Proteostasis Review Batch 6 — Gene Selection

Date: 2026-06-07
Branch: claude/proteostasis-50-genes-xFOZK

Context

Batches 1–5 are complete (pr-1217, 2026-06-03, 2026-06-06, 2026-06-07,
2026-06-07b). Batch 5 covered the cytosolic/ER chaperone & co-chaperone
folding machinery. Batch 6 moves to the Translation branch, selecting 50
unreviewed PN candidates (ok_for_propagation_to_go scope, no prior
*-ai-review.yaml).

Theme: co-translational quality control & translation surveillance

This is the most proteostasis-central slice of the Translation branch — the
machinery that monitors translation, rescues stalled/collided ribosomes,
degrades aberrant nascent chains, surveils faulty mRNAs, and co-translationally
modifies emerging nascent chains. It complements the related
RIBOSOME_QUALITY_CONTROL and INTEGRATED_STRESS_RESPONSE projects.

Deferred mega/pleiotropic genes

HUWE1 (giant ~4374-aa E3 with hundreds of substrates) and OGT
(O-GlcNAc transferase, pervasively pleiotropic) were considered but deferred to
dedicated reviews rather than diluting this batch.

Selected genes (50)

Ribosome-associated quality control (RQC) & ribosome rescue — 26

1. LTN1 (Listerin) — RQC E3 ubiquitin ligase that ubiquitinates 60S-stalled nascent chains
2. NEMF — RQC complex; CAT-tailing of stalled nascent chains, recruits LTN1
3. TCF25 — RQC complex subunit (RQC2-associated)
4. RACK1 — 40S ribosomal scaffold; collision sensing / ribosome QC hub
5. ZNF598 — E3 that ubiquitinates 40S (eS10/uS10) on ribosome collision (initiates RQC)
6. PELO (Dom34) — ribosome rescue / no-go & non-stop decay (with HBS1L)
7. HBS1L — GTPase partner of PELO in ribosome rescue
8. GTPBP1 — translational GTPase, ribosome-associated mRNA surveillance
9. GTPBP2 — translational GTPase, ribosome rescue (with PELO)
10. MKRN1 — RING E3, poly(A)/polylysine-stall ribosome QC
11. MKRN2 — makorin RING E3 paralog
12. RNF14 — RING E3 in ribosome-collision/RQC signaling
13. RNF25 — RING E3 in ribosome-associated quality control
14. GIGYF1 — 4EHP/EIF4E2 partner; translational repression on ribosome stalling
15. GIGYF2 — 4EHP/EIF4E2 partner; co-translational repression
16. EIF4E2 (4EHP) — cap-binding translational repressor in RQC/surveillance
17. EIF3J — loosely associated eIF3 subunit; ribosome recycling/QC
18. EIF5A — hypusine-containing elongation/termination factor; polyproline & stall resolution
19. DRG2 — developmentally regulated GTP-binding protein, translation-associated
20. NPLOC4 (NPL4) — p97/VCP cofactor; extracts ubiquitinated RQC substrates
21. UFD1 (UFD1L) — p97/VCP cofactor (with NPLOC4) for substrate unfolding/extraction
22. OTUD3 — deubiquitinase, ribosome-associated QC
23. USP21 — deubiquitinase, ribosome/RQC-associated
24. TRIP4 (ASC-1) — ASC-1 complex; ribosome-collision quality control
25. MAP3K20 (ZAKα) — ribotoxic stress response kinase; senses ribosome collisions
26. GCN1 — ribosome-collision sensor that activates GCN2/integrated stress response

UFMylation pathway (ER-ribosome co-translational QC) — 7

1. UFM1 — ubiquitin-fold modifier 1
2. UFC1 — UFM1-conjugating enzyme (E2)
3. UFL1 — UFM1 E3 ligase (ribosome/ER UFMylation)
4. UFSP1 — UFM1-specific protease
5. UFSP2 — UFM1-specific protease
6. UBA5 — UFM1-activating enzyme (E1)
7. DDRGK1 (UFBP1) — UFL1 cofactor / UFM1 substrate adaptor at the ER

Nonsense-mediated mRNA decay (translation-coupled surveillance) — 4

1. UPF1 — central NMD RNA helicase/ATPase
2. UPF2 — NMD core factor (UPF1–UPF3 bridge)
3. UPF3A — NMD core factor (EJC-associated)
4. UPF3B — NMD core factor (EJC-associated)

Nascent-chain N-terminal acetylation & husbandry — 8

1. HYPK — NatA-associated chaperone / huntingtin-interacting nascent-chain factor
2. NAA10 — NatA catalytic N-terminal acetyltransferase (Ogden syndrome)
3. NAA15 — NatA auxiliary subunit
4. NAA25 — NatB auxiliary subunit
5. NAA30 — NatC catalytic subunit
6. NAA35 — NatC auxiliary subunit
7. NAA38 — NatC/NatB-associated subunit (LSML)
8. NAA40 — NatD, N-terminal acetyltransferase for histones H2A/H4

Ribosome recycling, reinitiation & elongation control — 5

1. DENR — density-regulated; ribosome recycling / reinitiation (with MCTS1)
2. MCTS1 — MCTS1–DENR reinitiation complex
3. EIF2D — non-canonical initiation/recycling factor (Ligatin)
4. GTPBP6 — ribosome recycling-associated GTPase
5. EEF2K — eEF2 kinase; elongation control coupling stress to translation

Method

Same as batch 5: fetch-gene --no-fetch-titles scaffolding (with timeout
retries), per-annotation review against GO guidelines with verbatim
supported_by, populated description/core_functions/questions/experiments,
uv run ai-gene-review validate, then PN-mapping feedback.

Curation watch-points

• Avoid protein binding (GO:0005515) as core; for E3s use
  ubiquitin protein ligase activity, for the rescue GTPases use translational
  GTPase / ribosome-binding terms, for Nat subunits use
  N-terminal (peptidyl-)amino-acid acetyltransferase activity.
• Catalytic vs auxiliary subunits: NatA/B/C auxiliary subunits (NAA15, NAA25,
  NAA35, NAA38) and HYPK are non-catalytic — do not assign acetyltransferase
  catalytic activity; use complex/adaptor/auxiliary terms.
• RQC vs generic translation: keep broad translation (GO:0006412) terms
  non-core where the gene's specific role is collided-ribosome surveillance /
  rescue / RQC (cf. the EDF1 precedent).
• UFMylation enzyme roles: assign the correct E1/E2/E3/protease step; UFM1 is
  the modifier, not an enzyme.
• Moonlighting: RACK1, EIF5A, NAA10 have well-documented non-RQC moonlighting
  roles — capture the core translation/QC function, mark over-annotations.

Correction: USP21 / USP25 synonym collision

fetch-gene human USP21 resolved to USP25 (UniProt Q9UHP3, UBP25_HUMAN),
because UniProt lists USP21 as a gene-name synonym of USP25. The review was
relabeled to USP25 (a legitimate ERAD-associated proteostasis DUB) and its folder
renamed USP21/ -> USP25/. The correct USP21 (Q9UK80, UBP21_HUMAN) was then
fetched explicitly by accession and reviewed separately. Batch 6 therefore covers
51 genes (the 49 other selections + USP25 + USP21). Lesson: when a target gene
symbol is also a documented synonym of another gene, fetch by explicit UniProt
accession.