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FLASH GENE
Symbol SQSTM1 contributors: mct/ - updated : 12-11-2015
HGNC name sequestosome 1
HGNC id 11280
Corresponding disease
FTDALS3 frontotemporal dementia and/or amyotrophic lateral sclerosis 3
NADGP neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset
PDB3 Paget bone disease 3
Location 5q35.3      Physical location : 179.233.387 - 179.265.075
Synonym name
  • ubiquitin-binding protein P62
  • oxidative stress induced like
  • phosphotyrosine independent ligand for the Lck SH2 domain p62
  • ubiquitin-binding protein p62
  • Paget disease of bone 3
  • EBI3-associated protein of 60 kDa
  • Synonym symbol(s) P62, P60, A170, OSIL, ZIP3, p62B, ORCA, EBIAP
    DNA
    TYPE functioning gene
    SPECIAL FEATURE head to head
    STRUCTURE 31.69 kb     9 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    text structure no TATA box
    MAPPING cloned Y linked N status provisional
    Physical map
    LOC391856 5 similar to acetoacetyl-CoA synthetase; acetoacetate-CoA ligase; homolog of C. elegans supressor of ras 5 (sur-5) LOC391857 5 similar to hypothetical protein MGC2574 ZNF354B 5q35-3 zinc finger protein 354B LOC340042 5q35.3 similar to hypothetical protein MGC48972 PIGFP1 5q35 phosphatidylinositol glycan, class F, pseudogene 1 FLJ21628 5q35.3 hypothetical protein FLJ21628 ZNF454 5q35.3 zinc finger protein 454 GRM6 5q35 glutamate receptor, metabotropic 6 LOC391858 5 similar to F-box and WD-40 domain protein 2 LOC345462 5q35.3 similar to hypothetical protein 9630041N07 ZNF354C 5q35.3 zinc finger protein 354C LOC345463 5q35.3 similar to UNR protein ADAMTS2 5q23 a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif, 2 LOC391859 5 similar to Tb-291 membrane associated protein LOC389351 5 similar to 6-pyruvoyl-tetrahydropterin synthase RUFY1 5q35.3 RUN and FYVE domain containing 1 HNRPH1 5q353 heterogeneous nuclear ribonucleoprotein H1 (H) LOC202404 5q35.3 hypothetical LOC202404 LOC285679 5q35.3 hypothetical protein LOC285679 LOC389352 5 similar to High mobility group protein 4 (HMG-4) (High mobility group protein 2a) (HMG-2a) CANX 5q35 calnexin MAML1 5q35 mastermind-like 1 (Drosophila) FLJ12121 5q35.3 hypothetical protein FLJ12121 LTC4S 5q35 leukotriene C4 synthase MGAT4B 5q35 mannosyl (alpha-1,3-)-glycoprotein beta-1,4-N-acetylglucosaminyltransferase, isoenzyme B SQSTM1 5q35 sequestosome 1 LOC51149 5q35.3 truncated calcium binding protein KIAA0676 5q35.1-q35.3 truncated calcium binding protein RNF130 5q35.3 ring finger protein 130 LOC255426 LOC391860 5 similar to 40S ribosomal protein S8 MAPK9 5q35 mitogen-activated protein kinase 9 GFPT2 5q34-q35 glutamine-fructose-6-phosphate transaminase 2 KIAA1194 5q35.3 Homo sapiens KIAA1194 (KIAA1194), mRNA. SCGB3A1 5q35-qter secretoglobin, family 3A, member 1 FLT4 5q35.3 fms-related tyrosine kinase 4 LOC134082 5q35.3 similar to seven transmembrane helix receptor LOC134083 5q35.3 similar to Olfactory receptor 2Y1
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    8 - 2923 62 440 - 2010 20018885
    isoform 1
    9 - 2931 40 356 - 2010 20018885
    isoform 2
    9 - 2848 40 356 - 2010 20018885
    isoform 2
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal PB1 domain, needed for homo-polymerization, and MAPK14 interaction (NPI) domain,
  • a zinc-finger cysteine-rich region
  • a potential 6 protein binding domain
  • a PEST motif and several phosphorylation sites
  • a SH2 domain
  • two clusters of positively charged AAs resembling the basic monopartite nuclear localization signal (AAs 186189 (NLS1) and AAs 264267 (NLS2)
  • C-terminal UBA domain, and MAPK14 interaction (CPI) domain
  • HOMOLOGY
    interspecies homolog to murine Sqstm1
    Homologene
    FAMILY
    CATEGORY adaptor , receptor membrane G
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm
    basic FUNCTION
  • immediate-early response gene that responds to a variety of extracellular signals involved in proliferation, differentiation and particularly oxidative stress
  • potentially involved in the regulation of fate of ubiquinated proteins by segregation (formation)
  • functioning in multiple signal transduction pathways activated by receptor activator of NFKB ligand (RANKL), tumor necrosis factor (TNF-alpha) and IL-1, that promote osteoclast (OCL) formation at least in part through NFKB activation
  • functions as a scaffold protein to integrate and diversify signals from multiple receptors, including tumour necrosis factor receptor family members, interleukin receptors, and nerve growth factor receptors
  • critical role in cytokine-dependent MAPK14 signalling pathway
  • ubiquitin-binding adaptor or scaffold protein implicated in many cellular functions
  • proteotoxic stress response protein, that may act as a ubiquitin chain-targeting factor shuttling substrates for proteasomal degradation
  • play fundamental roles in the control of bone remodeling through the regulation of signaling pathways in different cell types
  • SQSTM1 and CALCOCO2 act cooperatively to drive efficient antibacterial autophagy by targeting the protein complexes they coordinate to distinct micro-domains associated with bacteria
  • DRAM1 and SQSTM1 regulate cell motility and invasion in GBM stem cells
  • novel function of the autophagy regulators DRAM1 and SQSTM1 in control of migration/invasion in cancer stem cells
