Clusterin: It’s Implication in Health and Diseases.
Keywords:
Clusterin, Cell Interactions, Complement, Injury, Lipoprotein
Abstract
Clusterin (CLU) is a glycoprotein with a nearly ubiquitous tissue distribution that has been reported to be implicated in several physiological processes as well as in many pathological conditions including ageing, diabetes, atherosclerosis, degenerative diseases and tumorigenesis including tumors of prostate, colon, and breast. Two distinct CLU mRNA isoforms,the conventional secreted form of CLU (sCLU) is thought to be a component of high density lipoprotein-cholesterol. sCLU functions as a chaperone for misfolded proteins and it is thought to promote survival by reducing oxidative stress. Nuclear CLU, formed by alternative splicing, is responsible for promoting apoptosis via a Bax-dependent pathway. This review will summarizes our understanding of the importance of CLU in various physiological functions and speculate on its role in disease.References
1. Yanzhuo Ma, Lingfeng Kong, Kai Nan, Shuying Qi, Leisheng Ru, Chao Ding, Dongmei Wang. Apolipoprotein-J prevents angiotensin II-induced apoptosis in neonatal rat ventricular cells. Lipids Health Dis. 2015; 21(14):114.
2. Fritz IB, Burdzy K, Setchell B, Blaschuk O. Ram rete testis fluid contains a protein (CLU) which influences cell-cell interactions in vitro. Biology of Reproduction 1983; 28(5): 1173-88.
3. Sylvester SR, Skinner MK, Griswold MD. A Sulfated glycoprotein synthesized by sertoli cells and by epididymal cells is a component of the sperm membrane. Biology of Reproduction 1984; 31(5): 1087-101.
4. Jenne DE, Tschopp J. Molecular structure and functional characterization of a human complement cytolysis inhibitor found in blood and seminal plasma: identity to sulfated glycoprotein 2, a constituent of rat testis fluid. Proc Natl AcadSci U S A. 1989; 86: 7123-27.
5. de Silva HV, Harmony JA, Stuart WD, Gil CM, Robbins J. Apolipoprotein J: structure and tissue distribution. Biochemistry 1990; 29, 5380-89.
6. Choi-Miura NH, Takahashi Y, Nakano Y, Tobe T, Tomita M. Identification of the disulfide bonds in human plasma protein SP-40,40 (apolipoprotein-J). J Biochem 1992; 112: 557–61.
7. Poon S, Rybchyn MS, Easterbrook-Smith SB, Carver JA, Pankhurst GJ, Wilson MR. Mildly acidic pH activates the extracellular molecular chaperone CLU. J BiolChem 2002; 277: 39532–40.
8. Wyatt AR, Yerbury JJ, Wilson MR. Structural characterization of CLU-chaperone client protein complexes. J BiolChem 2009; 284: 21920–7.
9. Wyatt AR, Yerbury JJ, Berghofer P, Greguric I, Katsifis A, Dobson CM, Wilson MR. CLU facilitates in vivo clearance of extracellular misfolded proteins. Cell Mol Life Sci 2011; 68: 3919–31.
10. Cascella R, Conti S, Tatini F, Evangelisti E, Scartabelli T, Casamenti F, Wilson MR, Chiti F, Cecchi C. Extracellular chaperones prevent Aβ42-induced toxicity in rat brains. BiochimBiophysActa 2013; 1832: 1217–26.
11. Fink TM, Zimmer M, Tschopp J, Etienne J, Jenne DE, Lichter P. Human CLU (CLI) Maps to 8p21 in Proximity to the Lipoprotein Lipase (LPL) Gene. Genomics, 1993; 16(2): 526-28.
12. Wong P, Taillefer D, Lakins J, Pineault J, Chader G, Tenniswood M. Molecular characterization of human TRPM-2/CLU, a gene associated with sperm maturation, apoptosis and neurodegeneration.Eur J Biochem1994; 221: 917–925.
13. F Rizzi, S Bettuzzi,Targeting CLU in prostate cancer J PhysiolPharmacol 2008; 59(9):265-74.
14. Prochnow H, Gollan R, Rohne P, Hassemer M, Koch-Brandt C, Baiersdorfer M. Non-secreted CLU isoforms are translated in rare amounts from distinct human mRNA variants and do not affect Bax-mediated apoptosis or the NF-kappaB signaling pathway. PLoS One 2013; 8:e75303.
15. O'Sullivan J, Whyte L, Drake J, Tenniswood M. Alterations in the posttranslational modification and intracellular trafficking of CLU in MCF-7 cells during apoptosis. Cell Death Differ 2003; 10:914-927.
