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Developmental stage

During myogenesis, there is a marked increase in levels in fully differentiated myotubes compared to undifferentiated myoblasts.

Domain

The UBA domain binds specifically 'Lys-63'-linked polyubiquitin chains of polyubiquitinated substrates (PubMed:12857745, PubMed:15340068, PubMed:28322253, PubMed:31857589). Mediates the interaction with TRIM55 (PubMed:15802564). Both the UBA and PB1 domains are necessary and sufficient for the localization into the ubiquitin-containing inclusion bodies (PubMed:15802564).

The PB1 domain mediates homooligomerization and interactions with FHOD3, MAP2K5, NBR1, PRKCI, PRKCZ and WDR81 (PubMed:12813044, PubMed:12887891, PubMed:15802564, PubMed:28404643). Both the PB1 and UBA domains are necessary and sufficient for the localization into the ubiquitin-containing inclusion bodies (PubMed:15802564).

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

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

Function

The protein expressed by the SQSTM1 gene is an autophagy receptor essential for selective macroautophagy (aggrephagy). It acts as a bridge between polyubiquitinated cargo and autophagosomes, interacting with both the cargo and an autophagy modifier from the MAP1 LC3 family. Alongside WDFY3, it plays a role in forming and autophagically degrading cytoplasmic ubiquitin-containing inclusions and recruiting ubiquitinated proteins to nuclear PML bodies. SQSTM1 may regulate NFKB1 activation by TNF-alpha, nerve growth factor (NGF), and interleukin-1, and may influence titin/TTN signaling in muscle cells. It may also affect signaling cascades via ubiquitination and be involved in cell differentiation, apoptosis, immune response, and regulation of potassium channels. The protein is involved in endosome organization by retaining vesicles in the perinuclear cloud; ubiquitination by RNF26 allows it to attract vesicle-associated adapters, forming a molecular bridge to organize endosomal pathways. Additionally, it promotes the relocalization of Lys-63-linked ubiquitinated STING1 to autophagosomes and acts as an activator of the NFE2L2/NRF2 pathway by interacting with KEAP1, which inactivates the BCR(KEAP1) complex, resulting in nuclear accumulation of NFE2L2/NRF2 and expression of cytoprotective genes. This supplementary information is collated from multiple sources and compiled automatically.

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

Phosphorylation at Ser-407 by ULK1 destabilizes the UBA dimer interface and increases binding affinity to ubiquitinated proteins (By similarity). Phosphorylation at Ser-407 also primes for subsequent phosphorylation at Ser-403 (By similarity). Phosphorylation at Ser-403 by CK2 or ULK1 promotes binding to ubiquitinated proteins by increasing the affinity between the UBA domain and polyubiquitin chains (PubMed:22017874, PubMed:25040165). 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 ULK1 promotes interaction with KEAP1 and inactivation of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes (PubMed:37306101). Phosphorylated in vitro by TTN (PubMed:15802564).

Ubiquitinated by UBE2J1 and RNF26 at Lys-435: 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, PubMed:33472082). Ubiquitination by UBE2D2 and UBE2D3 increases its ability to bind polyubiquitin chains by destabilizing the UBA dimer interface (PubMed:28322253). 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).

Acetylated at Lys-420 and Lys-435 by KAT5/TIP60, promotes activity by destabilizing the UBA dimer interface and increases binding affinity to ubiquitinated proteins (PubMed:31857589). Deacetylated by HDAC6 (PubMed:31857589).

Palmitoylation at Cys-289 and Cys-290 by ZDHHC19 is required for efficient autophagic degradation of SQSTM1-cargo complexes by promoting affinity for ATG8 proteins and recruitment of p62 bodies to autophagosomes (PubMed:37802024). Dealmitoylated at Cys-289 and Cys-290 by LYPLA1 (PubMed:37802024).

(Microbial infection) Cleaved by S.pyogenes SpeB protease; leading to its degradation (PubMed:24331465). Degradation by SpeB prevents autophagy, promoting to S.pyogenes intracellular replication (PubMed:24331465).

(Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1; leading to inhibition of the recruitment of MAP1LC3A/LC3 to SQSTM1-positive structures.

Tissue specificity

Ubiquitously expressed.

Cellular localization

  • Cytoplasmic vesicle
  • Autophagosome
  • Preautophagosomal structure
  • Cytoplasm
  • Cytosol
  • Nucleus
  • PML body
  • Late endosome
  • Lysosome
  • Nucleus
  • Endoplasmic reticulum
  • Cytoplasm
  • Myofibril
  • Sarcomere
  • In cardiac muscle, localizes to the sarcomeric band (By similarity). Localizes to cytoplasmic membraneless inclusion bodies, known as p62 bodies, containing polyubiquitinated protein aggregates (PubMed:11786419, PubMed:20357094, PubMed:22017874, PubMed:29343546, PubMed:29507397, PubMed:31857589, PubMed:37306101, PubMed:37802024). In neurodegenerative diseases, detected in Lewy bodies in Parkinson disease, neurofibrillary tangles in Alzheimer disease, and HTT aggregates in Huntington disease (PubMed:15158159). 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 (PubMed:11981755). Enriched in Rosenthal fibers of pilocytic astrocytoma (PubMed:11786419). In the cytoplasm, observed in both membrane-free ubiquitin-containing protein aggregates (sequestosomes) and membrane-surrounded autophagosomes (PubMed:15953362, PubMed:17580304). Colocalizes with TRIM13 in the perinuclear endoplasmic reticulum (PubMed:22178386). Co-localizes with TRIM5 in cytoplasmic bodies (PubMed:20357094). When nuclear export is blocked by treatment with leptomycin B, accumulates in PML bodies (PubMed:20168092).

Alternative names

ORCA, OSIL, SQSTM1, 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, p62

Target type

Proteins

Primary research area

Neuroscience

Molecular weight

47687Da

We found 38 products in 4 categories

Assay Kits

Reactive species

Detection method

Proteins & Peptides

Species of origin

Cell Lines & Lysates

Species or organism

Search our catalogue for 'SQSTM1' (38)

Products

ab109012

Anti-SQSTM1 / p62 antibody [EPR4844] - Autophagosome Marker

Lab Essentials
Recombinant
RabMAb
KO Validated

ab207305

Anti-SQSTM1 / p62 antibody [EPR18351] - Autophagosome Marker

Lab Essentials
Recombinant
RabMAb
KO Validated

ab314504

Anti-SQSTM1 / p62 antibody [RM1079] - Autophagosome Marker

Lab Essentials
Recombinant
RabMAb
KO Validated
20ul selling size

ab240635

Anti-SQSTM1 / p62 antibody [EPR23101-103] - Autophagosome Marker

Lab Essentials
Recombinant
RabMAb
KO Validated

ab280086

Anti-SQSTM1 / p62 antibody [3/P62 LCK LIGAND] - Autophagosome Marker

Lab Essentials
Recombinant
KO Validated
20ul selling size

ab289654

Human SQSTM1/p62 ELISA Kit

Recombinant
SimpleStep