Clusterin is aprotein that in humans is encoded by theCLUgene on chromosome 8.[5] CLU is an extracellularmolecular chaperone which binds to misfolded proteins in body fluids to neutralise their toxicity and mediate their cellular uptake by receptor-mediated endocytosis. Once internalised by cells, complexes between CLU and misfolded proteins are trafficked to lysosomes where they are degraded.[6] CLU is involved in manydiseases includingneurodegenerative diseases,cancers,inflammatory diseases, andaging.[7][8][9]
TheCLU gene contains nineexons and a variety of mRNA isoforms can be detected, although most of these are only ever expressed at very low levels (< 0.3% of the total). The full-length mRNA encoding the secreted isoform is by far the dominant species transcribed.[10] Secreted CLU (apolipoprotein J) is an approximately 60 kDa disulfide-linked heterodimeric glycoprotein which migrates in SDS-PAGE with an apparent molecular mass of 75-80 kDa.[11] Mature CLU is composed of disulfide-linked α- and β-chains. Although multiple previous publications proposed the existence of N-terminally truncated CLU protein isoforms in different cell compartments, recent work has highlighted the lack of direct evidence for this[12] and shown that the full-length CLU polypeptide, with variable levels of glycosylation (and hence variable apparent mass), can translocate from the ER/Golgi to the cytosol and nucleus during stress.[13]
Clusterin was first identified in ram rete testis fluid where it was shown to elicit in vitro clustering of rat Sertoli cells and erythrocytes, hence its name.[14]
CLU has functional similarities to members of the smallheat shock protein family and is thus amolecular chaperone. Unlike most other chaperone proteins, which aidintracellular proteins, CLU is trafficked through the ER/Golgi before normally being secreted. Within the secretory system, CLU has been suggested to facilitate the folding of secreted proteins in anATP-independent way.[9] The gene is highly conserved in species, and the protein is widely distributed in many tissues and organs, where it been implicated in a number of biological processes, includinglipid transport, membrane recycling,cell adhesion,programmed cell death, andcomplement-mediatedcell lysis.[7][8][9] Overexpression of secretory CLU can protect cells from apoptosis induced by cellular stress, such aschemotherapy,radiotherapy, orandrogen/estrogen depletion. CLU has been suggested to promote cell survival by a number of means, including inhibition of BAX on the mitochondrial membrane, activation of thephosphatidylinositol 3-kinase/protein kinase B pathway, modulation ofextracellular signal-regulated kinase (ERK) 1/2signaling andmatrix metallopeptidase-9 expression, promotion ofangiogenesis, and mediation of the nuclear factor kappa B (NF-κB) pathway. Meanwhile, its downregulation allows forp53 activation, which then skews the proapoptotic:antiapoptotic ratio of presentBcl-2 family members, resulting inmitochondrial dysfunction and cell death. p53 may also transcriptionally repress secretory CLU to further promote the proapoptotic cascade.[7]
Subsequent studies found elevated clusterin (CLU) protein levels in the blood of individuals with Alzheimer's disease, and these levels were correlated with faster cognitive decline. However, increased CLU levels did not reliably predict the onset of the disease.[17][18]
CLU may also play a role in other neurodegenerative diseases, such asHuntington disease.[8]
CLU has been implicated in multiple cancers through its role in promoting tumor cell survival and resistance to apoptosis. It facilitates the binding of BAX to Ku70, thereby preventing BAX from localizing to theouter mitochondrial membrane to initiate apoptosis.
Due to its central role in tumor biology, CLU has been investigated as a therapeutic target. Inhibition of CLU enhances the efficacy of chemotherapeutic agents.[7] One promising agent,custirsen, is an antisense oligonucleotide that targets CLU mRNA. It was shown to improve the activity ofHSP90 inhibitors by suppressing the heat shock response in castration-resistantprostate cancer, and was evaluated inphase III trials.[7][9]
CLU is also involved in the host response to infection. Inhepatitis C virus infection, CLU is upregulated in response to cellular stress and assists in viral assembly by stabilizing the viral core and NS5A proteins.[9]
^abcdefLin CC, Tsai P, Sun HY, Hsu MC, Lee JC, Wu IC, et al. (Nov 2014). "Apolipoprotein J, a glucose-upregulated molecular chaperone, stabilizes core and NS5A to promote infectious hepatitis C virus virion production".Journal of Hepatology.61 (5):984–993.doi:10.1016/j.jhep.2014.06.026.PMID24996046.
^Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, et al. (Oct 2009). "Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease".Nature Genetics.41 (10):1094–1099.doi:10.1038/ng.439.hdl:10281/9031.PMID19734903.S2CID24530130.
Trougakos IP, Gonos ES (Nov 2002). "Clusterin/apolipoprotein J in human aging and cancer".The International Journal of Biochemistry & Cell Biology.34 (11):1430–1448.doi:10.1016/S1357-2725(02)00041-9.PMID12200037.
Jenne DE, Tschopp J (Apr 1992). "Clusterin: the intriguing guises of a widely expressed glycoprotein".Trends in Biochemical Sciences.17 (4):154–159.doi:10.1016/0968-0004(92)90325-4.PMID1585460.
Ståhl AL, Kristoffersson A, Olin AI, Olsson ML, Roodhooft AM, Proesmans W, et al. (Jul 2009). "A novel mutation in the complement regulator clusterin in recurrent hemolytic uremic syndrome".Molecular Immunology.46 (11–12):2236–2243.doi:10.1016/j.molimm.2009.04.012.PMID19446882.
Balantinou E, Trougakos IP, Chondrogianni N, Margaritis LH, Gonos ES (May 2009). "Transcriptional and posttranslational regulation of clusterin by the two main cellular proteolytic pathways".Free Radical Biology & Medicine.46 (9):1267–1274.doi:10.1016/j.freeradbiomed.2009.01.025.PMID19353783.
Chou TY, Chen WC, Lee AC, Hung SM, Shih NY, Chen MY (May 2009). "Clusterin silencing in human lung adenocarcinoma cells induces a mesenchymal-to-epithelial transition through modulating the ERK/Slug pathway".Cellular Signalling.21 (5):704–711.doi:10.1016/j.cellsig.2009.01.008.PMID19166932.
Aigelsreiter A, Janig E, Sostaric J, Pichler M, Unterthor D, Halasz J, et al. (Apr 2009). "Clusterin expression in cholestasis, hepatocellular carcinoma and liver fibrosis".Histopathology.54 (5):561–570.doi:10.1111/j.1365-2559.2009.03258.x.PMID19413638.S2CID21277859.
Boland JM, Folpe AL, Hornick JL, Grogg KL (Aug 2009). "Clusterin is expressed in normal synoviocytes and in tenosynovial giant cell tumors of localized and diffuse types: diagnostic and histogenetic implications".The American Journal of Surgical Pathology.33 (8):1225–1229.doi:10.1097/PAS.0b013e3181a6d86f.PMID19542874.S2CID24444024.
Rizzi F, Caccamo AE, Belloni L, Bettuzzi S (May 2009). "Clusterin is a short half-life, poly-ubiquitinated protein, which controls the fate of prostate cancer cells".Journal of Cellular Physiology.219 (2):314–323.doi:10.1002/jcp.21671.PMID19137541.S2CID206047289.
Shannan B, Seifert M, Boothman DA, Tilgen W, Reichrath J (Sep 2006). "Clusterin and DNA repair: a new function in cancer for a key player in apoptosis and cell cycle control".Journal of Molecular Histology.37 (5–7):183–188.doi:10.1007/s10735-006-9052-7.PMID17048076.S2CID20041580.
Tunçdemir M, Ozturk M (Dec 2008). "The effects of ACE inhibitor and angiotensin receptor blocker on clusterin and apoptosis in the kidney tissue of streptozotocin-diabetic rats".Journal of Molecular Histology.39 (6):605–616.doi:10.1007/s10735-008-9201-2.PMID18949565.S2CID11598911.
