SQSTM1
GeneName
SQSTM1
Summary
SQSTM1, also known as p60, ORCA, or STAP, is a 48kDa multifunctional protein that plays a pivotal role in various cellular processes, particularly in autophagy and protein degradation pathways. It is predominantly expressed in the cytoplasm and is involved in the formation of autophagosomes and aggresomes. SQSTM1 acts as a receptor for ubiquitinated proteins, facilitating their degradation through the autophagy-lysosomal pathway. Additionally, it serves as a scaffold protein that participates in intracellular signalling and stress responses, linking various signalling pathways to cellular homeostasis. The protein is also implicated in the regulation of mitochondrial function and is associated with several cellular structures, including the endoplasmic reticulum, mitochondria, and P-bodies.
Importance
SQSTM1 is relevant to: - Autophagy and cellular quality control, as it mediates the degradation of damaged organelles and proteins, which is crucial for maintaining cellular health. - Neurodegenerative diseases, including Parkinson’s disease, where its aggregation is associated with the formation of Lewy bodies. - Cancer research, due to its role in regulating cell survival and apoptosis, as well as its involvement in signalling pathways that affect tumour growth. - Immune response modulation, given its participation in the regulation of inflammatory signalling pathways and stress responses.
Top Products
For researchers investigating SQSTM1, we highly recommend the top-selling recombinant antibody, Anti-SQSTM1 / p62 antibody [EPR4844] (ab109012). This antibody is well-cited, with 727 citations, reflecting its strong reputation in the field. It has been validated in knockout models, ensuring reliable performance in various applications, including Western blotting (WB), immunocytochemistry (ICC), immunoprecipitation (IP), and flow cytometry (FC). This versatility makes it an excellent choice for those seeking dependable detection of SQSTM1 in their experiments. The Anti-SQSTM1 / p62 antibody - Autophagosome Marker ELISA Kit (ab91526), with an impressive 346 citations, is an excellent option for researchers looking to accurately measure SQSTM1 levels in their studies.
Abcam Product Citation Summary
The data indicates a significant focus on the role of SQSTM1 in various biological contexts, particularly in studies related to autophagy, cancer, and cellular stress responses. The use of Abcam antibodies in diverse species, including humans, mice, and rats, highlights the relevance of SQSTM1 in both basic and translational research. The applications primarily involve Western blotting and immunohistochemistry, suggesting a strong interest in protein expression and localization in different tissues and conditions.
Abcam Product Citation Table
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
Molecular adapter required for selective macroautophagy (aggrephagy) by acting as a bridge between polyubiquitinated proteins and autophagosomes (PubMed:15340068, PubMed:15953362, PubMed:16286508, PubMed:17580304, PubMed:20168092, PubMed:22017874, PubMed:22622177, PubMed:24128730, PubMed:28404643, PubMed:29343546, PubMed:29507397, PubMed:31857589, PubMed:33509017, PubMed:34471133, PubMed:34893540, PubMed:35831301, PubMed:37306101, PubMed:37802024). Promotes the recruitment of ubiquitinated cargo proteins to autophagosomes via multiple domains that bridge proteins and organelles in different steps (PubMed:16286508, PubMed:20168092, PubMed:22622177, PubMed:24128730, PubMed:28404643, PubMed:29343546, PubMed:29507397, PubMed:34893540, PubMed:37802024). SQSTM1 first mediates the assembly and removal of ubiquitinated proteins by undergoing liquid-liquid phase separation upon binding to ubiquitinated proteins via its UBA domain, leading to the formation of insoluble cytoplasmic inclusions, known as p62 bodies (PubMed:15911346, PubMed:20168092, PubMed:22017874, PubMed:24128730, PubMed:29343546, PubMed:29507397, PubMed:31857589, PubMed:37802024). SQSTM1 then interacts with ATG8 family proteins on autophagosomes via its LIR motif, leading to p62 body recruitment to autophagosomes, followed by autophagic clearance of ubiquitinated proteins (PubMed:16286508, PubMed:17580304, PubMed:20168092, PubMed:22622177, PubMed:24128730, PubMed:28404643, PubMed:37802024). SQSTM1 is itself degraded along with its ubiquitinated cargos (PubMed:16286508, PubMed:17580304, PubMed:37802024). Also required to recruit ubiquitinated proteins to PML bodies in the nucleus (PubMed:20168092). Also involved in autophagy of peroxisomes (pexophagy) in response to reactive oxygen species (ROS) by acting as a bridge between ubiquitinated PEX5 receptor and autophagosomes (PubMed:26344566). Acts as an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1: interaction inactivates the BCR(KEAP1) complex by sequestering the complex in inclusion bodies, promoting nuclear accumulation of NFE2L2/NRF2 and subsequent expression of cytoprotective genes (PubMed:20452972, PubMed:28380357, PubMed:33393215, PubMed:37306101). Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 to autophagosomes (PubMed:29496741). 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, PubMed:33472082). Sequesters tensin TNS2 into cytoplasmic puncta, promoting TNS2 ubiquitination and proteasomal degradation (PubMed:25101860). May regulate the activation of NFKB1 by TNF, nerve growth factor (NGF) and interleukin-1 (PubMed:10356400, PubMed:10747026, PubMed:11244088, PubMed:12471037, PubMed:16079148, PubMed:19931284). May play a role in titin/TTN downstream signaling in muscle cells (PubMed:15802564). Adapter that mediates the interaction between TRAF6 and CYLD (By similarity).
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