Clusterin Explained

In humans, clusterin (CLU) is encoded by the CLU gene on chromosome 8.[1] 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. [2] CLU is involved in many diseases including neurodegenerative diseases, cancers, inflammatory diseases, and aging.[3] [4] [5]

Structure

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. [6] 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. [7] 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 [8] 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.[9]

Function

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.[10]

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.[5] 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.[3] [4] [5] 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.[3]

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.[11] [12] [13] [14] In addition to Alzheimer's disease, CLU may be involved in other neurodegenerative diseases such as Huntington disease.[4]

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.[3] 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.[3] [5]

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.[5] In addition to the above diseases, CLU has been linked to other conditions resulting from oxidative damage, including aging, glomerulonephritis, atherosclerosis, and myocardial infarction. [5]

Interactions

CLU has been shown to interact with many different protein ligands and several cell receptors.

Further reading

External links

Notes and References

  1. Web site: Entrez Gene: clusterin.
  2. Wyatt . Amy R. . Yerbury . Justin J. . Ecroyd . Heath . Wilson . Mark R. . 2013 . Extracellular chaperones and proteostasis . Annual Review of Biochemistry . 82 . 295–322 . 10.1146/annurev-biochem-072711-163904 . 1545-4509 . 23350744.
  3. Koltai T . Clusterin: a key player in cancer chemoresistance and its inhibition . OncoTargets and Therapy . 7 . 447–56 . 2014 . 24672247 . 10.2147/OTT.S58622 . 3964162 . free .
  4. Sansanwal P, Li L, Sarwal MM . Inhibition of intracellular clusterin attenuates cell death in nephropathic cystinosis . Journal of the American Society of Nephrology . 26 . 3 . 612–25 . Mar 2015 . 25071085 . 10.1681/ASN.2013060577 . 4341467.
  5. Lin CC, Tsai P, Sun HY, Hsu MC, Lee JC, Wu IC, Tsao CW, Chang TT, Young KC . 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 . Nov 2014 . 24996046 . 10.1016/j.jhep.2014.06.026 .
  6. Prochnow . Hans . Gollan . Rene . Rohne . Philipp . Hassemer . Matthias . Koch-Brandt . Claudia . Baiersdörfer . Markus . 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-κB signaling pathway . PLOS ONE . 8 . 9 . e75303 . 10.1371/journal.pone.0075303 . free . 1932-6203 . 3779157 . 24073260. 2013PLoSO...875303P .
  7. Kapron . J. T. . Hilliard . G. M. . Lakins . J. N. . Tenniswood . M. P. . West . K. A. . Carr . S. A. . Crabb . J. W. . 1997 . Identification and characterization of glycosylation sites in human serum clusterin . Protein Science . 6 . 10 . 2120–2133 . 10.1002/pro.5560061007 . 0961-8368 . 2143570 . 9336835.
  8. Satapathy . Sandeep . Wilson . Mark R. . 2021 . The Dual Roles of Clusterin in Extracellular and Intracellular Proteostasis . Trends in Biochemical Sciences . 46 . 8 . 652–660 . 10.1016/j.tibs.2021.01.005 . 0968-0004 . 33573881. 231897964 .
  9. Satapathy . Sandeep . Walker . Holly . Brown . James . Gambin . Yann . Wilson . Mark R. . 2023-09-26 . The N-end rule pathway regulates ER stress-induced clusterin release to the cytosol where it directs misfolded proteins for degradation . Cell Reports . 42 . 9 . 113059 . 10.1016/j.celrep.2023.113059 . 2211-1247 . 37660295. free .
  10. Fritz IB, Burdzy K, Sétchell B, Blaschuk O . Ram rete testis fluid contains a protein (clusterin) which influences cell-cell interactions in vitro . Biology of Reproduction . 28 . 5 . 1173–88 . Jun 1983 . 6871313 . 10.1095/biolreprod28.5.1173 . free .
  11. Martin Rossor . Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, Heun R, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O'Donovan M, Owen MJ, Williams J . 6 . Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease . Nature Genetics . 41 . 10 . 1088–93 . Oct 2009 . 19734902 . 2845877 . 10.1038/ng.440.
  12. Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fiévet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O, de Pancorbo MM, Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanché H, Dartigues JF, Tzourio C, Gut I, Van Broeckhoven C, Alpérovitch A, Lathrop M, Amouyel P . 6 . Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease . Nature Genetics . 41 . 10 . 1094–9 . Oct 2009 . 19734903 . 10.1038/ng.439 . 24530130 . 10281/9031 . free .
  13. Schrijvers EM, Koudstaal PJ, Hofman A, Breteler MM . Plasma clusterin and the risk of Alzheimer disease . JAMA . 305 . 13 . 1322–6 . Apr 2011 . 21467285 . 10.1001/jama.2011.381 . 36026598 .
  14. Web site: Plasma Protein Appears to Be Associated With Development and Severity of Alzheimer's Disease . 2010.

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