16. Kapron JT, Hilliard GM, Lakins JN, Tenniswood MP, West KA, CarrSA,Crabb JW. Identification and characterization of glycosylation sites in human serum CLU. Protein Sci.1997; 6:2120-2133.
17. Burkey BF, deSilva HV, Harmony JA. Intracellular processing of apolipoprotein J precursor to the mature heterodimer. J Lipid Res 1991; 32:1039-1048.
18. Rodriguez-Pineiro AM, de la Cadena MP, Lopez-Saco A,RodriguezBerrocal FJ. Differential expression of serum CLU isoforms in colorectal cancer. MolCell Proteomics 2006; 5:1647-1657.
19. Leskov KS, Klokov DY, Li J, Kinsella TJ, Boothman DA. Synthesis and functional analyses of nuclear CLU, a cell death protein. J Biol Chem. 2003;278:11590- 11600
20. Humphreys D, Carver JA, Easterbrook-Smith SB, Wilson MR. Clusterin has chaperone-like activity similar to that of small heat-shock proteins. J BiolChem 1999;274: 6875-6881
21. Poon S, Rybchyn MS, Easterbrook-Smith SB, Carver JA, Wilson, MR Clusterin is an ATP-independent chaperone with very broad substrate 17 specificity that stabilizes stressed proteins in a folding-competent state. Biochemistry 2000; 39: 15953-15960.
22. Yerbury JJ, Stewart EM, Wyatt AR, Wilson MR. Quality control of protein folding in extracellular space, EMBO Reports 2005; 6(12): 1131-1136.
23. Michel D, Chatelain G, North S, Brun G. Stress-induced transcription of the clusterin/apoJ gene. Biochemical J 1997; 328: 45-50.
24. Murphy BF, Kirszbaum L, et al. "SP-40,40, A newly identified normal human-serum protein found in the sc5b-9 complex of complement and in the immune deposits in glomerulonephritis." Journal of Clinical Investigation 1988;81(6): 1858-1864.
25. Jenne, D. E. and J. Tschopp Molecular-structure and functional-characterization of a human-complement cytolysis inhibitor found in blood and seminal plasma - identity to sulfated glycoprotein-2, a constituent of rat testis fluid. Proc Nat Acad of Sciences of the United States of America 1989;86(18): 7123-7127.
26. Kirszbaum L, J A Sharpe, et al. Molecular-cloning and characterization of the novel, human complement-associated protein, sp-40,40 - a link between the complement and reproductive systems." Embo Journal 1989;8(3): 711-718.
27. Baralla A, Sotgiu E, Deiana M, Pasella S, Pinna S, Mannu A, et al. Plasma clusterin and lipid profile: A link with aging and cardiovascular diseases in a population with a consistent number of centenarians. PLoS One. 2015;10:e0128029.
28. Bettuzzi S. Conclusions and perspectives. Adv Cancer Res. 2009;105:133–50.
29. Gelissen IC, Hochgrebe T, Wilson MR, Easterbrook-Smith SB, Jessup W, Dean RT, et al. Apolipoprotein J (clusterin) induces cholesterol export from macrophage-foam cells: A potential anti-atherogenic function? Biochem J. 1998;331(Pt 1):231–7.
30. Klock, G., M. Baiersdorfer, et al. (2009). Cell Protective Functions of Secretory Clusterin (sCLU). Advances in Cancer Research, 2009;104:S. 104: 115.
31. Rosenberg, M. E. and J. Silkensen. Clusterin - physiological and pathophysiologic considerations." International Journal of Biochemistry & Cell Biology 1995; 27(7): 633-645.
32. Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, et al.Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet. 2009;41:1094–9.
33. Nizard P, Tetley S, Le Dre´an Y, Watrin T, Le Goff P, et al. Stressinduced retrotranslocation of clusterin/ApoJ into the cytosol. Traffic 2007;8: 554–565.
34. Bettuzzi S, Rizzi F. Nuclear CLU (nCLU) and the fate of the cell. Adv Cancer Res 2009;104: 59–88.
35. Prochnow H, Gollan R, Rohne P, Hassemer M, Koch-Brandt C, et al. (2013) Non-secreted clusterin isoforms are translated in rare amounts from distinct human mRNA variants and do not affect Bax-mediated apoptosis or the NF-kB signaling pathway. PLoS One 2013;8: e75303.
36. Killick R, Ribe EM, Al-Shawi R, Malik B, Hooper C, et al. Clusterin regulates b-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCPJNK pathway. Mol Psychiatry 2014; 19: 88–98.
