# AIRE notes

## 2026-06-03 PN batch review

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

Core biology: AIRE is best supported as a nuclear chromatin-associated transcriptional regulator for thymic self-tolerance. It promotes central tolerance and prevents autoimmunity [PMID:26084028 "The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity."]. Mechanistically, AIRE binds histone H3 through PHD1 and preferentially recognizes H3K4me0 [PMID:18292755 "AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger"; PMID:18292755 "preferentially binds to non-methylated H3K4 (H3K4me0)"], with structural support for the H3-binding interface [PMID:19446523 "The structure reveals a detailed network of interactions between the protein and the amino-terminal residues of histone H3"]. AIRE also binds A/T-rich DNA motifs as oligomers [PMID:11533054 "AIRE dimers and tetramers, but not the monomers, can bind to G-doublets with the ATTGGTTA motif and the TTATTA-box."] and activates transcription in reporter/promoter contexts [PMID:11274163 "AIRE can activate the interferon beta minimal promoter in a transfection assay"; PMID:18292755 "in vivo AIRE binds to and activates promoters containing low levels of H3K4me3"].

PN projection: the PN report projects `GO:0061630 ubiquitin protein ligase activity` for AIRE from `Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING variant|PHD|other` [file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv]. I did not add this as a `NEW` annotation. The projection is a domain/family-bucket inference and the current AIRE evidence supports PHD histone-reader/chromatin/transcription functions, not catalytic ubiquitin transfer. AIRE's PHD domain is experimentally characterized as a histone-recognition zinc finger rather than an E3 ligase catalytic module [PMID:19446523 "PHD1 of AIRE belongs to the second class of PHD histone reader"]. I added a suggested question/experiment to test whether any direct E3 activity exists, but the current conservative curation decision is no GO ubiquitin ligase annotation.

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