Proteostasis Review Batch 7 — Gene Selection

Date: 2026-06-11
Branch: claude/gallant-hypatia-3rlpyb

Context

Batches 1–6 are complete (pr-1217, 2026-06-03, 2026-06-06,
2026-06-07, 2026-06-07b, 2026-06-07c). Batch 6 covered the Translation
branch's co-translational quality-control machinery (RQC, UFMylation, NMD,
N-terminal acetylation). Batch 7 moves squarely into the ER proteostasis
branch, selecting 50 unreviewed PN candidates (ok_for_propagation_to_go
scope, no prior *-ai-review.yaml).

Theme: ER protein biogenesis, folding, and ER-associated degradation (ERAD)

This batch walks the full ER-proteostasis lifecycle of a secretory/membrane
protein, from co-translational targeting and insertion, through glycoprotein
folding quality control, to ERAD-mediated disposal of terminally misfolded
clients. It complements the er_proteostasis mapping set and the batch-5
cytosolic/ER chaperone work, and feeds the ER_PHAGY and
UNFOLDED_PROTEIN_BINDING related projects.

Selected genes (50)

ER membrane protein insertion — EMC insertase (10)

1. EMC1 — EMC large lumenal/scaffold subunit
2. EMC2 — EMC cytosolic TPR subunit
3. EMC3 — EMC core insertase subunit (Oxa1 superfamily)
4. EMC4 — EMC membrane subunit
5. MMGT1 (EMC5) — EMC membrane subunit
6. EMC6 — EMC membrane subunit
7. EMC7 — EMC lumenal/membrane subunit
8. EMC8 — EMC cytosolic subunit
9. EMC9 — EMC cytosolic subunit (EMC8 paralog)
10. EMC10 — EMC lumenal subunit

Tail-anchored protein insertion — GET/TRC pathway (3)

1. GET1 (WRB) — ER membrane GET insertase receptor
2. GET3 (ASNA1/TRC40) — cytosolic TA-targeting ATPase
3. GET4 (TRC35) — pre-targeting complex / GET3 loading

SRP-dependent co-translational targeting (5)

1. SRP9 — Alu domain (elongation arrest)
2. SRP19 — S domain assembly
3. SRP68 — S domain
4. SRP72 — S domain
5. SRPRB — SRP receptor beta subunit

Translocon-associated & signal-peptide processing (8)

1. SEC62 — post-translational translocation / SEC62-SEC63
2. SEC63 — translocon-associated, BiP recruitment (J-domain)
3. SEC11A — signal peptidase catalytic subunit
4. SEC11C — signal peptidase catalytic subunit
5. SPCS1 — signal peptidase complex subunit
6. SPCS2 — signal peptidase complex subunit
7. SPCS3 — signal peptidase complex subunit
8. SERP1 (RAMP4) — translocon-associated stress protein

Glycoprotein folding QC — ERAD mannosidases & lectins (8)

1. EDEM1 — ERAD mannosidase-like (misfold recognition)
2. EDEM2 — ERAD mannosidase-like (initiates mannose trimming)
3. EDEM3 — ERAD mannosidase-like (α1,2-mannosidase)
4. MAN1B1 — ER α-mannosidase I (ERAD timer)
5. LMAN1 (ERGIC-53) — ER-Golgi cargo lectin (MCFD2 partner)
6. LMAN2 (VIP36) — ER-Golgi cargo lectin
7. LMAN1L — LMAN1 paralog (testis)
8. LMAN2L (VIPL) — VIP36-like lectin

ER oxidative folding & prolyl hydroxylation (8)

1. P3H1 — prolyl 3-hydroxylase 1 (collagen; ER complex with CRTAP/PPIB)
2. P3H2 — prolyl 3-hydroxylase 2
3. P4HA1 — prolyl 4-hydroxylase alpha-1 (collagen)
4. P4HA2 — prolyl 4-hydroxylase alpha-2
5. P4HA3 — prolyl 4-hydroxylase alpha-3
6. TXNDC11 — ER thioredoxin-domain protein
7. TXNDC12 — ER thioredoxin-domain protein (ERp18/ERp19)
8. TXNDC16 — ER thioredoxin-domain protein (ERp90)

ERAD ubiquitin machinery & membrane cofactors (8)

1. RNF5 (RMA1) — ER membrane RING E3 ligase
2. RNF185 — ER membrane RING E3 ligase (MARCH6-like branch)
3. RNF170 — ER membrane RING E3 ligase (IP3R ERAD)
4. FAF2 (UBXD8) — p97/VCP UBX cofactor, ERAD/lipid droplet
5. UBAC2 — ERAD membrane component (RHBDD1/UBAC2)
6. ERLIN1 — ER lipid-raft SPFH/prohibitin, IP3R ERAD
7. ERLIN2 — ER lipid-raft SPFH/prohibitin, IP3R ERAD
8. SERP2 — SERP1 paralog, translocon-associated stress protein

Method

Same as batches 5–6: fetch-gene scaffolding (uniprot + goa + seeded
-ai-review.yaml + cached publications), per-annotation review against GO
guidelines with verbatim supported_by, populated
description/core_functions/suggested_questions/suggested_experiments,
reference reference_review adjudication, then uv run ai-gene-review validate.

Curation watch-points

• Avoid bare protein binding (GO:0005515) as core. EMC/SPC/SRP/GET
  subunits should use complex part_of terms plus the complex's molecular
  function where the subunit contributes (e.g. EMC membrane insertase activity
  GO:0032977, signal peptidase GO:0008233/GO:0004252).
• Catalytic vs structural subunits. Of the signal peptidase complex only
  SEC11A/SEC11C are catalytic (serine endopeptidase); SPCS1/2/3 are accessory —
  do not assign peptidase catalytic activity to the SPCS subunits. Of the SRP,
  only the RNA-binding/receptor roles apply per subunit. EMC catalytic insertase
  activity is centered on EMC3 (Oxa1/YidC-like) with EMC6; cytosolic subunits
  (EMC2/8/9) are scaffolds.
• Mannosidase activity vs lectin recognition. EDEM1/2/3 and MAN1B1 act as
  mannose-trimming / misfold-recognition factors (EDEM1 may be lectin-like
  rather than catalytic; EDEM2 has demonstrated mannosidase activity). LMAN1/2
  and paralogs are cargo lectins, not hydrolases — use carbohydrate/mannose
  binding + ER-Golgi transport, not glycosidase activity.
• Prolyl hydroxylases. P3H1/P3H2 are 3-hydroxylases; P4HA1/2/3 are the
  catalytic alpha subunits of the α2β2 prolyl 4-hydroxylase (β = P4HB/PDI).
  Capture 2-oxoglutarate/Fe(II)-dependent dioxygenase MF and collagen biogenesis
  BP; keep generic "protein binding" non-core.
• ERAD E3 specificity. RNF5/RNF185/RNF170 are membrane RING E3s; use
  ubiquitin protein ligase activity + ERAD pathway, not bare ubiquitination.
  RNF170 and ERLIN1/ERLIN2 share the IP3R ERAD complex — capture that without
  over-broadening.
• Paralog caution (PN domain-based inclusions). LMAN1L, LMAN2L,
  DCAF-style testis/low-evidence paralogs, EMC9 (EMC8 paralog), SERP2,
  and SEC11A vs SEC11C tissue paralogs may rest largely on family
  membership/IBA — distinguish defensible core function from family propagation,
  and use KEEP_AS_NON_CORE/UNDECIDED where direct evidence is thin.