37. Rahul S. Desikan, Wesley K. Thompson, Dominic Holland,The role of clusterin in amyloid-β associated neurodegeneration JAMA Neurol 2014; 71(2): 180–187
38. Harr SD, Uint L, Hollister R, Hyman BT, Mendez AJ: Brain expression of apolipoproteins E, J, and A-I in Alzheimer's disease. J Neurochem 1996; 66:2429–2435.
39. Baig S, Palmer LE, Owen MJ, Williams J, Kehoe PG, Love S: Clusterin mRNA and protein in Alzheimer's disease. J Alzheimers Dis 2012; 28:337–344.
40. Yu JT, Tan L. The role of clusterin in Alzheimer's disease: pathways, pathogenesis, and therapy.Mol Neurobiol. 2012; 45(2):314–26.
41. Zhou W, Ross MM, Tessitore A, Ornstein D, Vanmeter A, Liotta LA, Petricoin EF 3rd: An initial characterization of the serum phosphoproteome. J Proteome Res 2009; 8:5523–5531
42. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87-108 [PMID: 25651787 DOI: 10.3322/caac.21262]
43. Wong P, Borst DE, Farber D, et al. Increased TRPM-2/clusterin mRNA levels during the time of retinal degeneration in mouse models of retinitis pigmentosa. Biochem Cell Biol 1994; 72: 439-446 [PMID:7605616]
44. Zhang Q, Zhou W, Kundu S, et al. The leader sequence triggers and enhances several functions of clusterin and is instrumental in the progression of human prostate cancer in vivo and in vitro. BJU Int 2006; 98: 452-460
45. Leskov KS, Araki S, Lavik JP, et al. CRM1 proteinmediated regulation of nuclear clusterin (nCLU), an ionizing radiation-stimulated, Bax-dependent pro-death factor. J Biol Chem 2011; 286: 40083-40090
46. Sintich SM, Steinberg J, Kozlowski JM, Lee C, Pruden S, Sayeed S, Sensibar JA. Cytotoxic sensitivity to tumor necrosis factor-alpha in PC3 and LNCaP prostatic cancer cells is regulated by extracellular levels of SGP-2 (clusterin). Prostate 1999; 39: 87-93 [PMID: 10221563]
47. Gleave M, Miyake H. Use of antisense oligonucleotides targeting the cytoprotective gene, clusterin, to enhance androgen- and chemo-sensitivity in prostate cancer. World J Urol 2005; 23: 38-46
48. Trougakos IP, So A, Jansen B, Gleave ME, Gonos ES. Silencing expression of the clusterin/apolipoprotein j gene in human cancer cells using small interfering RNA induces spontaneous apoptosis, reduced growth ability, and cell sensitization to genotoxic andoxidative stress. Cancer Res 2004; 64: 1834-1842 [PMID: 14996747]
49. Nakouzi Al N , Wang CK , Beraldi E , et al Clusterin knockdown sensitizes prostate cancer cells to taxane by modulating mitosis. EMBO Molecular Medicine 2016; 8(7):761-768.
2. Fritz IB, Burdzy K, Setchell B, Blaschuk O. Ram rete testis fluid contains a protein (CLU) which influences cell-cell interactions in vitro. Biology of Reproduction 1983; 28(5): 1173-88.
3. Sylvester SR, Skinner MK, Griswold MD. A Sulfated glycoprotein synthesized by sertoli cells and by epididymal cells is a component of the sperm membrane. Biology of Reproduction 1984; 31(5): 1087-101.
4. Jenne DE, Tschopp J. Molecular structure and functional characterization of a human complement cytolysis inhibitor found in blood and seminal plasma: identity to sulfated glycoprotein 2, a constituent of rat testis fluid. Proc Natl AcadSci U S A. 1989; 86: 7123-27.
5. de Silva HV, Harmony JA, Stuart WD, Gil CM, Robbins J. Apolipoprotein J: structure and tissue distribution. Biochemistry 1990; 29, 5380-89.
6. Choi-Miura NH, Takahashi Y, Nakano Y, Tobe T, Tomita M. Identification of the disulfide bonds in human plasma protein SP-40,40 (apolipoprotein-J). J Biochem 1992; 112: 557–61.
7. Poon S, Rybchyn MS, Easterbrook-Smith SB, Carver JA, Pankhurst GJ, Wilson MR. Mildly acidic pH activates the extracellular molecular chaperone CLU. J BiolChem 2002; 277: 39532–40.
8. Wyatt AR, Yerbury JJ, Wilson MR. Structural characterization of CLU-chaperone client protein complexes. J BiolChem 2009; 284: 21920–7.
