Clusterin
Clusterin is a protein that in humans 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]
Structure
[edit]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]
Function
[edit]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]
Clinical significance
[edit]Alzheimer's disease
[edit]Two independent genome-wide association studies identified a statistical association between a single-nucleotide polymorphism (SNP) in the CLU gene and the risk of developing Alzheimer's disease.[15][16]
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 as Huntington disease.[8]
Cancer
[edit]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 the outer mitochondrial membrane to initiate apoptosis.
In clear cell renal cell carcinoma, CLU regulates ERK1/2 signaling and matrix metallopeptidase-9 expression to promote tumor cell migration, invasion, and metastasis. In epithelial ovarian cancer, CLU enhances angiogenesis and chemoresistance. It is also involved in the PI3K/AKT/mTOR pathway and NF-κB pathway, further supporting cell survival and resistance to therapy. In contrast, CLU expression is downregulated in testicular seminoma, making these tumors more sensitive to chemotherapy. CLU has also been implicated in breast cancer, pancreatic cancer, hepatocellular carcinoma, and melanoma.
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 of HSP90 inhibitors by suppressing the heat shock response in castration-resistant prostate cancer, and was evaluated in phase III trials.[7][9]
Infectious diseases
[edit]CLU is also involved in the host response to infection. In hepatitis 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]
Other conditions
[edit]Beyond its roles in neurodegeneration, cancer, and infection, CLU has been associated with conditions related to oxidative stress, including aging, glomerulonephritis, atherosclerosis, and myocardial infarction.[9]
Interactions
[edit]CLU has been shown to interact with many different protein ligands and several cell receptors.[12]
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000120885 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022037 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: clusterin".
- ^ Wyatt AR, Yerbury JJ, Ecroyd H, Wilson MR (2013). "Extracellular chaperones and proteostasis". Annual Review of Biochemistry. 82: 295–322. doi:10.1146/annurev-biochem-072711-163904. ISSN 1545-4509. PMID 23350744.
- ^ a b c d e Koltai T (2014). "Clusterin: a key player in cancer chemoresistance and its inhibition". Oncotargets and Therapy. 7: 447–456. doi:10.2147/OTT.S58622. PMC 3964162. PMID 24672247.
- ^ a b c Sansanwal P, Li L, Sarwal MM (Mar 2015). "Inhibition of intracellular clusterin attenuates cell death in nephropathic cystinosis". Journal of the American Society of Nephrology. 26 (3): 612–625. doi:10.1681/ASN.2013060577. PMC 4341467. PMID 25071085.
- ^ a b c d e f Lin 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. PMID 24996046.
- ^ Prochnow H, Gollan R, Rohne P, Hassemer M, Koch-Brandt C, Baiersdörfer M (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. Bibcode:2013PLoSO...875303P. doi:10.1371/journal.pone.0075303. ISSN 1932-6203. PMC 3779157. PMID 24073260.
- ^ Kapron JT, Hilliard GM, Lakins JN, Tenniswood MP, West KA, Carr SA, et al. (1997). "Identification and characterization of glycosylation sites in human serum clusterin". Protein Science : A Publication of the Protein Society. 6 (10): 2120–2133. doi:10.1002/pro.5560061007. ISSN 0961-8368. PMC 2143570. PMID 9336835.
- ^ a b Satapathy S, Wilson MR (2021). "The Dual Roles of Clusterin in Extracellular and Intracellular Proteostasis". Trends in Biochemical Sciences. 46 (8): 652–660. doi:10.1016/j.tibs.2021.01.005. ISSN 0968-0004. PMID 33573881. S2CID 231897964.
- ^ Satapathy S, Walker H, Brown J, Gambin Y, Wilson MR (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. doi:10.1016/j.celrep.2023.113059. ISSN 2211-1247. PMID 37660295.
- ^ Fritz IB, Burdzy K, Sétchell B, Blaschuk O (Jun 1983). "Ram rete testis fluid contains a protein (clusterin) which influences cell-cell interactions in vitro". Biology of Reproduction. 28 (5): 1173–1188. doi:10.1095/biolreprod28.5.1173. PMID 6871313.
- ^ Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, et al. (Oct 2009). "Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease". Nature Genetics. 41 (10): 1088–1093. doi:10.1038/ng.440. PMC 2845877. PMID 19734902.
- ^ 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. PMID 19734903. S2CID 24530130.
- ^ Schrijvers EM, Koudstaal PJ, Hofman A, Breteler MM (Apr 2011). "Plasma clusterin and the risk of Alzheimer disease". JAMA. 305 (13): 1322–1326. doi:10.1001/jama.2011.381. PMID 21467285. S2CID 36026598.
- ^ "Plasma Protein Appears to Be Associated With Development and Severity of Alzheimer's Disease". 2010.
Further reading
[edit]- Krumbiegel M, Pasutto F, Mardin CY, Weisschuh N, Paoli D, Gramer E, et al. (Jun 2009). "Exploring functional candidate genes for genetic association in german patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma". Investigative Ophthalmology & Visual Science. 50 (6): 2796–2801. doi:10.1167/iovs.08-2339. PMID 19182256.
- Cerhan JR, Novak AJ, Fredericksen ZS, Wang AH, Liebow M, Call TG, et al. (Jun 2009). "Risk of non-Hodgkin lymphoma in association with germline variation in complement genes". British Journal of Haematology. 145 (5): 614–623. 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): 1430–1448. 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): 154–159. doi:10.1016/0968-0004(92)90325-4. PMID 1585460.
- 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. 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): 1267–1274. doi:10.1016/j.freeradbiomed.2009.01.025. PMID 19353783.
- Wei L, Xue T, Wang J, Chen B, Lei Y, Huang Y, et al. (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): 704–711. 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): 302–307. 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, 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. PMID 19413638. S2CID 21277859.
- Pucci S, Mazzarelli P, Paola M, Sesti F, Fabiola S, Boothman DA, et al. (Feb 2009). "Interleukin-6 affects cell death escaping mechanisms acting on Bax-Ku70-Clusterin interactions in human colon cancer progression". Cell Cycle. 8 (3). Georgetown, Tex.: 473–481. doi:10.4161/cc.8.3.7652. PMC 2853871. PMID 19177010.
- Trougakos IP, Lourda M, Antonelou MH, Kletsas D, Gorgoulis VG, Papassideri IS, et al. (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): 1225–1229. doi:10.1097/PAS.0b013e3181a6d86f. PMID 19542874. S2CID 24444024.
- Chandra P, Plaza JA, Zuo Z, Diwan AH, Koeppen H, Duvic M, et al. (Apr 2009). "Clusterin expression correlates with stage and presence of large cells in mycosis fungoides". American Journal of Clinical Pathology. 131 (4): 511–515. 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): 314–323. 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): 1124–1134. 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): 183–188. doi:10.1007/s10735-006-9052-7. PMID 17048076. S2CID 20041580.
- Shannan B, Seifert M, Leskov K, Willis J, Boothman D, Tilgen W, et al. (Jan 2006). "Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer". Cell Death and Differentiation. 13 (1): 12–19. doi:10.1038/sj.cdd.4401779. PMID 16179938.
- Otowa T, Yoshida E, Sugaya N, Yasuda S, Nishimura Y, Inoue K, et al. (Feb 2009). "Genome-wide association study of panic disorder in the Japanese population". Journal of Human Genetics. 54 (2): 122–126. 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): 605–616. doi:10.1007/s10735-008-9201-2. PMID 18949565. S2CID 11598911.
External links
[edit]- Clusterin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Apolipoproteins and Applied Research