Clusterin

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 (

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.

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. 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. 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.

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.

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.

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

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. 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.

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.

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.

Interactions

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

References

References

1. "Entrez Gene: clusterin".
2. (2013). "Extracellular chaperones and proteostasis". Annual Review of Biochemistry.
3. (2014). "Clusterin: a key player in cancer chemoresistance and its inhibition". OncoTargets and Therapy.
4. (Mar 2015). "Inhibition of intracellular clusterin attenuates cell death in nephropathic cystinosis". Journal of the American Society of Nephrology.
5. (Nov 2014). "Apolipoprotein J, a glucose-upregulated molecular chaperone, stabilizes core and NS5A to promote infectious hepatitis C virus virion production". Journal of Hepatology.
6. (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.
7. (1997). "Identification and characterization of glycosylation sites in human serum clusterin". Protein Science.
8. (2021). "The Dual Roles of Clusterin in Extracellular and Intracellular Proteostasis". Trends in Biochemical Sciences.
9. (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.
10. (Jun 1983). "Ram rete testis fluid contains a protein (clusterin) which influences cell-cell interactions in vitro". Biology of Reproduction.
11. (Oct 2009). "Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease". Nature Genetics.
12. (Oct 2009). "Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease". Nature Genetics.
13. (Apr 2011). "Plasma clusterin and the risk of Alzheimer disease". JAMA.
14. (2010). "Plasma Protein Appears to Be Associated With Development and Severity of Alzheimer's Disease".