Clusterin

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Species	Human	Mouse
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Clusterin (apolipoprotein J) is a 75 - 80 kDa disulfide-linked heterodimeric protein associated with the clearance of cellular debris and apoptosis. In humans, clusterin is encoded by the CLU gene on chromosome 8. CLU is a molecular chaperone responsible for aiding protein folding of secreted proteins, and its three isoforms have been differentially implicated in pro- or antiapoptotic processes. Through this function, CLU is involved in many diseases related to oxidative stress, including neurodegenerative diseases, cancers, inflammatory diseases, and aging.

Structure

The CLU gene contains nine exons and expresses three isoforms alternatively-spliced at the first exon. The encoded protein isoforms all localize to different subcellular compartments: one isoform localizes to the nucleus; a second isoform localizes to the cytoplasm; and the third is secreted from the cell. They also perform opposing functions: the nuclear CLU binds Ku70 to release BAX and induce apoptosis, whereas the cytosolic and secretory isoforms inhibit apoptosis. The nuclear isoform encodes a 49 kDa protein, while the secretory isoform, which is the main gene transcript, encodes a 75–80 kDa protein after maturation (glycosylation, secretion, and dimerization). The mature protein is a 449-residue, heterodimeric, disulfide-linked glycoprotein composed of two subunits of 40 kDa α- and β-chains.

Function

Clusterin was first identified in ram rete testis fluid where it showed signs of clustering with rat sertoli cells and erythrocytes, hence its name.

CLU is a member of the small heat shock protein family and, thus, a molecular chaperone. Unlike most other chaperone proteins, which aid intracellular proteins, CLU is a Golgi chaperone that facilitates the folding of secreted proteins in an ATP-independent way. The gene is highly conserved in species, and the protein is widely distributed in many tissues and organs, where it participates in a number of biological processes, including lipid transport, membrane recycling, cell adhesion, programmed cell death, and complement-mediated cell lysis. Overexpression of the secretory CLU isoform protects the cell from apoptosis induced by cellular stress, such as chemotherapy, radiotherapy, or androgen/estrogen depletion. CLU promotes 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 extracellularular 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.

Clinical associations

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. In addition to Alzheimer’s disease, CLU is involved in other neurodegenerative diseases such as Huntington disease.

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. 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 is currently in phase III trials.

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. CLU expression in the kidney also plays a role in renal diseases, such as nephropathic cystinosis, which is a major cause of Fanconi syndrome. In addition to the above diseases, CLU has been linked to other conditions resulting from oxidative damage, including aging, glomerulonephritis, atherosclerosis, and myocardial infarction.

Interactions

CLU has been shown to interact with Ku70.

Further reading

• 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.
• Ståhl AL, Kristoffersson A, Olin AI, Olsson ML, Roodhooft AM, Proesmans W, Karpman D (Jul 2009). "A novel mutation in the complement regulator clusterin in recurrent hemolytic uremic syndrome". Molecular Immunology. 46 (11–12): 2236–43. doi:10.1016/j.molimm.2009.04.012. PMID 19446882.
• 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.
• 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". Journal of Cutaneous Pathology. 36 (3): 302–7. doi:10.1111/j.1600-0560.2008.01036.x. PMID 19220628.
• 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.
• 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. 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.
• 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.
• 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.
• 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 Mol ecular Histology. 39 (6): 605–16. doi:10.1007/s10735-008-9201-2. PMID 18949565.

External links

• Clusterin at the US National Library of Medicine Medical Subject Headings (MeSH)
• Apolipoproteins and Applied Research