SQSTM1 (p62 / sequestosome-1) — Gene Review Notes
UniProt: Q13501 (SQSTM_HUMAN), 440 aa. HGNC:11280. Synonyms: ORCA, OSIL, A170, ZIP, p62, EBIAP/p60.
Domain architecture (from UniProt feature table)
- PB1 domain (aa 3–102): Phox/Bem1; mediates homo-oligomerization (front-to-back arrays) and hetero-oligomerization with PRKCI/PRKCZ, NBR1, MAP2K5, FHOD3, WDR81. Required (with UBA) for localization into ubiquitin inclusion bodies [UniProt DOMAIN; PMID:12813044; PMID:12887891; PMID:15802564].
- ZZ-type zinc finger (aa 123–173): coordinates Zn(2+) (8 binding residues); mediates interaction with RIPK1 [UniProt; PMID:10747026]. Source of GO:0008270 zinc ion binding.
- TRAF6-binding (TB) motif (aa 228–233): binds TRAF6, scaffolds NF-kB activation [UniProt MOTIF].
- LIR / LC3-interacting region (aa 336–341; broader MAP1LC3B-binding region 321–342): binds ATG8-family proteins (LC3A/B/C, GABARAP/L1/L2); essential for autophagosome recruitment [PMID:17580304; PMID:23908376].
- KIR (KEAP1-interacting region) (aa 347–352): binds KEAP1 when phosphorylated at Ser-349 (also reported as Ser-351 in some nomenclatures); competes with NRF2 for KEAP1 Kelch domain [UniProt REGION 347–352; PMID:20452972; PMID:37306101].
- UBA domain (aa 389–434): binds (preferentially K63-linked) polyubiquitin; auto-inhibited as a dimer, relieved by phosphorylation (S403/S407), ubiquitination (K420), or acetylation (K420/K435) [PMID:12857745; PMID:15340068; PMID:28322253; PMID:31857589].
Core biology (synthesized)
p62/SQSTM1 is the prototypical selective autophagy receptor. It bridges polyubiquitinated cargo (via UBA) to the nascent autophagosome (via LIR–ATG8 binding), while its PB1 domain drives oligomerization/polymerization that, together with multivalent ubiquitin binding, drives liquid–liquid phase separation into "p62 bodies" — membraneless condensates that concentrate ubiquitinated cargo for engulfment [PMID:29343546 "p62 filaments capture and present ubiquitinated cargos for autophagy"; PMID:29507397 "Polyubiquitin chain-induced p62 phase separation drives autophagic cargo segregation"; PMID:31857589].
Substrate breadth: aggrephagy (ubiquitinated protein aggregates) [PMID:17580304; PMID:16286508; PMID:22017874], plus more specialized selective autophagy: pexophagy (ROS-induced, via ubiquitinated PEX5) PMID:26344566, xenophagy/antibacterial autophagy [PMID:36221902; PMID:27880896], inflammasome/RIPosome control [PMID:30612879; PMID:27498865], and a supporting (non-essential) role in PINK1/Parkin mitophagy — p62 is recruited to depolarized mitochondria and required for their perinuclear clustering, but is dispensable for mitochondrial clearance itself [PMID:20890124 "required for Parkin-induced mitochondrial clustering but not mitophagy"; PMID:20457763].
Signaling scaffold (PB1/ZZ/TB-dependent): NF-kB activation downstream of IL-1/TRAF6, NGF/TrkA, and TNF/RIPK1; binds atypical PKCs (PRKCZ/PRKCI). Also negatively regulates TLR4 signaling by acting on the TRAF6–ECSIT complex PMID:31281713.
KEAP1–NRF2 antioxidant axis: phospho-S349 p62 sequesters KEAP1 into p62 bodies, derepressing NRF2 (NFE2L2) and inducing the antioxidant/phase-II response; SQSTM1 is itself an NRF2 target gene (positive feedback) [PMID:20452972 "p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop"; PMID:23274085; PMID:37306101]. This axis underlies cytoprotection including protection against ferroptosis in HCC cells PMID:26403645.
