In humans, clusterin (CLU) is encoded by the CLU gene on chromosome 8.[5] CLU is an extracellular molecular 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 many diseases including neurodegenerative diseases, cancers, inflammatory diseases, and aging.[7][8][9]
Quick Facts CLU, Identifiers ...
CLU |
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Identifiers |
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Aliases | CLU, AAG4, APO-J, APOJ, CLI, CLU1, CLU2, KUB1, NA1/NA2, SGP-2, SGP2, SP-40, TRPM-2, TRPM2, clusterin |
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External IDs | OMIM: 185430; MGI: 88423; HomoloGene: 1382; GeneCards: CLU; OMA:CLU - orthologs |
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RNA expression pattern |
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Bgee | Human | Mouse (ortholog) |
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Top expressed in | - external globus pallidus
- Achilles tendon
- paraflocculus of cerebellum
- palpebral conjunctiva
- optic nerve
- Brodmann area 10
- right uterine tube
- middle frontal gyrus
- Brodmann area 9
- right testis
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| Top expressed in | - iris
- ciliary body
- epithelium of lens
- habenula
- paraventricular nucleus of hypothalamus
- dorsomedial hypothalamic nucleus
- Epithelium of choroid plexus
- dorsal tegmental nucleus
- subiculum
- ventral tegmental area
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BioGPS | |
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Wikidata |
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The CLU gene contains nine exons 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 small heat shock protein family and is thus a molecular chaperone. Unlike most other chaperone proteins, which aid intracellular 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 an ATP-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, including lipid transport, membrane recycling, cell adhesion, programmed cell death, and complement-mediated cell lysis.[7][8][9] Overexpression of secretory CLU can protect cells from apoptosis induced by cellular stress, such as chemotherapy, radiotherapy, or androgen/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 the phosphatidylinositol 3-kinase/protein kinase B pathway, modulation of extracellular signal-regulated kinase (ERK) 1/2 signaling and matrix metallopeptidase-9 expression, promotion of angiogenesis, and mediation of the nuclear factor kappa B (NF-κB) pathway. Meanwhile, its downregulation allows for p53 activation, which then skews the proapoptotic:antiapoptotic ratio of present Bcl-2 family members, resulting in mitochondrial dysfunction and cell death. p53 may also transcriptionally repress secretory CLU to further promote the proapoptotic cascade.[7]
Two independent genome-wide association studies found a statistical association between a SNP within the clusterin gene and the risk of having Alzheimer's disease. Further studies have suggested that people who already have Alzheimer's disease have more clusterin in their blood, and that clusterin levels in blood correlate with faster cognitive decline in individuals with Alzheimer's disease, but have not found that clusterin levels predicted the onset of Alzheimer's disease.[15][16][17][18] In addition to Alzheimer's disease, CLU may be involved in other neurodegenerative diseases such as Huntington disease.[8]
CLU may promote tumorigenesis by facilitating BAX-KLU70 binding and, consequently, preventing BAX from localizing to the outer mitochondrial membrane to stimulate cell death. In clear cell renal cell carcinoma, CLU functions to regulate ERK 1/2 signaling and matrix metallopeptidase-9 expression to promote tumor cell migration, invasion, and metastasis. In epithelial ovarian cancer, CLU has been observed to promote angiogenesis and chemoresistance. Other pathways CLU participates in to downplay apoptosis in tumor cells include the PI3K/AKT/mTOR pathway and NF-κB pathway. Unlike most other cancers, which feature upregulated CLU levels to enhance tumor cell survival, testicular seminoma features downregulated CLU levels, allowing for increased sensitivity to chemotherapy treatments. Other cancers CLU has been implicated in include breast cancer, pancreatic cancer, hepatocellular carcinoma, and melanoma.
As evident by its key roles in cancer development, CLU can serve as a therapeutic target for fighting tumor growth and chemoresistance. Studies revealed that inhibition of CLU resulted in increased effectiveness of chemotherapeutic agents to kill tumor cells.[7] In particular, custirsen, an antisense oligonucleotide that blocks the CLU mRNA transcript, enhanced heat-shock protein 90 (HSP90) inhibitor activity by suppressing the heat-shock response in castrate-resistant prostate cancer, and was tested in phase III trials.[7][9]
CLU activity is also involved in infectious diseases, such as hepatitis C. CLU is induced by the stress of hepatitis C viral infection, which disrupts glucose regulation. The chaperone protein then aids hepatitis C viral assembly by stabilizing its core and NS5A units.[9] In addition to the above diseases, CLU has been linked to other conditions resulting from oxidative damage, including aging, glomerulonephritis, atherosclerosis, and myocardial infarction. [9]
CLU has been shown to interact with many different protein ligands and several cell receptors. [12]
Lin CC, Tsai P, Sun HY, Hsu MC, Lee JC, Wu IC, Tsao CW, Chang TT, Young KC (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): 984–93. doi:10.1016/j.jhep.2014.06.026. PMID 24996046.
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): 1094–9. doi:10.1038/ng.439. hdl:10281/9031. PMID 19734903. S2CID 24530130.
- Krumbiegel M, Pasutto F, Mardin CY, Weisschuh N, Paoli D, Gramer E, Zenkel M, Weber BH, Kruse FE, Schlötzer-Schrehardt U, Reis A (Jun 2009). "Exploring functional candidate genes for genetic association in german patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma". Investigative Ophthalmology & Visual Science. 50 (6): 2796–801. doi:10.1167/iovs.08-2339. PMID 19182256.