9. Wyatt AR, Yerbury JJ, Berghofer P, Greguric I, Katsifis A, Dobson CM, Wilson MR. CLU facilitates in vivo clearance of extracellular misfolded proteins. Cell Mol Life Sci 2011; 68: 3919–31.
10. Cascella R, Conti S, Tatini F, Evangelisti E, Scartabelli T, Casamenti F, Wilson MR, Chiti F, Cecchi C. Extracellular chaperones prevent Aβ42-induced toxicity in rat brains. BiochimBiophysActa 2013; 1832: 1217–26.
11. Fink TM, Zimmer M, Tschopp J, Etienne J, Jenne DE, Lichter P. Human CLU (CLI) Maps to 8p21 in Proximity to the Lipoprotein Lipase (LPL) Gene. Genomics, 1993; 16(2): 526-28.
12. Wong P, Taillefer D, Lakins J, Pineault J, Chader G, Tenniswood M. Molecular characterization of human TRPM-2/CLU, a gene associated with sperm maturation, apoptosis and neurodegeneration.Eur J Biochem1994; 221: 917–925.
13. F Rizzi, S Bettuzzi,Targeting CLU in prostate cancer J PhysiolPharmacol 2008; 59(9):265-74.
14. Prochnow H, Gollan R, Rohne P, Hassemer M, Koch-Brandt C, Baiersdorfer M. Non-secreted CLU isoforms are translated in rare amounts from distinct human mRNA variants and do not affect Bax-mediated apoptosis or the NF-kappaB signaling pathway. PLoS One 2013; 8:e75303.
15. O'Sullivan J, Whyte L, Drake J, Tenniswood M. Alterations in the posttranslational modification and intracellular trafficking of CLU in MCF-7 cells during apoptosis. Cell Death Differ 2003; 10:914-927.
16. Kapron JT, Hilliard GM, Lakins JN, Tenniswood MP, West KA, CarrSA,Crabb JW. Identification and characterization of glycosylation sites in human serum CLU. Protein Sci.1997; 6:2120-2133.
17. Burkey BF, deSilva HV, Harmony JA. Intracellular processing of apolipoprotein J precursor to the mature heterodimer. J Lipid Res 1991; 32:1039-1048.
18. Rodriguez-Pineiro AM, de la Cadena MP, Lopez-Saco A,RodriguezBerrocal FJ. Differential expression of serum CLU isoforms in colorectal cancer. MolCell Proteomics 2006; 5:1647-1657.
19. Leskov KS, Klokov DY, Li J, Kinsella TJ, Boothman DA. Synthesis and functional analyses of nuclear CLU, a cell death protein. J Biol Chem. 2003;278:11590- 11600
20. Humphreys D, Carver JA, Easterbrook-Smith SB, Wilson MR. Clusterin has chaperone-like activity similar to that of small heat-shock proteins. J BiolChem 1999;274: 6875-6881
21. Poon S, Rybchyn MS, Easterbrook-Smith SB, Carver JA, Wilson, MR Clusterin is an ATP-independent chaperone with very broad substrate 17 specificity that stabilizes stressed proteins in a folding-competent state. Biochemistry 2000; 39: 15953-15960.
22. Yerbury JJ, Stewart EM, Wyatt AR, Wilson MR. Quality control of protein folding in extracellular space, EMBO Reports 2005; 6(12): 1131-1136.
23. Michel D, Chatelain G, North S, Brun G. Stress-induced transcription of the clusterin/apoJ gene. Biochemical J 1997; 328: 45-50.
24. Murphy BF, Kirszbaum L, et al. "SP-40,40, A newly identified normal human-serum protein found in the sc5b-9 complex of complement and in the immune deposits in glomerulonephritis." Journal of Clinical Investigation 1988;81(6): 1858-1864.
25. Jenne, D. E. and J. Tschopp Molecular-structure and functional-characterization of a human-complement cytolysis inhibitor found in blood and seminal plasma - identity to sulfated glycoprotein-2, a constituent of rat testis fluid. Proc Nat Acad of Sciences of the United States of America 1989;86(18): 7123-7127.
26. Kirszbaum L, J A Sharpe, et al. Molecular-cloning and characterization of the novel, human complement-associated protein, sp-40,40 - a link between the complement and reproductive systems." Embo Journal 1989;8(3): 711-718.
27. Baralla A, Sotgiu E, Deiana M, Pasella S, Pinna S, Mannu A, et al. Plasma clusterin and lipid profile: A link with aging and cardiovascular diseases in a population with a consistent number of centenarians. PLoS One. 2015;10:e0128029.
