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FLASH GENE
Symbol CLU contributors: mct/npt/pgu/shn - updated : 08-06-2016
HGNC name clusterin
HGNC id 2095
Location 8p21.1      Physical location : 27.454.450 - 27.472.327
Synonym name
  • clusterin (complement lysis inhibitor, SP-40,40, sulfated glycoprotein 2, testosterone-repressed prostate message 2, apolipoprotein J
  • apolipoprotein J
  • complement lysis inhibitor
  • complement cytolysis inhibitor
  • sulfated glycoprotein 2
  • testosterone-repressed prostate message 2
  • aging-associated protein 4
  • complement-associated protein SP-40,40
  • ku70-binding protein 1
  • Synonym symbol(s) APOJ, APO-J, CLI, SGP2, SP40, SP-40, KUPB1, TRPM2, TRPM-2, XIP8, SGP-2, AAG4, KUB1, MGC24903, AAG4, NA1/NA2, KUB1, sCLU
    DNA
    TYPE functioning gene
    STRUCTURE 14.52 kb     9 Exon(s)    1 Copie(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    cytosine-phosphate-guanine/HTF
    text structure
  • region between -218 and -106 bp, contains a particular heat-shock element, named CLE for 'clusterin element', bound by HSF1 (heat-shock factor 1) and HSF2 upon proteasome inhibition
  • a non-canonical E-box (NCE-box) motif in the proximal upstream region within the clusterin promoter is necessary for insulin-stimulated hepatic expression of clusterin via SREBF1
  • MAPPING cloned Y linked N status confirmed
    Map pter - D8S382 - D8S1839 - CLU - D8S1820 - D8S1809 - cen
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    9 splicing 2877 70 449 - 2010 20028970
  • lacking exon 2
  • coding for the longest product
  • secreted isoform, glycosylated presecretory form (psCLU)
  • has a cytoprotective and chaperone role
  • anti-apoptotic secreted form
  • psCLU form of CLU has regulatory activity on NF-kappaB
  • 8 splicing 2871 - - - -
    transcript variant 4, non-coding RNA.
    9 splicing 3012 - - - -
    transcript variant 3, non-coding RNA
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Nervousbraindiencephalonhypothalamus  
     spinal cord    
    Reproductivemale systemtestis   
    Skin/Tegumentskin    
    Visualeyeretina   
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connective    
    Epithelialbarrier liningretinal pigment epithelium (RPE)  
    Nervouscentral   
    Nervousperipherous   
    cells
    SystemCellPubmedSpeciesStageRna symbol
     digestive
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period
    cell cycle     cell cycle
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • C-terminal coiled-coil domain with Ku70 binding activity
  • DeltaCLU domain involved in NF-kappaB pathway regulation
  • secondary structure a CLUSTERIN alpha chain, a CLUSTERIN beta chain
    conjugated GlycoP , LipoP
    mono polymer heteromer , dimer
    HOMOLOGY
    interspecies ortholog to Clu, Rattus norvegicus
    ortholog to Clu, Mus musculus
    ortholog to clu, Danio rerio
    ortholog to CLU, Pan troglodytes
    Homologene
    FAMILY
  • clusterin family
  • CATEGORY chaperone/stress , antigen , transport carrier
    SUBCELLULAR LOCALIZATION extracellular
        intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,nucleus
    basic FUNCTION
  • involved in lipid transport, epithelial cell differentiation, tumorigenesis, and apoptosis
  • potentially involved in spermatogenesis
  • maybe involved in DNA double-strand break repair by end joining (non homologous recombination) V(D)J recombination and apoptosis
  • participating in the terminal complement reaction, serving as a granule constituent in neuronal and endocrine cells
  • recognized as a thyroid autoantigen (70kDa) (G22P1) binding protein
  • playing a protective role against chronic glomerular kidney disease and modifiyng immune complex metabolism and disposal
  • having anti-apoptotic and anti-inflammatory functions in the exocrine pancreas and protective during inflammation of exocrine pancreas
  • may play an important role in hepatocellular metastasis
  • regulates TGF- signaling pathway by modulating the stability of SMAD2/3 proteins
  • limits progression of autoimmune myocarditis and protects the heart from postinflammatory tissue destruction
  • inhibits stress-induced precipitation of a very broad range of structurally divergent protein substrates
  • stabilizes stressed proteins in a state competent for refolding by heat shock protein 70
  • can influence structure, toxicity, and accumulation of the amyloid-beta peptide in brain
  • extracellular chaperone that has been functionally implicated in DNA repair, cell-cycle regulation, apoptotic cell death and tumorigenesis
  • potentially represents the only chaperone that regulates protein stability both extra- and intracellularly
  • chaperone-like role for clusterin in facilitating the degradation of ATP7A, ATP7B
  • new role for intracellular clusterin in mediating Cu-ATPase quality control and hence in the normal maintenance of copper homeostasis, and in promoting cell survival in the context of disease
  • involved in the disposal of oxidized/defected material through diseased red blood cells vesiculation
  • clusterin and COMMD1 represent alternative and independent systems regulating Cu-ATPase quality control, and consequently contributing to the maintenance of copper homeostasis
  • novel function for CLU as an inducer of TNF in macrophages and their chemotactic migration, suggesting that CLU has a tumor-promoting effect
  • can stimulate various chemotactic cytokines, including TNF and play a critical role in macrophage chemotaxis
  • glycosylated intracellular CLU forms may act as a redox sensor under oxidative stress conditions
  • glycoprotein involved in various biological processes, including attenuation of complement activity, sperm maturation, apoptosis, and reverse lipid transport
