AHR PN Consistency Notes
- Generated: 2026-06-18
- Project: PROTEOSTASIS
- Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
- UniProt: P35869
- AIGR review status: COMPLETE
- Review batch: proteostasis-batch-2026-06-03 (PR 1353)
- Batch change status: added
Source Files Checked
Deep Research Files
AIGR Review Snapshot
- 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/core annotation action counts: ACCEPT: 73; KEEP_AS_NON_CORE: 10; MARK_AS_OVER_ANNOTATED: 4; MODIFY: 15
PN Consistency Summary
- Consistency: Large but well-managed divergence. PN frames AHR as a CUL4 substrate adaptor in the UPS branch. Deep research (falcon) and review establish AHR's canonical identity as a ligand-activated bHLH-PAS nuclear receptor / RNA Pol II transcription factor (HSP90/XAP2/p23 cytosolic complex → ARNT heterodimer → XRE binding). The review/notes explicitly did NOT accept the PN GO:1990756 projection: AHR's own subtype/type are
no_mapping, and the parent group is flagged manual_gene_level_review_required_before_gene_review_change. Notes acknowledge CUL4B^AHR E3 activity from the literature (Xie 2024 review; ER-α/AR/β-catenin targets) but retain it as an open question, not an annotation. Internally consistent; PN UPS role deliberately not propagated.
- PN story / NEW pressure: PN asserts an MF (GO:1990756, verified real/non-obsolete) absent from GOA. AHR-as-CUL4-adaptor is supported only by a subset of (largely review/secondary) literature and is mechanistically contested vs. AHR being itself a CUL4 substrate. Verdict: over-reaches as a gene-level GO assertion now — correctly deferred (suggested_question + suggested_experiment to test direct substrate-bridging vs AHR turnover). The genuine AHR core functions (nuclear receptor activity, heterodimerization, sequence-specific DNA binding, Hsp90 binding) are already richly annotated.
- Evidence alignment: No overlap between PN refs (PMID:17392787, 28416634 — uncached, not used) and the review's evidence base (PMID:34521881, 28602820, 7961644, 11259606, 15641800, 32818467, etc.). The review builds the canonical TF case independently; the PN UPS citations are neither verified nor relied upon. Divergent reference sets, reconciled by treating the UPS role as unverified.
- Verdict: PN UPS/CUL4-adaptor projection (GO:1990756) over-reaches; correctly NOT propagated to AHR (left as open question). Core TF/nuclear-receptor function fully captured. Recommended edits: none to YAML. [MAP]: keep AHR/ARNT/TBL3 and PAS subtypes
no_mapping; gate the Cul4A/Cul4B substrate-adaptor group GO:1990756 behind per-gene review (AHR is the cautionary case). [REF]: optionally fetch/verify PN PMID:17392787 & 28416634 to substantiate or retire the AHR UPS placement.
Full Consistency Review
- UniProt: P35869 · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE
- PN placement:
Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate adaptor|AHR / ARNT / TBL3 complex|PAS ; PN-node mapping: subtype(PAS)/type(AHR/ARNT/TBL3) no_mapping; group (Cul4A/Cul4B substrate adaptor) mapped GO:1990756 ubiquitin-like ligase-substrate adaptor activity (new_to_goa); class (E3 ligases) context_only too_broad GO:0061630; branch no_mapping. PN references: PMID:17392787, 28416634 (titles not in dossier; not cached locally).
- Consistency: Large but well-managed divergence. PN frames AHR as a CUL4 substrate adaptor in the UPS branch. Deep research (falcon) and review establish AHR's canonical identity as a ligand-activated bHLH-PAS nuclear receptor / RNA Pol II transcription factor (HSP90/XAP2/p23 cytosolic complex → ARNT heterodimer → XRE binding). The review/notes explicitly did NOT accept the PN GO:1990756 projection: AHR's own subtype/type are
no_mapping, and the parent group is flagged manual_gene_level_review_required_before_gene_review_change. Notes acknowledge CUL4B^AHR E3 activity from the literature (Xie 2024 review; ER-α/AR/β-catenin targets) but retain it as an open question, not an annotation. Internally consistent; PN UPS role deliberately not propagated.
- PN story / NEW pressure: PN asserts an MF (GO:1990756, verified real/non-obsolete) absent from GOA. AHR-as-CUL4-adaptor is supported only by a subset of (largely review/secondary) literature and is mechanistically contested vs. AHR being itself a CUL4 substrate. Verdict: over-reaches as a gene-level GO assertion now — correctly deferred (suggested_question + suggested_experiment to test direct substrate-bridging vs AHR turnover). The genuine AHR core functions (nuclear receptor activity, heterodimerization, sequence-specific DNA binding, Hsp90 binding) are already richly annotated.
- Mapping strategy: Gene does not change the node. The Cul4A/Cul4B substrate-adaptor group→GO:1990756 mapping is too liberal for AHR; AHR's leaf nodes are appropriately
no_mapping, and the review upholds that. This is a stronger "do not propagate" case than broader-term rejections (TOMM20/HSPA8/RAB7A) because the asserted MF is a different biological role from AHR's primary function.
- Evidence alignment: No overlap between PN refs (PMID:17392787, 28416634 — uncached, not used) and the review's evidence base (PMID:34521881, 28602820, 7961644, 11259606, 15641800, 32818467, etc.). The review builds the canonical TF case independently; the PN UPS citations are neither verified nor relied upon. Divergent reference sets, reconciled by treating the UPS role as unverified.
- Verdict: PN UPS/CUL4-adaptor projection (GO:1990756) over-reaches; correctly NOT propagated to AHR (left as open question). Core TF/nuclear-receptor function fully captured. Recommended edits: none to YAML. [MAP]: keep AHR/ARNT/TBL3 and PAS subtypes
no_mapping; gate the Cul4A/Cul4B substrate-adaptor group GO:1990756 behind per-gene review (AHR is the cautionary case). [REF]: optionally fetch/verify PN PMID:17392787 & 28416634 to substantiate or retire the AHR UPS placement.
PN Dossier Context
- review_batch: proteostasis-batch-2026-06-03
- review_yaml: genes/human/AHR/AHR-ai-review.yaml
- PN workbook rows: 1
PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul4A/Cul4B substrate adaptor | AHR / ARNT / TBL3 complex | PAS
- UniProt: P35869
- In branches: UPS
- Signature domains: (none)
- Auxiliary domains: IPR000014
- PN references (titles):
- PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate adaptor|AHR / ARNT / TBL3 complex|PAS
status=no_mapping scope= GO=[]
rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate adaptor|AHR / ARNT / TBL3 complex
status=no_mapping scope= GO=[]
rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate adaptor
status=mapped scope=ok_for_propagation_to_go GO=[GO:1990756 ubiquitin-like ligase-substrate adaptor activity]
rationale: This PN group captures substrate receptors/adaptors for cullin/UBL ligase systems. The shared GO molecular-function target is ubiquitin-like ligase-substrate adaptor activity.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
status=no_mapping scope= GO=[]
rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.
Projected GO annotations (1)
- GO:1990756 ubiquitin-like ligase-substrate adaptor activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate adaptor
Note
This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.