28. Bettuzzi S. Conclusions and perspectives. Adv Cancer Res. 2009;105:133–50.
29. Gelissen IC, Hochgrebe T, Wilson MR, Easterbrook-Smith SB, Jessup W, Dean RT, et al. Apolipoprotein J (clusterin) induces cholesterol export from macrophage-foam cells: A potential anti-atherogenic function? Biochem J. 1998;331(Pt 1):231–7.
30. Klock, G., M. Baiersdorfer, et al. (2009). Cell Protective Functions of Secretory Clusterin (sCLU). Advances in Cancer Research, 2009;104:S. 104: 115.
31. Rosenberg, M. E. and J. Silkensen. Clusterin - physiological and pathophysiologic considerations." International Journal of Biochemistry & Cell Biology 1995; 27(7): 633-645.
32. Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, et al.Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet. 2009;41:1094–9.
33. Nizard P, Tetley S, Le Dre´an Y, Watrin T, Le Goff P, et al. Stressinduced retrotranslocation of clusterin/ApoJ into the cytosol. Traffic 2007;8: 554–565.
34. Bettuzzi S, Rizzi F. Nuclear CLU (nCLU) and the fate of the cell. Adv Cancer Res 2009;104: 59–88.
35. Prochnow H, Gollan R, Rohne P, Hassemer M, Koch-Brandt C, et al. (2013) Non-secreted clusterin isoforms are translated in rare amounts from distinct human mRNA variants and do not affect Bax-mediated apoptosis or the NF-kB signaling pathway. PLoS One 2013;8: e75303.
36. Killick R, Ribe EM, Al-Shawi R, Malik B, Hooper C, et al. Clusterin regulates b-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCPJNK pathway. Mol Psychiatry 2014; 19: 88–98.
37. Rahul S. Desikan, Wesley K. Thompson, Dominic Holland,The role of clusterin in amyloid-β associated neurodegeneration JAMA Neurol 2014; 71(2): 180–187
38. Harr SD, Uint L, Hollister R, Hyman BT, Mendez AJ: Brain expression of apolipoproteins E, J, and A-I in Alzheimer's disease. J Neurochem 1996; 66:2429–2435.
39. Baig S, Palmer LE, Owen MJ, Williams J, Kehoe PG, Love S: Clusterin mRNA and protein in Alzheimer's disease. J Alzheimers Dis 2012; 28:337–344.
40. Yu JT, Tan L. The role of clusterin in Alzheimer's disease: pathways, pathogenesis, and therapy.Mol Neurobiol. 2012; 45(2):314–26.
41. Zhou W, Ross MM, Tessitore A, Ornstein D, Vanmeter A, Liotta LA, Petricoin EF 3rd: An initial characterization of the serum phosphoproteome. J Proteome Res 2009; 8:5523–5531
42. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87-108 [PMID: 25651787 DOI: 10.3322/caac.21262]
43. Wong P, Borst DE, Farber D, et al. Increased TRPM-2/clusterin mRNA levels during the time of retinal degeneration in mouse models of retinitis pigmentosa. Biochem Cell Biol 1994; 72: 439-446 [PMID:7605616]
44. Zhang Q, Zhou W, Kundu S, et al. The leader sequence triggers and enhances several functions of clusterin and is instrumental in the progression of human prostate cancer in vivo and in vitro. BJU Int 2006; 98: 452-460
45. Leskov KS, Araki S, Lavik JP, et al. CRM1 proteinmediated regulation of nuclear clusterin (nCLU), an ionizing radiation-stimulated, Bax-dependent pro-death factor. J Biol Chem 2011; 286: 40083-40090
46. Sintich SM, Steinberg J, Kozlowski JM, Lee C, Pruden S, Sayeed S, Sensibar JA. Cytotoxic sensitivity to tumor necrosis factor-alpha in PC3 and LNCaP prostatic cancer cells is regulated by extracellular levels of SGP-2 (clusterin). Prostate 1999; 39: 87-93 [PMID: 10221563]
47. Gleave M, Miyake H. Use of antisense oligonucleotides targeting the cytoprotective gene, clusterin, to enhance androgen- and chemo-sensitivity in prostate cancer. World J Urol 2005; 23: 38-46
48. Trougakos IP, So A, Jansen B, Gleave ME, Gonos ES. Silencing expression of the clusterin/apolipoprotein j gene in human cancer cells using small interfering RNA induces spontaneous apoptosis, reduced growth ability, and cell sensitization to genotoxic andoxidative stress. Cancer Res 2004; 64: 1834-1842 [PMID: 14996747]
49. Nakouzi Al N , Wang CK , Beraldi E , et al Clusterin knockdown sensitizes prostate cancer cells to taxane by modulating mitosis. EMBO Molecular Medicine 2016; 8(7):761-768.
Published
2017-03-20
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