SQSTM1

Domain

The UBA domain binds specifically 'Lys-63'-linked polyubiquitin chains of polyubiquitinated substrates. Mediates the interaction with TRIM55. Both the UBA and PB1 domains are necessary and sufficient for the localization into the ubiquitin-containing inclusion bodies.

The PB1 domain mediates homooligomerization and interactions with FHOD3, MAP2K5, NBR1, PRKCI, PRKCZ and WDR81. Both the PB1 and UBA domains are necessary and sufficient for the localization into the ubiquitin-containing inclusion bodies.

The ZZ-type zinc finger mediates the interaction with RIPK1.

The LIR (LC3-interacting region) motif mediates the interaction with ATG8 family proteins.

Function

Autophagy receptor required for selective macroautophagy (aggrephagy). Functions as a bridge between polyubiquitinated cargo and autophagosomes. Interacts directly with both the cargo to become degraded and an autophagy modifier of the MAP1 LC3 family (PubMed:16286508, PubMed:20168092, PubMed:24128730, PubMed:28404643, PubMed:22622177). Along with WDFY3, involved in the formation and autophagic degradation of cytoplasmic ubiquitin-containing inclusions (p62 bodies, ALIS/aggresome-like induced structures). Along with WDFY3, required to recruit ubiquitinated proteins to PML bodies in the nucleus (PubMed:24128730, PubMed:20168092). May regulate the activation of NFKB1 by TNF-alpha, nerve growth factor (NGF) and interleukin-1. May play a role in titin/TTN downstream signaling in muscle cells. May regulate signaling cascades through ubiquitination. Adapter that mediates the interaction between TRAF6 and CYLD (By similarity). May be involved in cell differentiation, apoptosis, immune response and regulation of K(+) channels. Involved in endosome organization by retaining vesicles in the perinuclear cloud: following ubiquitination by RNF26, attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport (PubMed:27368102). Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 to autophagosomes (PubMed:29496741). Acts as an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1: interaction inactivates the BCR(KEAP1) complex, promoting nuclear accumulation of NFE2L2/NRF2 and subsequent expression of cytoprotective genes (PubMed:20452972, PubMed:28380357).

Involvement in disease

Paget disease of bone 3

PDB3

A disorder of bone remodeling characterized by increased bone turnover affecting one or more sites throughout the skeleton, primarily the axial skeleton. Osteoclastic overactivity followed by compensatory osteoblastic activity leads to a structurally disorganized mosaic of bone (woven bone), which is mechanically weaker, larger, less compact, more vascular, and more susceptible to fracture than normal adult lamellar bone.

None

The disease is caused by variants affecting the gene represented in this entry.

In a cell model for Huntington disease (HD), appears to form a shell surrounding aggregates of mutant HTT that may protect cells from apoptosis, possibly by recruiting autophagosomal components to the polyubiquitinated protein aggregates.

Frontotemporal dementia and/or amyotrophic lateral sclerosis 3

FTDALS3

A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. Some FTDALS3 patients may also develop Paget disease of bone.

None

The disease is caused by variants affecting the gene represented in this entry.

Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset

NADGP

A neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline. Disease onset is in childhood or adolescence. NADGP transmission pattern is consistent with autosomal recessive inheritance.

None

The disease is caused by variants affecting the gene represented in this entry.

Myopathy, distal, with rimmed vacuoles

DMRV

An autosomal dominant myopathy with adult onset, characterized by muscle weakness of the distal upper and lower limbs, walking difficulties, and proximal weakness of the shoulder girdle muscles. Muscle biopsy shows rimmed vacuoles.

None

The disease is caused by variants affecting the gene represented in this entry.

A chromosomal aberration involving SQSTM1 is found in a form of acute lymphoblastic leukemia. Translocation t(5;9)(q35;q34) with NUP214.

Post-translational modifications

Phosphorylated. May be phosphorylated by PRKCZ (By similarity). Phosphorylated in vitro by TTN (PubMed:15802564). Phosphorylation at Ser-403 by ULK1 is stimulated by SESN2 (PubMed:25040165). Phosphorylated at Ser-403 by TBK1, leading to promote relocalization of 'Lys-63'-linked ubiquitinated STING1 to autophagosomes (PubMed:29496741). Phosphorylation at Ser-349 by MTOR promotes interaction with KEAP1 and inactivation of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes (By similarity).

Ubiquitinated by RNF26: ubiquitinated SQSTM1 attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport (PubMed:27368102). Deubiquitination by USP15 releases target vesicles for fast transport into the cell periphery (PubMed:27368102). Ubiquitinated by the BCR(KEAP1) complex at Lys-420, increasing SQSTM1 sequestering activity and promoting its degradation (PubMed:28380357). Ubiquitinated via 'Lys-29' and 'Lys-33'-linked polyubiquitination leading to xenophagic targeting of bacteria and inhibition of their replication (PubMed:27880896).

Tissue specificity

Ubiquitously expressed.

Cellular localization

• Cytoplasm
• Cytosol
• Late endosome
• Lysosome
• Cytoplasmic vesicle
• Autophagosome
• Nucleus
• Endoplasmic reticulum
• Nucleus
• PML body
• Cytoplasm
• Myofibril
• Sarcomere
• In cardiac muscle, localizes to the sarcomeric band (By similarity). Commonly found in inclusion bodies containing polyubiquitinated protein aggregates. In neurodegenerative diseases, detected in Lewy bodies in Parkinson disease, neurofibrillary tangles in Alzheimer disease, and HTT aggregates in Huntington disease. In protein aggregate diseases of the liver, found in large amounts in Mallory bodies of alcoholic and nonalcoholic steatohepatitis, hyaline bodies in hepatocellular carcinoma, and in SERPINA1 aggregates. Enriched in Rosenthal fibers of pilocytic astrocytoma. In the cytoplasm, observed in both membrane-free ubiquitin-containing protein aggregates (sequestosomes) and membrane-surrounded autophagosomes. Colocalizes with TRIM13 in the perinuclear endoplasmic reticulum. Co-localizes with TRIM5 in cytoplasmic bodies. When nuclear export is blocked by treatment with leptomycin B, accumulates in PML bodies.

Alternative names

• Sequestosome-1
• EBI3-associated protein of 60 kDa
• Phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa
• Ubiquitin-binding protein p62
• EBIAP
• p60
• ORCA
• OSIL
• SQSTM1

Database links

• entrezGene:8878
• omim:601530
• swissprot:Q13501

Target type

Proteins

Primary research area

Neuroscience

Molecular weight

47687Da