Biology:Clusterin

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Clusterin is a protein that in humans 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 significance

Alzheimer's disease

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.[11][12]

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.[13][14]

CLU may also play a role in other neurodegenerative diseases, such as Huntington disease.[4]

Cancer

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.[3] 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.[3][5]

Prostate

The CLU transcript — at that time designated testosterone-repressed prostate message-2 (TRPM-2) — was idenfied as the most highly overexpressed gene during castration-induced involution of the rat ventral prostate, through complete cDNA cloning and sequencing.[15] This finding established CLU as a marker of androgen-dependent apoptotic regression and opened subsequent investigation into its role in human prostate carcinogenesis.

Subsequently it was demonstrated that CLU expression is systematically downregulated during progression of human prostate cancer. A meta-analysis of available microarray data showed that CLU mRNA is significantly downregulated in prostate tumor tissue compared to normal prostate in 14 out of 15 independent studies, supporting its classification as a tumor suppressor gene in this context.[16] The tumor suppressor role of CLU has been extended to other cancer types, including colon, ovarian, and lung carcinoma and neuroblastoma.[16]

The apparent contradictions in the literature regarding the pro- or anti-apoptotic role of CLU have been in part resolved by clarifying the existence of distinct protein isoforms with opposite functions: the secreted isoform (sCLU, approximately 60 kDa) has cytoprotective and anti-apoptotic properties, while a nuclear isoform (nCLU, lacking the signal peptide encoded by exon 2) exerts pro-apoptotic activity.[16][17] This isoform-dependent duality is critical for interpreting experimental results across different model systems.

The tumor suppressor function of CLU in prostate cancer was confirmed in vivo using the TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate) mouse model. TRAMP mice with homozygous deletion of CLU showed highly aggressive tumor development with earlier onset, a greater number of primary tumors, and poorly differentiated metastatic tumors compared to CLU-wild-type TRAMP controls.[18]

A mechanistic connection between CLU and green tea catechins in prostate cancer chemoprevention was established by the same group: CLU expression was found to be restored in TRAMP mice responding to chemoprevention with green tea catechins, suggesting that EGCG exerts part of its chemopreventive activity through reactivation of CLU as a tumor suppressor.[19] This observation was clinically relevant given the results of a randomized, double-blind, placebo-controlled trial [20] demonstrating that oral administration of a standardized green tea catechin preparation (600 mg/day, 51.88% EGCG) for 12 months significantly reduced the incidence of prostate cancer in men with high-grade prostatic intraepithelial neoplasia (HG-PIN).[20]

Infectious diseases

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.[5]

Other conditions

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.[5]

Interactions

CLU has been shown to interact with many different protein ligands and several cell receptors.[8]

References

  1. ↑ "Entrez Gene: clusterin". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=1191. 
  2. ↑ "Extracellular chaperones and proteostasis". Annual Review of Biochemistry 82: 295–322. 2013. doi:10.1146/annurev-biochem-072711-163904. ISSN 1545-4509. PMID 23350744. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "Clusterin: a key player in cancer chemoresistance and its inhibition". OncoTargets and Therapy 7: 447–456. 2014. doi:10.2147/OTT.S58622. PMID 24672247. 
  4. ↑ 4.0 4.1 4.2 "Inhibition of intracellular clusterin attenuates cell death in nephropathic cystinosis". Journal of the American Society of Nephrology 26 (3): 612–625. March 2015. doi:10.1681/ASN.2013060577. PMID 25071085. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 "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. November 2014. doi:10.1016/j.jhep.2014.06.026. PMID 24996046. 
  6. ↑ "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). 2013. doi:10.1371/journal.pone.0075303. ISSN 1932-6203. PMID 24073260. Bibcode: 2013PLoSO...875303P. 
  7. ↑ "Identification and characterization of glycosylation sites in human serum clusterin". Protein Science 6 (10): 2120–2133. 1997. doi:10.1002/pro.5560061007. ISSN 0961-8368. PMID 9336835. 
  8. ↑ 8.0 8.1 "The Dual Roles of Clusterin in Extracellular and Intracellular Proteostasis". Trends in Biochemical Sciences 46 (8): 652–660. 2021. doi:10.1016/j.tibs.2021.01.005. ISSN 0968-0004. PMID 33573881. 
  9. ↑ "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). 2023-09-26. doi:10.1016/j.celrep.2023.113059. ISSN 2211-1247. PMID 37660295. 
  10. ↑ "Ram rete testis fluid contains a protein (clusterin) which influences cell-cell interactions in vitro". Biology of Reproduction 28 (5): 1173–1188. June 1983. doi:10.1095/biolreprod28.5.1173. PMID 6871313. 
  11. ↑ "Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease". Nature Genetics 41 (10): 1088–1093. October 2009. doi:10.1038/ng.440. PMID 19734902. 
  12. ↑ "Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease". Nature Genetics 41 (10): 1094–1099. October 2009. doi:10.1038/ng.439. PMID 19734903. 
  13. ↑ "Plasma clusterin and the risk of Alzheimer disease". JAMA 305 (13): 1322–1326. April 2011. doi:10.1001/jama.2011.381. PMID 21467285. 
  14. ↑ "Plasma Protein Appears to Be Associated With Development and Severity of Alzheimer's Disease". 2010. https://www.sciencedaily.com/releases/2010/07/100705190536.htm#. 
  15. ↑ "Identification of an androgen-repressed mRNA in rat ventral prostate as coding for sulphated glycoprotein 2 by cDNA cloning and sequence analysis". The Biochemical Journal 257 (1): 293–296. January 1989. doi:10.1042/bj2570293. PMID 2920020. 
  16. ↑ 16.0 16.1 16.2 "The clusterin paradigm in prostate and breast carcinogenesis". Endocrine-Related Cancer 17 (1): R1–17. March 2010. doi:10.1677/ERC-09-0140. PMID 19903745. 
  17. ↑ "Clusterin (CLU) and Prostate Cancer". Advances in Cancer Research. 105. Elsevier. 2009. pp. 1–19. doi:10.1016/S0065-230X(09)05001-5. ISBN 978-0-12-381429-6. 
  18. ↑ "Genetic inactivation of ApoJ/clusterin: effects on prostate tumourigenesis and metastatic spread". Oncogene 28 (49): 4344–4352. December 2009. doi:10.1038/onc.2009.286. PMID 19784068. 
  19. ↑ "The chemopreventive action of catechins in the TRAMP mouse model of prostate carcinogenesis is accompanied by clusterin over-expression". Carcinogenesis 25 (11): 2217–2224. November 2004. doi:10.1093/carcin/bgh235. PMID 15358631. 
  20. ↑ 20.0 20.1 "Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study". Cancer Research 66 (2): 1234–1240. January 2006. doi:10.1158/0008-5472.CAN-05-1145. PMID 16424063. 

Further reading



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