Endosome organization: ubiquitinated p62 (RNF26/UBE2J1, K435) acts as a perinuclear molecular bridge retaining endosomal vesicles for organized cargo transport PMID:27368102.
Disease: dominant gain/loss SQSTM1 variants cause Paget disease of bone (PDB3), FTD/ALS (FTDALS3), distal myopathy with rimmed vacuoles; recessive loss causes childhood neurodegeneration with ataxia/dystonia/gaze palsy (NADGP). SQSTM1-NUP214 fusion in T-ALL.
Review decisions rationale
- Core MF: ubiquitin-modified protein reader activity (GO:0140036) / K63-polyUb-dependent binding (GO:0070530) / ubiquitin binding (GO:0043130); protein-macromolecule adaptor (GO:0030674) bridging cargo to ATG8; molecular condensate scaffold activity (GO:0140693); protein sequestering activity (GO:0140311). All ACCEPT where IDA-supported.
- Core BP: aggrephagy (GO:0035973), macroautophagy (GO:0016236), protein targeting to vacuole involved in autophagy (GO:0071211), membraneless organelle assembly (GO:0140694). ACCEPT.
- KEAP1/NRF2 & signaling scaffold: real, well-supported but secondary to the receptor function → mostly ACCEPT for direct experimental (positive regulation of autophagy, NF-kB regulation, TLR4 negative regulation) and KEEP_AS_NON_CORE for broad process terms.
- bare protein binding (GO:0005515): ~50 IPI annotations from interactome screens and specific partners. Per curation guidelines, uninformative → KEEP_AS_NON_CORE (do not REMOVE experimental IPI).
- identical protein binding (GO:0042802): real (PB1-mediated homo-oligomerization), informative-ish → KEEP_AS_NON_CORE (oligomerization is genuine).
- mitophagy (GO:0000423) / autophagy of mitochondrion (GO:0000422): p62 contributes to mitophagy (recruited to damaged mito; clustering) but is dispensable for clearance → KEEP_AS_NON_CORE rather than core; experimental IGI/NAS retained, defer to curators.
- Reactome cytosol TAS (many duplicates): correct localization, generic pathway context → ACCEPT a representative / KEEP_AS_NON_CORE the redundant ones.
- Ensembl GO_REF:0000107 ortholog-transfer IEA (temperature homeostasis, response to ischemia, brown fat cell proliferation, energy homeostasis, synapse/glutamatergic synapse, sperm midpiece, LTP, ionotropic glutamate receptor binding): pleiotropic mouse-derived; biologically plausible but peripheral → KEEP_AS_NON_CORE (not REMOVE; experimentally grounded in mouse orthologs).
- GO:0035255 ionotropic glutamate receptor binding / synapse terms: ortholog-transfer; keep non-core.
- GO:0046578 regulation of Ras protein signal transduction (NAS, PMID:8618896): early RASA1/Lck-binding paper; weak/historical → KEEP_AS_NON_CORE.
- GO:0045944 positive regulation of transcription by Pol II (TAS Reactome NRIF): indirect; KEEP_AS_NON_CORE.
- GO:0043065 positive regulation of apoptotic process (TAS Reactome NRIF cell death): indirect/context-specific → KEEP_AS_NON_CORE.
Provenance of key claims
Review session journal (2026-06-14)
Completed full review of the ~272 GOA annotations. Verified GO IDs used in core_functions/replacements via QuickGO API: GO:0140311 "protein sequestering activity" and GO:0035591 "signaling adaptor activity" confirmed. All other GO IDs taken directly from existing (pre-validated) annotations.
Cached full-text checked for grounding: PMID:29343546, 29507397, 31857589, 37306101, 37802024 (phase separation / p62 bodies), 26344566 (pexophagy), 31281713 (TLR4 negative regulation), 27368102 (endosome organization), 36221902/30612879 (xenophagy/inflammasome), 34893540 (N-terminal Cys oxygen/oxidative-stress sensor → ubiquitin reader/adaptor), 20890124/20457763 (mitophagy nuance), 34471133 (reconstitution of ubiquitin condensate / phagophore assembly site).
