Clusterin (
apolipoprotein
Apolipoproteins are proteins that bind lipids (oil-soluble substances such as fats, cholesterol and fat soluble vitamins) to form lipoproteins. They transport lipids in blood, cerebrospinal fluid and lymph.
The lipid components of lipoproteins ...
J) is a 75-80 kDa disulfide-linked heterodimeric
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
associated with the clearance of cellular debris and
apoptosis.
In humans, clusterin is encoded by the ''CLU''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
on chromosome 8.
CLU is a
molecular chaperone
In molecular biology, molecular chaperones are proteins that assist the conformational folding or unfolding of large proteins or macromolecular protein complexes. There are a number of classes of molecular chaperones, all of which function to assi ...
responsible for aiding
protein folding
Protein folding is the physical process by which a protein chain is translated to its native three-dimensional structure, typically a "folded" conformation by which the protein becomes biologically functional. Via an expeditious and reproduc ...
of
secreted 440px
Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical ...
proteins, and its three
isoform
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...
s have been differentially implicated in
pro- or antiapoptotic processes. Through this function, CLU is involved in many
disease
A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
s related to
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
, including
neurodegenerative disease
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
s,
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
s,
inflammatory diseases
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecu ...
, and
aging.
Structure
The ''CLU'' gene contains nine
exons and expresses three isoforms
alternatively-spliced at the first exon.
The encoded protein isoforms all localize to different
subcellular compartments: one isoform localizes to the
nucleus
Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
*Atomic nucleus, the very dense central region of an atom
* Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucl ...
; a second isoform localizes to the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
; and the third is secreted from the cell.
They also perform opposing functions: the nuclear CLU binds
Ku70
Ku70 is a protein that, in humans, is encoded by the ''XRCC6'' gene.
Function
Together, Ku70 and Ku80 make up the Ku heterodimer, which binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway o ...
to release
BAX and induce apoptosis, whereas the cytosolic and secretory isoforms inhibit apoptosis.
The nuclear isoform encodes a 49 kDa protein, while the secretory isoform, which is the main gene transcript, encodes a 75–80 kDa protein after maturation (
glycosylation, secretion, and
dimerization).
The mature protein is a 449-residue, heterodimeric, disulfide-linked
glycoprotein composed of two
subunits of ~34-40 kDa α- and β-chains.
Function
Clusterin was first identified in ram rete testis fluid where it showed signs of clustering with rat sertoli cells and erythrocytes, hence its name.
CLU is a member of the small
heat shock protein
Heat shock proteins (HSP) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including expo ...
family and, thus, a
molecular chaperone
In molecular biology, molecular chaperones are proteins that assist the conformational folding or unfolding of large proteins or macromolecular protein complexes. There are a number of classes of molecular chaperones, all of which function to assi ...
. Unlike most other chaperone proteins, which aid
intracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
proteins, CLU is a
Golgi chaperone that facilitates 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 participates in a number of biological processes, including
lipid
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids includ ...
transport, membrane recycling,
cell adhesion,
programmed cell death
Programmed cell death (PCD; sometimes referred to as cellular suicide) is the death of a cell (biology), cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usually confers ...
, and
complement
A complement is something that completes something else.
Complement may refer specifically to:
The arts
* Complement (music), an interval that, when added to another, spans an octave
** Aggregate complementation, the separation of pitch-clas ...
-mediated
cell lysis
Lysis ( ) is the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic (that is, "lytic" ) mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a ''lysate''. In molecular bio ...
.
Overexpression of the secretory CLU isoform protects the cell from apoptosis induced by cellular stress, such as
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
,
radiotherapy, or
androgen
An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...
/
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
depletion. CLU promotes cell survival by a number of means, including inhibition of BAX on the mitochondrial membrane, activation of the
phosphatidylinositol 3-kinase
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
/
protein kinase B pathway, modulation of
extracellularular 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
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
) pathway. Meanwhile, its downregulation allows for
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
activation, which then skews the proapoptotic:antiapoptotic ratio of present
Bcl-2 family
The Bcl-2 familyTC# 1.A.21 consists of a number of evolutionarily-conserved proteins that share Bcl-2 homology (BH) domains. The Bcl-2 family is most notable for their regulation of apoptosis, a form of programmed cell death, at the mitochondrion ...
members, resulting in
mitochondrial dysfunction and cell death. p53 may also transcriptionally repress secretory CLU to further promote the proapoptotic cascade.