- Cerhan JR, Novak AJ, Fredericksen ZS, Wang AH, Liebow M, Call TG, Dogan A, Witzig TE, Ansell SM, Habermann TM, Kay NE, Slager SL (Jun 2009). "Risk of non-Hodgkin lymphoma in association with germline variation in complement genes". British Journal of Haematology. 145 (5): 614–23. doi:10.1111/j.1365-2141.2009.07675.x. PMC 2820509. PMID 19344414.
- Trougakos IP, Gonos ES (Nov 2002). "Clusterin/apolipoprotein J in human aging and cancer". The International Journal of Biochemistry & Cell Biology. 34 (11): 1430–48. doi:10.1016/S1357-2725(02)00041-9. PMID 12200037.
- Jenne DE, Tschopp J (Apr 1992). "Clusterin: the intriguing guises of a widely expressed glycoprotein". Trends in Biochemical Sciences. 17 (4): 154–9. doi:10.1016/0968-0004(92)90325-4. PMID 1585460.
- 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): 1267–74. doi:10.1016/j.freeradbiomed.2009.01.025. PMID 19353783.
- Wei L, Xue T, Wang J, Chen B, Lei Y, Huang Y, Wang H, Xin X (Aug 2009). "Roles of clusterin in progression, chemoresistance and metastasis of human ovarian cancer". International Journal of Cancer. 125 (4): 791–806. doi:10.1002/ijc.24316. PMID 19391138. S2CID 23162609.
- 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): 704–11. doi:10.1016/j.cellsig.2009.01.008. PMID 19166932.
- Olsen SH, Ma L, Schnitzer B, Fullen DR (Mar 2009). "Clusterin expression in cutaneous CD30-positive lymphoproliferative disorders and their histologic simulants" (PDF). Journal of Cutaneous Pathology. 36 (3): 302–7. doi:10.1111/j.1600-0560.2008.01036.x. hdl:2027.42/73222. PMID 19220628. S2CID 8915250.
- Aigelsreiter A, Janig E, Sostaric J, Pichler M, Unterthor D, Halasz J, Lackner C, Zatloukal K, Denk H (Apr 2009). "Clusterin expression in cholestasis, hepatocellular carcinoma and liver fibrosis". Histopathology. 54 (5): 561–70. doi:10.1111/j.1365-2559.2009.03258.x. PMID 19413638. S2CID 21277859.
- Pucci S, Mazzarelli P, Paola M, Sesti F, Fabiola S, Boothman DA, David BA, Spagnoli LG, Luigi SG (Feb 2009). "Interleukin-6 affects cell death escaping mechanisms acting on Bax-Ku70-Clusterin interactions in human colon cancer progression". Cell Cycle. 8 (3): 473–81. doi:10.4161/cc.8.3.7652. PMC 2853871. PMID 19177010.
- Trougakos IP, Lourda M, Antonelou MH, Kletsas D, Gorgoulis VG, Papassideri IS, Zou Y, Margaritis LH, Boothman DA, Gonos ES (Jan 2009). "Intracellular clusterin inhibits mitochondrial apoptosis by suppressing p53-activating stress signals and stabilizing the cytosolic Ku70-Bax protein complex". Clinical Cancer Research. 15 (1): 48–59. doi:10.1158/1078-0432.CCR-08-1805. PMC 4483278. PMID 19118032.
- 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): 1225–9. doi:10.1097/PAS.0b013e3181a6d86f. PMID 19542874. S2CID 24444024.
- Chandra P, Plaza JA, Zuo Z, Diwan AH, Koeppen H, Duvic M, Medeiros LJ, Prieto VG (Apr 2009). "Clusterin expression correlates with stage and presence of large cells in mycosis fungoides". American Journal of Clinical Pathology. 131 (4): 511–5. doi:10.1309/AJCPH43ZDVLSOSNB. PMID 19289586.
- 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): 314–23. doi:10.1002/jcp.21671. PMID 19137541. S2CID 206047289.
- Liao FT, Lee YJ, Ko JL, Tsai CC, Tseng CJ, Sheu GT (May 2009). "Hepatitis delta virus epigenetically enhances clusterin expression via histone acetylation in human hepatocellular carcinoma cells". The Journal of General Virology. 90 (Pt 5): 1124–34. doi:10.1099/vir.0.007211-0. PMID 19264665.
- 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): 183–8. doi:10.1007/s10735-006-9052-7. PMID 17048076. S2CID 20041580.
- Shannan B, Seifert M, Leskov K, Willis J, Boothman D, Tilgen W, Reichrath J (Jan 2006). "Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer". Cell Death and Differentiation. 13 (1): 12–9. doi:10.1038/sj.cdd.4401779. PMID 16179938.
- Otowa T, Yoshida E, Sugaya N, Yasuda S, Nishimura Y, Inoue K, Tochigi M, Umekage T, Miyagawa T, Nishida N, Tokunaga K, Tanii H, Sasaki T, Kaiya H, Okazaki Y (Feb 2009). "Genome-wide association study of panic disorder in the Japanese population". Journal of Human Genetics. 54 (2): 122–6. doi:10.1038/jhg.2008.17. PMID 19165232.
- 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): 605–16. doi:10.1007/s10735-008-9201-2. PMID 18949565. S2CID 11598911.