Proteostasis Review Batch 9 — Gene Selection

Date: 2026-06-14
Branch: claude/proteostasis-network-genes-o9mnh5

Context

Batches 1–8 are complete (pr-1217, 2026-06-03, 2026-06-06, 2026-06-07,
2026-06-07b, 2026-06-07c, 2026-06-11, 2026-06-13). Batch 8 covered the
UPS branch Cullin–RING ligase substrate-recognition & assembly modules
(F-box SCF/CRL1 receptors, CRL4 core, CAND2/GLMN). Batch 9 moves into the
Autophagy–Lysosome Pathway (ALP) branch, which is the best-supported PN
branch for row-level reuse (per-row notes and references for ~1001/1003 rows).

Theme: Selective autophagy cargo recognition

This batch walks the substrate-selection machinery of selective autophagy —
the receptors that read ubiquitin/cargo marks and bridge them to the Atg8/LC3
conjugation machinery, the kinase axis that activates those receptors, the
TRIM-family receptors/regulators, and the ubiquitin-tagging E3 ligases that
generate the autophagy signal. It exercises the PN ALP-branch
Autophagy substrate selection -> {Selective autophagy receptor, Marking substrates for selective autophagy, Autophagy receptor regulation} types,
selected from the ok_for_propagation_to_go candidate-addition pool with no
prior *-ai-review.yaml.

Selected genes (20)

Core selective autophagy receptors (6)

SQSTM1 (p62/sequestosome-1) — prototypical SAR; PB1/ZZ/TB/LIR/KIR/UBA;
aggrephagy/mitophagy/xenophagy + KEAP1-NRF2 + NF-κB/mTORC1 scaffolding
NBR1 — PB1/ZZ/UBA/LIR receptor; aggrephagy & pexophagy, parallels p62
OPTN (optineurin) — LIR + UBAN ubiquitin-binding receptor; mitophagy &
xenophagy; TBK1 partner; ALS/glaucoma
CCDC50 (Ymer) — TBK1-binding K63-polyUb autophagy receptor
NUFIP1 — ribophagy receptor (LIR, binds LC3B) + snoRNP assembly
RETREG2 (FAM134A) — reticulophagy/ER-phagy receptor (RHD + LIR)

TBK1 activation axis (3)

TBK1 — Ser/Thr kinase; phosphorylates OPTN/SQSTM1/NDP52 to drive selective
autophagy + master innate antiviral/IFN kinase
AZI2 (NAP1) — TBK1/IKKε adaptor, positive regulator
TANK — TBK1/IKKε adaptor/scaffold (IFN induction) + NF-κB restraint

TRIM-family receptors/regulators (4)

TRIM5 (TRIM5α) — retroviral-capsid PRR; RING E3; precision-autophagy
TRIM13 (RFP2) — ER-anchored RING E3; ERAD & reticulophagy
TRIM16 — RING-less; galectin-3-interacting lysophagy/aggrephagy receptor
TRIM17 — RING E3; neuronal apoptosis (MCL1) + target-selective autophagy

Ubiquitin-tagging E3 ligases feeding selective autophagy (4)

SIAH1 — RING E3; α-synuclein/synphilin; Parkin-independent mitophagy
RNF41 (NRDP1) — RING E3; ErbB3/BIRC6/Parkin/USP8; receptor turnover
RNF166 — RING E3; K29/K33 ubiquitination promoting xenophagy
LRSAM1 — RING + LRR E3; ubiquitinates intracellular bacteria for xenophagy

Other selective-autophagy regulators (3)

MEFV (pyrin/TRIM20) — inflammasome sensor; precision autophagy of
inflammasome components; FMF
NLRX1 — mitochondrial NLR; TUFM-dependent autophagy + MAVS regulation
MAP1S — MAP1 family; bridges LC3/LRPPRC to microtubules/mitochondria

Deferred

HUWE1 (mega/pleiotropic UPS hub, deferred since batch 6/8) and DNM1L,
MFN1, VDAC1, USP30, MARCHF5, MUL1, PARL, PGAM5, TSPO, IMMT,
TUFM, SLC25A4/A5, TBC1D15/17, RAB26, BNIP1, SNCAIP, HK2, SREBF1/2
and related mitophagy/lysosomal-environment ALP candidates were left for a
dedicated mitophagy/CMA batch.

Results

All 20 review YAMLs pass schema, term (label + verbatim-quote), and
best-practices validation (uv run ai-gene-review validate --terms). Across
1222 reviewed annotations the action mix was:

Action	Count
KEEP_AS_NON_CORE	690
ACCEPT	505
MARK_AS_OVER_ANNOTATED	19
NEW	5
UNDECIDED	2
REMOVE	1

Notable curation calls

Receptor MF framing. The recurring core call is the selective-autophagy
cargo-adaptor/receptor function: ubiquitin binding (UBA/UBAN/ZZ) +
Atg8/LC3 (LIR) binding bridging cargo to the autophagosome. Bare
protein binding (GO:0005515) — abundant on these hub genes (e.g. ~70 IPI
entries on each of SQSTM1, OPTN, TBK1) — was uniformly kept non-core in
favor of the informative adaptor/receptor MF (GO:0030674,
GO:0140036/GO:0160247).
RING vs RING-less E3 catalysis. Genuine catalytic RING E3s (SIAH1, RNF41,
RNF166, LRSAM1, TRIM5/13/17) kept catalytic ubiquitin protein ligase activity as core. The RING-less TRIMs were handled conservatively:
TRIM16 ACCEPTed only the experimentally-supported atypical B-box
autoubiquitination MF (PMID:22629402) and kept the EC-based IEA copy non-core;
MEFV/pyrin's IBA ubiquitin protein ligase activity (no functional RING)
was MARK_AS_OVER_ANNOTATED as a TRIM-family phylogenetic over-propagation.
NEW terms for receptor functions absent from GOA. Verified via QuickGO and
added as NEW/proposed_new_terms: GO:0034517 ribophagy + GO:0160247
autophagy cargo adaptor activity (NUFIP1, CCDC50), GO:0035973 aggrephagy +
GO:0160247 (NBR1), xenophagy/defense/IFN terms (RNF166), and
GO:0010508 positive regulation of autophagy (NLRX1).
Disputed-direction regulatory terms left in place but flagged. NLRX1 IBA
negative regulation of NF-κB and AZI2 ortholog-IEA negative regulation of canonical NF-κB conflict with the human literature (both can be positive
regulators); per guardrails these mouse/IBA electronic annotations were
MARK_AS_OVER_ANNOTATED / kept non-core rather than removed.
The single REMOVE is NBR1 mitochondrial intermembrane space (GO:0005758,
IEA/Ensembl-Compara) — biologically implausible for a cytosolic receptor with
no mitochondrial import signal.
UNDECIDED (2). NBR1 signaling receptor complex (GO:0043235, IDA) and
RNF41 small GTPase binding (GO:0030695, IPI) — experimental annotations
whose full text could not be verified from the abstract-only cache; deferred
to curators rather than removed.
Citation issues flagged in reference_review. SIAH1 zinc ion binding
IDA cites PMID:11863358 (an APOBEC RNA-editing paper with no SIAH1 mention) —
marked WRONG_IDENTIFIER/relevance: NONE; the annotation itself was
ACCEPTed because zinc binding is independently established (PMID:16085652).

The mega-hub HUWE1 and the dedicated mitophagy/CMA effector set were left out
of scope for a future batch.

Warnings (1)