  • controls thermogenesis in a cell-autonomous manner, independently of brown adipocyte development or differentiation and is a novel regulator of mitochondrial function and brown fat thermogenesis
  • is a critical regulator of the hypoxia response and EGLN3 activity, by inducing EGLN3 aggregation and degradation under normoxia
  • SQSTM1 is decreased through autophagy-mediated degradation, while ELAVL1 through the proteasomal pathway
  • plays a key role in regulating the recruitment of F-actin network assemblies to the microtubule organizing center (MTOC), a critical cellular function that is required for successful autophagic clearance of protein aggregates (PMIDS:
  • implicated as an adaptor protein to mediate autophagic clearance of insoluble protein aggregates in age-related diseases, including age-related macular degeneration (AMD)
  • SQSTM1 and autophagy synergize to promote tumor growth, suggesting that inhibition of both pathways could be more effective than targeting either alone for cancer therapy
  • plays a critical role in recognizing/loading cargo (e.g., malfolded proteins) into autophagosomes for lysosomal degradation
  • PINK1, PARK2 and SQSTM1 have been shown to regulate mitophagy, leaving hitherto ill-defined the contribution by key players in 'general' autophagy
  • SQSTM1 is a critical regulator in CD40-mediated NFKB1 signaling via TRAF6
  • multidomain scaffolding protein involved in various key cellular processes, including the removal of damaged mitochondria by its function as a selective autophagy receptor
  • in dividing cells, contributes to the early regulation of mitophagy including perinuclear clustering of mitochondria and autophagosome formation upon depolarization, but it is redundant for mitochondrial removal and autophagic flux
  • CELLULAR PROCESS cell life, differentiation
    cell life, proliferation/growth
    protein, ubiquitin dependent proteolysis
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction
    a component
  • associating with MAP3K3 in a complex and regulating NF-kappaB activation
  • is able to form large aggregates containing ubiquitinated proteins
  • SQSTM1-NFE2L2-NQO1 cascade functions to assure mammalian longevity by stabilizing mitochondrial integrity
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • LCK (phosphotyrosine-independent ligand for LCK SH2 domain
  • ubiquitin
  • TRAF6 for RANK-induced NFKB activation
  • interacting with LC3 and thus tethering protein aggregates to autophagic machineries
  • SQSTM1 and WDFY3 interact to organize misfolded, ubiquitinated proteins into protein bodies that become degraded by autophagy
  • regulates ERK activity, interacts with MAPK14, and regulate cytokine-dependent MAPK14 activity
  • functional interaction between SQSTM1 and WDFY3 in osteoclasts under conditions of cell stress
  • interacts in an amino acid-dependent manner with MTOR and RAPTOR
  • TRIM13 interacts with p62/SQSTM1 and co-localizes with ZFYVE1
  • participates in the insulin-signaling pathway through its interactions with IRS1
  • AMER1, PALB2, and SQSTM1 bind KEAP1 to activate NFE2L2
  • induces autophagy by disrupting the association between BCL2 and BECN1
  • is assembled on selective autophagic cargos such as ubiquitinated organelles and subsequently phosphorylated in an MTOR-dependent manner, implying coupling of the KEAP1-NFE2L2 system to autophagy
  • binds to TWIST1 and inhibits degradation of TWIST1
  • HACE1 ubiquitylates OPTN and promotes its interaction with p62/SQSTM1 to form the autophagy receptor complex, thus accelerating autophagic flux
  • targeting SQSTM1 induces cargo loading failure and converts autophagy to apoptosis via BIK
  • SESN2 is a stress-inducible protein, recently shown to bind to SQSTM1 and promoting autophagic degradation of such SQSTM1 targets
  • SESN2 physically associates with Unc-51-like protein kinase 1 (ULK1) and SQSTM1 to form a complex in which both SESN2 and SQSTM1 become phosphorylated by ULK1 at multiple sites
  • RAF1/MEK/ERK can regulate cellular levels of MAP1LC3B and SQSTM1 at expression levels
  • CHDH is not a substrate of PARK2 but interacts with SQSTM1 independently of PARK2 to recruit SQSTM1 into depolarized mitochondria
  • cell & other
    REGULATION
    induced by various forms of cellular stress
    Other degraded by autophagy, and acts as a cargo receptor for autophagic degradation of ubiquitinated targets
    ASSOCIATED DISORDERS
    corresponding disease(s) PDB3 , NADGP , FTDALS3
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    accumulation in the drusen rich macular area suggesting impaired autophagy in the pathology of age-related macular degeneration (AMD)
    constitutional germinal mutation      
    in patients with either FTLD or ALS
    Susceptibility
  • to the development of Paget disease
  • to familial and sporadic ALS
  • Variant & Polymorphism other
  • (P392L) expression on osteoclasts is not sufficient to induce the full pagetic phenotype but cause a predisposition to the development of Paget disease by increasing the sensitivity of osteoclast precursors to osteoclastogenic cytokines
  • p.Ala53Thr and p.Pro439Leu, associated with sporadic ALS
  • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS