## 2026-06-03 - PROTEOSTASIS PN review pass

ADRB2 was fetched for the Proteostasis PN batch with `just fetch-gene human ADRB2`. The Falcon deep-research job was attempted with the project fallback command, `just deep-research-falcon human ADRB2 --fallback perplexity-lite`, but Falcon timed out after 600 seconds and the fallback provider failed with a 401 quota error. No `ADRB2-deep-research-falcon.md` or fallback deep-research report was created, so this review uses the local UniProt record, GOA-derived review stub, cached publications, Reactome records, and PN projection reports.

ADRB2 is a seven-transmembrane beta-2 adrenergic receptor. UniProt summarizes it as a catecholamine GPCR that couples to both G(s) and G(i) proteins and binds epinephrine with higher affinity than norepinephrine [file:human/ADRB2/ADRB2-uniprot.txt, "G protein-coupled receptor for catecholamines that couples to"; file:human/ADRB2/ADRB2-uniprot.txt, "approximately 30-fold greater affinity than norepinephrine (NE)"]. The classic mutagenesis paper supports catecholamine binding, Gs coupling, and adenylate cyclase stimulation [PMID:2831218, "associated with high affinity ligand binding, Gs coupling, and adenylate cyclase"].

The PN projection places ADRB2 under `Autophagy-Lysosome Pathway > Autophagy substrate selection > Marking substrates for selective autophagy > Lipophagy > Upstream lipophagy signaling`, projecting `GO:0061724 lipophagy` while noting that GOA already has `GO:1904504 positive regulation of lipophagy`. The source paper supports ADRB2 stimulation as an upstream signal that increases autophagy-targeted lipid droplets and contributes to hormone-stimulated lipolysis [PMID:23708524, "ADRB2 stimulation has caused a marked increase in the autophagy-targeted LDs for lysosomal degradation"; PMID:23708524, "during ADRB2 stimulation, a subset of LDs are packaged into autophagosomes and delivered to the lysosomes for degradation"]. However, the paper identifies RAB7 as the direct lipid-droplet lipophagy machinery factor [PMID:23708524, "RAB7 plays a pivotal role in the regulation of this autolysosome-mediated lipid degradation in fat cells"]. Curation conclusion: keep the existing `positive regulation of lipophagy` and `positive regulation of autophagosome maturation` as supported non-core adipocyte signaling outputs, but do not add direct `lipophagy` for ADRB2.

ADRB2 trafficking annotations are real but secondary to receptor signaling. The receptor undergoes agonist-induced internalization, recycling, ubiquitin-dependent lysosomal sorting, and Golgi-associated palmitoylation itinerary [PMID:9507004, "trafficking of the beta2AR via the clathrin-coated pit endosomal pathway to lysosomes"; PMID:19424180, "sort internalized receptors to the lysosomes for degradation"; PMID:27481942, "traffics along a previously undescribed intracellular itinerary via the Golgi complex"]. These support endosome, lysosome, clathrin-coated vesicle membrane, Golgi, and endosome-to-lysosome transport as non-core receptor lifecycle contexts.

Generic `protein binding` rows are not informative ADRB2 molecular functions. Specific interaction contexts such as receptor oligomerization, beta-arrestin/NHERF/SNX27/ubiquitin-ligase trafficking partners, amyloid-beta binding, and Kir3/adenylyl cyclase signaling complexes can be retained as non-core where directly supported, but the core molecular function should remain beta-2 adrenergic receptor activity and catecholamine-triggered GPCR signaling.

## Falcon deep research findings (2026-06-07)

A Falcon (Edison Scientific) deep-research report (`ADRB2-deep-research-falcon.md`) was successfully generated, replacing the earlier failed attempt noted above. Key findings, emphasizing what is NEW relative to the existing review:

- Endosomal / sustained GPCR signaling and the "megaplex" concept: GPCRs including beta2AR can continue activating G proteins after internalization into endosomes, and a single receptor can simultaneously engage G protein (via the transmembrane core) and beta-arrestin (via the phosphorylated tail) in a "megaplex" assembly [PMID:38643023 "some GPCRs continue to activate G proteins after having been internalized into endosomes"; Flores-Espinoza & Thomsen 2024, doi:10.1016/j.tibs.2024.03.006]. This reframes the endosome as a potential signaling-competent compartment, not only a degradation/recycling waystation as the existing review treats it. Treated here as an emerging mechanistic concept (review synthesis), so it informs notes/questions but is NOT used to change any localization annotation.

- beta-arrestin scaffolding to inflammatory kinase/transcription programs: in airway/respiratory contexts, beta2AR GRK/beta-arrestin signaling links not only to ERK but also to p38 MAPK and NF-kB, with downstream consequences including mucus-gene (MUC5AC) transcription and airway smooth-muscle proliferation [PMID:39408565 "beta2AR is implicated in bronchodilation, mucociliary clearance, and anti-inflammatory effects"; Manti et al. 2024, doi:10.3390/ijms251910234]. The existing review already accepts positive regulation of MAPK cascade; the p38/NF-kB inflammatory branch is additional context but not separately annotated here without primary ADRB2-specific experimental support.

- Biased agonism and immune-cell signaling (NEW physiological context): a 2024 study using CRISPR/Cas9 ADRB2 knockout in human T cells reported that the biased agonist nebivolol suppressed IL-17A and Th17 responses in an ADRB2-dependent, NF-kB p65-dependent manner without changing CREB phosphorylation, implying pathway-selective (biased) outputs downstream of ADRB2 [Hajiaghayi et al. 2024, Front Immunol, doi:10.3389/fimmu.2024.1446424 (PMID:39445009)]. Interesting for biased-signaling questions; not annotated (single study, specialized immune context).

- Cardiomyocyte compartmentalization: beta2AR is enriched in / confined to the T-tubular network in cardiomyocytes, supporting spatially constrained signaling and Gs-to-Gi switching with beta-arrestin scaffolding of PDEs/DGKs and EGFR transactivation [Grogan et al. 2023, Cardiovasc Res, doi:10.1093/cvr/cvac171 (PMID:36534965)]. Consistent with existing cardiac non-core annotations; adds spatial-encoding detail only.

- Pharmacogenomic / disease links (NEW disease detail): common coding variants rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu), plus rarer Thr164Ile, are the main ADRB2 pharmacogenetic variants. rs1042714 was associated with lung function and bronchodilator response in asthma (e.g., delta-FEV1 p=0.023; bronchodilator response p=0.040) [de Sousa et al. 2024, Genet Mol Res, doi:10.4238/gmr2311], and an rs1042713 G allele showed association with essential hypertension in East Asians (OR ~1.26). Multiple reviews conclude the bronchodilator-response pharmacogenetics remain mixed/inconsistent and NOT yet clinically actionable as a single-gene tool [Ntenti et al. 2025, doi:10.3390/genes16030314; Buddhadev et al. 2026 (provisional, 0 citations), doi:10.21911/aai.2026.1162]. Buddhadev et al. is a very recent low-citation source and is treated as provisional; not used to drive any annotation.

- No findings contradict the existing review's annotation decisions. The Falcon report's higher-confidence mechanistic content (endosomal signaling, beta-arrestin/MAPK, T-tubule localization, Gs/Gi bifurcation) reinforces the current ACCEPT/KEEP_AS_NON_CORE calls. Two new primary references (PMID:38643023 endosomal GPCR signaling review; PMID:39408565 beta2AR respiratory review) added to YAML references as statement-only, full_text_unavailable entries.