Clinical associations
Two independent
genome-wide association studies
In genomics, a genome-wide association study (GWA study, or GWAS), also known as whole genome association study (WGA study, or WGAS), is an observational study of a genome-wide set of genetic variants in different individuals to see if any varian ...
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.
[
*] In addition to Alzheimer's disease, CLU is involved in other neurodegenerative diseases such as
Huntington disease
Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unst ...
.
CLU may promote tumorigenesis by facilitating BAX-KLU70 binding and, consequently, preventing BAX from localizing to the
outer mitochondrial membrane
A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...
to stimulate cell death. In
clear cell renal cell carcinoma
Clear-cell renal-cell carcinoma (CCRCC) is a type of renal-cell carcinoma.
Genetics Cytogenetics
* Alterations of chromosome 3p segments occurs in 70–90% of CCRCCs
* Inactivation of von Hippel–Lindau disease ( VHL) gene by gene mutation a ...
, CLU functions to regulate ERK 1/2 signaling and matrix
metallopeptidase
A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myogen ...
-9 expression to promote tumor
cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular dire ...
, invasion, and
metastasis
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then ...
. In
epithelial ovarian cancer
Surface epithelial-stromal tumors are a class of ovarian neoplasms that may be benign or malignant. Neoplasms in this group are thought to be derived from the ovarian surface epithelium (modified peritoneum) or from ectopic endometrial or Fallo ...
, 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
A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testosteron ...
seminoma
A seminoma is a germ cell tumor of the testicle or, more rarely, the mediastinum or other extra-gonadal locations. It is a malignant neoplasm and is one of the most treatable and curable cancers, with a survival rate above 95% if discovered in ...
features downregulated CLU levels, allowing for increased sensitivity to chemotherapy treatments. Other cancers CLU has been implicated in include
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a r ...
,
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.
In particular,
custirsen, an antisense oligonucleotide that blocks the CLU mRNA transcript, enhanced heat-shock protein 90 (
HSP90
Hsp90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, ...
) inhibitor activity by suppressing the heat-shock response in castrate-resistant
prostate cancer, and is currently in
phase III trials
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
.
CLU activity is also involved in infectious diseases, such as
hepatitis C. CLU is induced by the stress of hepatitis C
viral infection
A viral disease (or viral infection) occurs when an organism's body is invaded by pathogenic viruses, and infectious virus particles (virions) attach to and enter susceptible cells.
Structural Characteristics
Basic structural characteristics, ...
, which disrupts
glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...
regulation. The chaperone protein then aids hepatitis C viral assembly by stabilizing its core and NS5A units.
CLU expression in the
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...
also plays a role in
renal disease
Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can b ...
s, such as
nephropathic cystinosis, which is a major cause of
Fanconi syndrome
Fanconi syndrome or Fanconi's syndrome (, ) is a syndrome of inadequate reabsorption in the proximal renal tubules of the kidney. The syndrome can be caused by various underlying congenital or acquired diseases, by toxicity (for example, from tox ...
.
In addition to the above diseases, CLU has been linked to other conditions resulting from oxidative damage, including aging,
glomerulonephritis
Glomerulonephritis (GN) is a term used to refer to several kidney diseases (usually affecting both kidneys). Many of the diseases are characterised by inflammation either of the glomeruli or of the small blood vessels in the kidneys, hence the ...
,
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...
, and
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
.
Interactions
CLU has been shown to interact with
Ku70
Ku70 is a protein that, in humans, is encoded by the ''XRCC6'' gene.
Function
Together, Ku70 and Ku80 make up the Ku heterodimer, which binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway o ...
.
References
Further reading
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External links
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Apolipoproteins and Applied Research
{{Chaperones
Proteins