AIRE PN Consistency Notes
- Generated: 2026-06-18
- Project: PROTEOSTASIS
- Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
- UniProt: O43918
- AIGR review status: COMPLETE
- Review batch: proteostasis-batch-2026-06-03 (PR 1358)
- Batch change status: added
Source Files Checked
Deep Research Files
AIGR Review Snapshot
- Description: AIRE is a nuclear autoimmune regulator expressed most prominently in medullary thymic epithelial cells, where it promotes central self-tolerance by enabling promiscuous expression of tissue-restricted antigen genes. The protein contains an HSR oligomerization domain, a SAND domain, and two PHD zinc fingers; PHD1 acts as a histone H3K4me0 reader that helps target AIRE to poorly active chromatin and supports transcriptional activation of self-antigen genes. AIRE also forms nuclear-body-like structures and interacts with chromatin and transcription/RNA-processing partners. Loss-of-function or dominant-negative AIRE variants impair these transcriptional tolerance programs and cause autoimmune polyendocrine syndrome type 1 or related organ-specific autoimmune phenotypes.
- Existing/core annotation action counts: ACCEPT: 21; KEEP_AS_NON_CORE: 19; MARK_AS_OVER_ANNOTATED: 8; MODIFY: 5; REMOVE: 2
PN Consistency Summary
- Consistency: Major contradiction between PN annotation and review. PN classifies AIRE as a catalytic E3 ligase (RING-variant/PHD) and projects GO:0061630 as a new GOA annotation. The review and notes treat AIRE strictly as a nuclear chromatin reader / Pol II transcriptional activator (PHD1 = H3K4me0 histone reader, PMID:18292755, 19446523) and explicitly decline to add GO:0061630, adding instead a suggested experiment to test for absent E3 activity. Deep research (manual) and review are internally consistent; the PN node is the outlier.
- PN story / NEW pressure: PN asserts an E3-ligase MF not in GOA. GO:0061630 is a real term, but for AIRE this is a domain-bucket inference (PHD≈RING fold) not supported by the cached AIRE evidence, which characterizes the PHD as a histone-recognition module, not a catalytic ligase. Verdict: over-reaches as currently projected; treat as candidate requiring direct ubiquitin-transfer evidence, not an automatic ADD. (Some non-cached mouse literature reports AIRE E2-binding/E3-like activity — flag for full-text check before any REMOVE/ADD verdict; reviewer's conservative non-adoption is defensible.)
- Evidence alignment: Divergent. PN cites PMIDs 14734522 and 15150263 (not in the review's reference list); review is built on the chromatin/transcription corpus (PMID:11533054, 18292755, 19446523, 26084028). No PMID overlap — the PN E3 case rests on references the review never adjudicated.
- Verdict: PN E3-ligase placement/projection over-reaches for AIRE; review correctly withholds GO:0061630 pending direct evidence.
Full Consistency Review
- UniProt: O43918 · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE
- PN placement:
Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING variant|PHD|other ; PN-node mapping: PHD/RING-variant subtype+type no_mapping; group (RING variant) mapped→GO:0061630 (ubiquitin protein ligase activity, propagate); class context_only (too_broad). Projection: GO:0061630 new_to_goa.
- Consistency: Major contradiction between PN annotation and review. PN classifies AIRE as a catalytic E3 ligase (RING-variant/PHD) and projects GO:0061630 as a new GOA annotation. The review and notes treat AIRE strictly as a nuclear chromatin reader / Pol II transcriptional activator (PHD1 = H3K4me0 histone reader, PMID:18292755, 19446523) and explicitly decline to add GO:0061630, adding instead a suggested experiment to test for absent E3 activity. Deep research (manual) and review are internally consistent; the PN node is the outlier.
- PN story / NEW pressure: PN asserts an E3-ligase MF not in GOA. GO:0061630 is a real term, but for AIRE this is a domain-bucket inference (PHD≈RING fold) not supported by the cached AIRE evidence, which characterizes the PHD as a histone-recognition module, not a catalytic ligase. Verdict: over-reaches as currently projected; treat as candidate requiring direct ubiquitin-transfer evidence, not an automatic ADD. (Some non-cached mouse literature reports AIRE E2-binding/E3-like activity — flag for full-text check before any REMOVE/ADD verdict; reviewer's conservative non-adoption is defensible.)
- Mapping strategy: The RING-variant group→GO:0061630 propagation is biologically safe for canonical RING E3s but mis-fires on the PHD/"other" subtype that AIRE occupies. The subtype is already no_mapping; the issue is the parent group propagating catalytic activity down to a histone-reader PHD. Mapping should not project GO:0061630 onto PHD-only members lacking ligase evidence.
- Evidence alignment: Divergent. PN cites PMIDs 14734522 and 15150263 (not in the review's reference list); review is built on the chromatin/transcription corpus (PMID:11533054, 18292755, 19446523, 26084028). No PMID overlap — the PN E3 case rests on references the review never adjudicated.
- Verdict: PN E3-ligase placement/projection over-reaches for AIRE; review correctly withholds GO:0061630 pending direct evidence.
- Recommended edits: [MAP] Mark AIRE (and other PHD-"other" members) as a gene-level exception to the RING-variant→GO:0061630 propagation, or downgrade that subtree to context_only, since PHD-reader members are not demonstrated catalytic E3s. [REF] Adjudicate PMID:14734522 and PMID:15150263 (the PN E3 references) — fetch full text and record a reference_review before any E3 verdict.
PN Dossier Context
- review_batch: proteostasis-batch-2026-06-03
- review_yaml: genes/human/AIRE/AIRE-ai-review.yaml
- PN workbook rows: 1
PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | RING variant | PHD | other
- UniProt: O43918
- In branches: UPS
- Signature domains: IPR001965
- Auxiliary domains: (none)
- PN references (titles):
- PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING variant|PHD|other
status=no_mapping scope= GO=[]
rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING variant|PHD
status=no_mapping scope= GO=[]
rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING variant
status=mapped scope=ok_for_propagation_to_go GO=[GO:0061630 ubiquitin protein ligase activity]
rationale: This PN group is a catalytic ubiquitin E3 ligase bucket. The shared GO molecular-function target is ubiquitin protein ligase activity.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
status=no_mapping scope= GO=[]
rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.
Projected GO annotations (1)
- GO:0061630 ubiquitin protein ligase activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING variant
Note
This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.