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FLASH GENE

Symbol

CLU

contributors: mct/npt/pgu/shn - updated : 08-06-2016

HGNC name	clusterin
HGNC id	2095

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001831 9 splicing 2877 NP_001822 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 NR_045494 8 splicing 2871 - - - - transcript variant 4, non-coding RNA. NR_038335 9 splicing 3012 - - - - transcript variant 3, non-coding RNA

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Nervous brain diencephalon hypothalamus       spinal cord         Reproductive male system testis       Skin/Tegument skin         Visual eye retina

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective         Epithelial barrier lining retinal pigment epithelium (RPE)     Nervous central       Nervous peripherous

cells

System Cell Pubmed Species Stage Rna 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-â 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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed immunology inflammatory   possibility of using clusterin as a therapeutic agent for TTR amyloidosis cancer reproductive breast targeting CLU could represent a promising therapeutic strategy in association with antiestrogen treatment in breast cancer patients neurology neurodegenerative alzheimer protects against in vitro amyloid-beta (1-40) neurotoxicity neurology acquired   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