimerizes with ARNT to form the nuclear DNA-binding transcription-factor complex. This heterodimeric state is required for efficient AHR response element binding and target-gene activation. Crystal structures of ligand-bound AHR:ARNT:DNA complexes show an unconventional assembly with intimate PAS-B to PAS-B association between AHR and ARNT, with the AHR PAS-B domain serving as the principal ligand-binding pocket.
supported_by:
- reference_id: PMID:28602820
supporting_text: AHR is activated by xenobiotics, notably dioxin
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
- molecular_function:
id: GO:0051879
label: Hsp90 protein binding
directly_involved_in:
- id: GO:0009410
label: response to xenobiotic stimulus
locations:
- id: GO:0005737
label: cytoplasm
in_complex:
id: GO:0034752
label: cytosolic aryl hydrocarbon receptor complex
description: Inactive AHR is maintained in a cytosolic chaperone-associated receptor complex. HSP90/p23/XAP2 interactions support ligand-binding conformation, cytoplasmic retention, and ligand-dependent nuclear import.
supported_by:
- reference_id: PMID:11259606
supporting_text: The molecular chaperone complex hsp90-p23 interacts with the dioxin receptor
- reference_id: PMID:34521881
supporting_text: The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation.
proposed_new_terms: []
suggested_questions:
- question: Does endogenous human AHR directly function as a CRL4/CUL4A-CUL4B substrate adaptor, or is the PN UPS placement better interpreted as broad complex/domain context plus AHR turnover rather than an AHR molecular function?
experts: []
- question: Which immune and developmental AHR outputs should be treated as broadly physiological annotations versus ligand-, tissue-, or disease-specific non-core contexts?
experts: []
- question: Now that AHR:ARNT:DNA structures define the PAS-B domain as the principal ligand-binding pocket and reveal a PAS-B/PAS-B heterodimer interface, should a ligand-binding molecular-function term (e.g., a small-molecule/xenobiotic sensor activity) be added to better capture AHR ligand recognition distinct from its DNA-binding and dimerization activities?
experts: []
suggested_experiments:
- hypothesis: AHR should only receive GO:1990756 if it directly bridges a substrate to a CUL4 ubiquitin-ligase complex.
description: Reconstitute candidate DDB1-CUL4A/CUL4B-AHR/ARNT/TBL3 assemblies and test whether AHR directly recruits a defined substrate for ubiquitination, including CUL4 dependence, AHR mutant controls, and comparison with established DCAF substrate receptors.
experiment_type: in vitro ubiquitination and complex reconstitution
- hypothesis: The PN AHR UPS projection may reflect regulated degradation of AHR rather than substrate-adaptor activity by AHR.
description: Use endogenous-tagged AHR cells with proteasome inhibition, CUL4/DDB1 perturbation, and quantitative IP-MS/proximity labeling to distinguish AHR as a CUL4 substrate, a stable CRL4 complex component, or a substrate-recruiting adaptor.
experiment_type: endogenous proteomics and perturbation assay
