Proteostasis Review Batch 3 — Gene Selection

Date: 2026-06-06
Branch: claude/proteostasis-gene-review-w59I5

Context

The two prior batches are complete:
- proteostasis-pr-1217 (50 human genes, merged 2026-06-02)
- proteostasis-batch-2026-06-03 (50 human genes, alphabetical sweep AAAS..ATP6V0D1 from the PN projected candidate-additions report)

All five priority_genes.tsv no-local-dir targets (BTF3, HSPA12A, HSPA12B,
AARSD1, BAG6) now also have local reviews.

This batch selects 20 more genes from the PN projected candidate-additions
report (reports/pn_projection/pn_projected_candidate_additions.tsv), all of
which are (a) PN-projected candidates with ok_for_propagation_to_go scope and
(b) had no local *-ai-review.yaml before this batch.

Rather than continuing the pure alphabetical sweep (which next hits a long run
of family/domain-based BTB-domain inclusions of lower individual value), this
batch is chosen to be biologically coherent and high-value across the three
main proteostasis branches.

Selected genes (20)

ALP — lysosomal acidification (V-ATPase, completing the V0 set from batch 2)

1. ATP6V1A — V-ATPase V1 catalytic A subunit
2. ATP6V1B2 — V-ATPase V1 B2 subunit
3. ATP6V1C1 — V-ATPase V1 C1 subunit
4. ATP6V1D — V-ATPase V1 D subunit
5. ATP6V1E1 — V-ATPase V1 E1 subunit
6. ATP6V1F — V-ATPase V1 F subunit
7. ATP6V1G1 — V-ATPase V1 G1 subunit
8. ATP6V1H — V-ATPase V1 H subunit
9. ATP6V0E1 — V-ATPase V0 e1 subunit

ALP — selective autophagy / mitophagy receptors

1. BNIP3L (NIX) — mitophagy receptor
2. BCL2L13 — mammalian Atg32-like mitophagy receptor
3. CALCOCO1 — ER-phagy / Golgiphagy receptor (CoCoA)

ER proteostasis — folding & quality control

1. CANX — calnexin, ER lectin chaperone (calnexin/calreticulin cycle)
2. CALR — calreticulin, ER lectin chaperone
3. CCDC47 — ER multipass membrane protein biogenesis / calnexin-associated
4. CAMLG — GET/TRC pathway (tail-anchored membrane protein insertion)
5. AUP1 — ERAD / lipid-droplet ubiquitination adaptor

Cytosolic co-chaperone & UPS regulation

1. BAG2 — BAG-domain HSP70 co-chaperone (nucleotide exchange factor)
2. CACYBP (SIP) — Siah-1 interacting protein, ubiquitination adaptor
3. CAND1 — cullin-associated/dissociation factor; CRL E3 ligase regulator

Method

For each gene:
- uv run ai-gene-review fetch-gene human <GENE> --output-dir . (UniProt, GOA,
cached publications, seeded -ai-review.yaml).
- Research from cached publications + UniProt + literature; notes recorded in
<GENE>-notes.md with provenance.
- Each seeded GOA annotation reviewed per GO guidelines (ACCEPT /
KEEP_AS_NON_CORE / MODIFY / MARK_AS_OVER_ANNOTATED / REMOVE / etc.) with
supported_by evidence.
- description, core_functions, suggested_questions, suggested_experiments
populated.
- Validated with uv run ai-gene-review validate ... / just validate.

Completion summary (2026-06-06)

All 20 reviews completed and validated (schema + term + reference validators all
pass). Selected curation highlights:

• V-ATPase subunits (ATP6V1A/B2/C1/D/E1/F/G1/H, ATP6V0E1): core role is
  ATP-hydrolysis-driven proton transport in the V1/V0 rotary mechanism; the
  recurring over-annotations were bare protein binding, generic membrane,
  extracellular exosome (lysosomal-proteomics contamination), and indirect
  regulation of macroautophagy. Genuine secondary roles retained as non-core
  include ATP6V1H's clathrin/AP-2 adaptor role and ATP6V1D/E1 mTORC1 and
  apical-membrane functions. ATP6V1E1 had one IPI protein binding REMOVED
  (tristetraprolin/CCL3 mRNA paper — probable curation error).
• ER folding/QC (CANX, CALR, CCDC47, CAMLG, AUP1): calnexin/calreticulin
  cycle (lectin chaperone + ER Ca2+) accepted as core; CALR surface/"eat-me"
  and MHC-I peptide-loading roles kept as non-core. CCDC47 PAT-complex and
  CAMLG GET-complex membrane-protein-biogenesis roles accepted; both required
  moving complex terms into core_functions.in_complex.
• Autophagy/mitophagy receptors (BNIP3L, BCL2L13, CALCOCO1): the defining
  selective-autophagy receptor MF/BP terms are largely absent from GOA. Added
  as proposed_new_terms (mitophagy receptor activity for BNIP3L/BCL2L13;
  reticulophagy/Golgiphagy receptor activity for CALCOCO1). CALCOCO1's older
  transcriptional-coactivator (CoCoA) annotations kept as non-core. BNIP3L
  defense response to virus marked UNDECIDED (cited paper is about apoptosis;
  the real NIX-MAVS link is viral immune evasion, not host defense).
• Co-chaperone / UPS regulation (BAG2, CACYBP, CAND1): BAG2 HSP70 NEF +
  CHIP-inhibition accepted; CAND1 captured as a CRL exchange/assembly regulator
  (not a catalytic enzyme); CACYBP as a Siah1-SKP1 E3 adaptor bridging S100/
  calcium signaling to ubiquitination.

Tracking row added to review_batches.tsv as proteostasis-batch-2026-06-06.