  • activation of prosurvival autophagy by hypoxia in kidney cells requires CLU expression and may be a key cytoprotective mechanism of CLU in the protection of the kidney from hypoxia/ischemia-mediated injury
  • exhibits characteristics of soluble innate immunity receptors, as assessed by its ability to bind some bacteria strains
  • potentiates the phagocytosis of late apoptotic cells by macrophages
  • facilitates apoptotic cell clearance and prevents apoptotic cell-induced autoimmune responses
  • CELLULAR PROCESS cell life, proliferation/growth
    cell life, cell death/apoptosis
    nucleotide, repair, recombination
    PHYSIOLOGICAL PROCESS inflammation , carcinogenesis
    PATHWAY
    metabolism lipid/lipoprotein
    signaling
  • hypothalamic CLU-LRP2 axis is a novel anorexigenic signalling pathway that is tightly coupled with long-form leptin receptor-mediated signalling
  • a component
  • antiparallel disulfide-linked heterodimer
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • Glycoprotein 330, gp330
  • paraoxonase
  • amphiphilic C5b-9 complex
  • complement C7, C8 beta, and the b domain of C9
  • type II TGF beta receptor (RII)
  • amyloid-beta (A beta) plaques
  • Abeta1-40
  • Ku70
  • leptin
  • Bax
  • Hrd1/synoviolin
  • alpha-actinin
  • CLU facilitates exchange of glycosyl phosphatidylinositol-linked SPAM1 between reproductive luminal fluids and sperm membranes
  • wild-type TTR and TTR variants V30M and L55P
  • Chibby
  • ATP7A and ATP7B
  • anti-apoptotic Bcl-2 family proteins
  • COMMD1
  • multifunctional extracellular chaperone clusterin is a cathepsin K-binding protein
  • induce the expression of MMP9 in macrophages, and MMP9 is known to be essential for tumor cell migration and invasion
  • binds to apolipoprotein E receptor 2 (LRP8) and very low density lipoprotein receptor (VLDLR) and is internalized by cells expressing either one of these receptors
  • nuclear CLU expression is regulated by direct binding of HIF1A to HRE sites and is epigenetically controlled by methylation of its promoter region
  • sCLU reduces osteoclastogenesis formation by inhibiting the actions of CSF1, thereby suggesting its protective role in bone erosion
  • cell & other
  • altered elastic fibers in aged human skin
  • REGULATION
    Other CRM1
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in frontal cortex in Alzheimer disease
    constitutional     --low  
    in glomerular diseases causing nephrotic syndrome
    tumoral     --low  
    in pancreatic cancer in progression, in prostate cancer low-and high-grade,
    constitutional     --over  
    in pancreas during the acute phase of pancreatitis
    tumoral     --over  
    n epithelial ovarian cancer appears to be correlated with increased tumor angiogenesis, consistent with the established role of CLU as an oncogene in the biology of ovarian cancer
    Susceptibility
  • to Alzheimer disease
  • to Fuchs' corneal dystrophy
  • Variant & Polymorphism other
  • polymorphisms increasing the risk of Alzheimer disease
  • SNPs in CLU, in association with APOE epsilon4 homozygotes associated to familial late-onset Alzheimer disease
  • C allele confers a 1.16 greater odds of developing late-onset AD than the T allele, and carriers of this CLU gene risk variant showed a distinct profile of lower white matter integrity that may increase vulnerability to developing AD later in life
  • variant rs11136000 leading to altered coupling between hippocampus and prefrontal cortex during memory processing, providing a neurogenetic mechanism for CLU-associated risk and protection
  • association of CLU (rs17466684) wih Fuchs' corneal dystrophy
  • Candidate gene candidate to be part of a cellular defence mechanism against neurodegenerative diseases associated with misfolded protein accumulation or decrease in proteasome activity
    Marker
  • CLU CSF levels could serve as a potential marker for Parkinson disease (PD), dementia with Lewy bodies (DLB), differentiation (Significantly higher CSF clusterin levels were found in PD and lower in DLB)
  • abnormal sCLU expression associated with tumor progression could be a potential diagnostic and prognostic biomarker for hepatocellular carcinoma
  • circulating clusterin level may be a surrogate marker for obesity-associated systemic inflammation
  • seminal clusterin can be considered as a marker for the quick assessment of semen quality in male infertility studies
  • Therapy target
    SystemTypeDisorderPubmed
    immunologyinflammatory 
    possibility of using clusterin as a therapeutic agent for TTR amyloidosis
    cancerreproductivebreast
    targeting CLU could represent a promising therapeutic strategy in association with antiestrogen treatment in breast cancer patients
    neurologyneurodegenerativealzheimer
    protects against in vitro amyloid-beta (1-40) neurotoxicity
    neurologyacquired 
    may be a therapeutic target to modulate non-caspase-dependent neuronal death following acute brain injury
    ANIMAL & CELL MODELS
  • depletion of endogenous nCLU protein using siRNA specific to its truncated mRNA increased clonogenic survival of ionizing radiation (IR)-exposed cells
  • Inflammatory lesions were more diffuse and extensive in apoJ-deficient mice and inflammation was more severe, mice exhibited cardiac function impairment and severe myocardial scarring
  • Clusterin-deficient mice had 50% less brain injury following neonatal hypoxic-ischemic
  • apoE(-/-)/clusterin(-/-) mice had earlier age-dependent Abeta and markedly increased Abeta and amyloid deposition and elevated CSF and brain interstitial fluid Abeta
  • Clu(-/-) mice develop symptoms of autoimmunity, including the generation of anti-dsDNA antibodies, deposition of immunoglobulins and complement components within kidneys, and splenomegaly