SQSTM1 - dismech genes

Normal function · from ai-gene-review (Q13501, commit 79fe13b38970) · AI-generated, not KB evidence

SQSTM1 (sequestosome-1, p62) is a multidomain cytoplasmic adaptor protein and the prototypical selective autophagy receptor. Its N-terminal PB1 domain drives homo-oligomerization (front-to-back filament-like arrays) and hetero-oligomerization with partners such as the atypical protein kinases PRKCZ/PRKCI, NBR1 and MAP2K5; a ZZ-type zinc finger binds RIPK1; a TRAF6-binding (TB) motif scaffolds TRAF6; an LC3-interacting region (LIR) binds ATG8-family proteins (LC3A/B/C, GABARAP/L1/L2); a KEAP1-interacting region (KIR) binds KEAP1 when phosphorylated at Ser-349; and a C-terminal UBA domain binds polyubiquitin, with a strong preference for K63-linked chains. By simultaneously binding ubiquitinated cargo through the UBA domain and the growing autophagosome through the LIR, p62 bridges ubiquitin-tagged substrates to the autophagy machinery. Multivalent ubiquitin binding combined with PB1-mediated polymerization drives liquid-liquid phase separation into "p62 bodies," membraneless condensates that concentrate ubiquitinated cargo for engulfment; p62 and its cargo are then degraded together. This underlies aggrephagy (clearance of ubiquitinated protein aggregates) and more specialized selective autophagy including pexophagy (via ubiquitinated PEX5), xenophagy/antibacterial autophagy and control of inflammasome and RIPosome components. p62 also contributes to PINK1/Parkin mitophagy, where it is recruited to depolarized mitochondria and mediates their perinuclear clustering, though it is largely dispensable for the mitochondrial clearance step itself. Independent of autophagy, phospho-Ser349 p62 sequesters KEAP1 into condensates, derepressing the transcription factor NRF2 (NFE2L2) to induce cytoprotective antioxidant/phase-II genes; SQSTM1 is itself an NRF2 target, forming a positive feedback loop. Through its PB1, ZZ and TB modules p62 serves as a signaling scaffold for NF-kB activation downstream of IL-1/TRAF6, NGF/TrkA and TNF/RIPK1, and it modulates additional pathways including mTORC1 signaling. p62 levels are an established readout of autophagic flux, and SQSTM1 variants cause Paget disease of bone, frontotemporal dementia/ALS, distal myopathy with rimmed vacuoles, and (recessively) childhood-onset neurodegeneration.

Acts as the prototypical selective autophagy receptor, recognizing ubiquitinated cargo (preferentially K63-linked polyubiquitin) through its UBA domain and bridging it to ATG8-family proteins on the autophagosome via its LIR motif, thereby delivering cargo for autophagic degradation.

molecular function: ubiquitin-modified protein reader activity · directly involved in: aggrephagy; protein targeting to vacuole involved in autophagy · locations: cytosol; autophagosome

Functions as a protein-macromolecule adaptor and molecular condensate scaffold that, through PB1-mediated oligomerization combined with multivalent ubiquitin binding, drives liquid-liquid phase separation into p62 bodies - membraneless organelles that concentrate and sequester ubiquitinated cargo for selective autophagy.

molecular function: molecular condensate scaffold activity · directly involved in: membraneless organelle assembly; aggrephagy

Acts as an activator of the NFE2L2/NRF2 antioxidant pathway by sequestering KEAP1 (via the phospho-Ser349 KIR motif) into p62 bodies, preventing KEAP1-mediated NRF2 degradation and inducing cytoprotective gene expression; SQSTM1 is itself an NRF2 target, forming a positive feedback loop.

molecular function: protein sequestering activity · directly involved in: cellular response to stress

Serves as a signaling adaptor/scaffold that assembles multiprotein complexes (e.g. atypical PKCs, TRAF6, RIPK1) to regulate NF-kB and related innate-immune signaling, including negative regulation of TLR4 signaling through control of the TRAF6-ECSIT complex.

molecular function: signaling adaptor activity · directly involved in: regulation of canonical NF-kappaB signal transduction

In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

Disorder	Relationship	Where the gene appears
Paget Disease of Bone	causative	mechanism: SQSTM1 UBA-Domain Variant Impairs Selective Autophagy subtype: SQSTM1-related
Huntington Disease	untyped Pathophysiological Role
SQSTM1-Related Childhood-Onset Neurodegeneration	untyped CAUSATIVE germline	mechanism: Biallelic SQSTM1 Loss-of-Function
SQSTM1-related Multisystem Proteinopathy	untyped germline CLINGEN: moderate (FTDALS3)	mechanism: Enhanced RANKL-NF-kB Signalling in Osteoclast Precursors; Heterozygous SQSTM1 Variant Alters p62 Domains; Impaired KEAP1-NRF2 Antioxidant Response; Impaired p62-Mediated Selective Autophagy; Persistent Stress Granules subtype: DMRV; FTDALS3; PDB3
Amyotrophic Lateral Sclerosis	no genetic record	mechanism: Impaired Autophagy

ClinGen gene–disease validity · snapshot 2026-10-03 · matched to entries by MONDO

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

ClinGen disease	MOI	Classification	dismech entry
frontotemporal dementia and/or amyotrophic lateral sclerosis 3 MONDO:0014640	AD	Moderate 2022-12-13	SQSTM1-related Multisystem Proteinopathy untyped

Mechanism modules · computed from kb/

disabled_macroautophagy via Amyotrophic Lateral Sclerosis, SQSTM1-related Multisystem Proteinopathy