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