Abstract-only (defer to curators, no REMOVE of experimental): 17580304, 20452972, 12857745, 22017874, 23274085, 26403645, 27498865, 25127057, 8650207.
Action policy applied:
- Core MF (ACCEPT, IDA): GO:0140036 ubiquitin-modified protein reader, GO:0070530 K63-polyUb-dependent binding, GO:0043130 ubiquitin binding, GO:0030674 protein-macromolecule adaptor, GO:0140693 molecular condensate scaffold, GO:0140311 protein sequestering. GO:0042802 identical protein binding = genuine PB1 oligomerization, KEEP_AS_NON_CORE.
- Core BP (ACCEPT): GO:0035973 aggrephagy, GO:0016236 macroautophagy, GO:0071211 protein targeting to vacuole in autophagy, GO:0140694 membraneless organelle assembly, GO:0030163 protein catabolic process, GO:0000425 pexophagy.
- Localizations: GO:0005776 autophagosome, GO:0005829 cytosol ACCEPT (core sites of action); the many Reactome cytosol TAS duplicates KEEP_AS_NON_CORE (one representative ACCEPT). Lysosome/late endosome/ER/PML body/inclusion body/aggresome = real but non-core compartments KEEP_AS_NON_CORE.
- Signaling scaffold (NF-kB, NRF2/KEAP1, TLR4): ACCEPT direct experimental MF/BP, KEEP_AS_NON_CORE broad/indirect.
- bare protein binding GO:0005515 (~55 IPI): KEEP_AS_NON_CORE (uninformative but experimental — never REMOVE).
- Ensembl ortholog-transfer IEA GO_REF:0000107 (temperature homeostasis, ischemia, brown fat, energy homeostasis, synapse/glutamatergic synapse, sperm midpiece, LTP, mitochondrion, Lewy body): KEEP_AS_NON_CORE (mouse-grounded, peripheral). Mitochondrion IEA over-broad but plausible.
- GO:0043065 apoptosis (Reactome NRIF TAS), GO:0045944 pos reg transcription (Reactome NRIF), GO:0046578 reg Ras signaling (NAS): indirect/historical, KEEP_AS_NON_CORE.
2026-11-03 ORGANELLES batch 4 (mitochondrion rows)
- Rows: GO:0005739 IEA (GO_REF:0000107, Ensembl projection from mouse Q64337), located_in. No sub-compartment rows. Action stays KEEP_AS_NON_CORE; reason extended to record the check.
- Projection source: mouse Sqstm1 has one mitochondrion row, a UniProt IDA from PMID:32047033 (QuickGO, 2026-11-03), not circular, no NOT row dropped. In that paper p62 is recruited to depolarised mitochondria PMID:32047033; human data agree PMID:20098416.
- UniProt gives no mitochondrial location for human SQSTM1 (autophagosome, cytosol, PML body, late endosome, lysosome...).
- Outcome: root only. Recruited cargo-receptor pool on ubiquitinated outer-membrane proteins (TRAF3/BRAF precedent); no anchor or transit peptide, so GO:0005741 not added.
2026-11-06 ORGANELLES ER batch 4 (endoplasmic reticulum rows)
- Rows: GO:0005783 IEA (GO_REF:0000044, SL-0095) and EXP (PMID:22178386). Mitochondrion rows from batch 4 untouched.
- UniProt: "Endoplasmic reticulum {ECO:0000269|PubMed:22178386}". PMID:22178386 is abstract-only; it is about the ER-resident E3 ligase TRIM13, which interacts with p62 in ER-stress autophagy; the p62 location assay is not stated in the abstract.
- Outcome: both stay KEEP_AS_NON_CORE on curator deference; p62 is soluble, so the ER pool is recruited on the cytosolic face (consistent with the recruited mitochondrial pool call); root only, no membrane/lumen row.