1. Gene Aliases

Clu, Clusterin, TRPM-2, SGP-2, KUB1, Testosterone-Repressed Prostate Message 2, Sulfated Glycoprotein 2, Apolipoprotein J, SP-40, CLU1, CLU2, APOJ, CLI, Complement-Associated Protein SP-40,40, Complement Cytolysis Inhibitor, Complement Lysis Inhibitor, Ku70-Binding Protein 1, NA1/NA2, Epididymis Secretory Sperm Binding Protein, Aging-Associated Gene 4 Protein, Aging-Associated Protein 4, APO-J, TRPM2, Apo-J, AAG4, SGP2

[https://www.genecards.org/cgi-bin/carddisp.pl?gene=CLU]

2. Association with Toxicity and/or Disease at a Transcriptional Level

3. Summary of Protein Family and Structure

4. Proteins Known to Interact with Gene Product

Interactions with experimental support

The interactions list has been truncated to include only interactions with the strongest support from the literature.

5. Links to Gene Databases

6. GO Terms, MSigDB Signatures, Pathways Containing Gene with Descriptions of Gene Sets

Pathways:

GO terms:

cell morphogenesis [The developmental process in which the size or shape of a cell is generated and organized. GO:0000902]

cellular response to growth factor stimulus [Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a growth factor stimulus. GO:0071363]

central nervous system myelin maintenance [The process in which the structure and material content of mature central nervous system myelin is kept in a functional state. GO:0032286]

chaperone-mediated protein complex assembly [The aggregation, arrangement and bonding together of a set of components to form a protein complex, mediated by chaperone molecules that do not form part of the finished complex. GO:0051131]

chaperone-mediated protein folding [The process of inhibiting aggregation and assisting in the covalent and noncovalent assembly of single chain polypeptides or multisubunit complexes into the correct tertiary structure that is dependent on interaction with a chaperone. GO:0061077]

endocrine pancreas development [The process whose specific outcome is the progression of the endocrine pancreas over time, from its formation to the mature structure. The endocrine pancreas is made up of islet cells that produce insulin, glucagon and somatostatin. GO:0031018]

estrous cycle [A type of ovulation cycle, which occurs in most mammalian therian females, where the endometrium is resorbed if pregnancy does not occur. GO:0044849]

immune complex clearance [A process directed at removing immune complexes from the body. Immune complexes are clusters of antibodies bound to antigen, to which complement may also be fixed, and which may precipitate or remain in solution. GO:0002434]

intrinsic apoptotic signaling pathway [The series of molecular signals in which an intracellular signal is conveyed to trigger the apoptotic death of a cell. The pathway starts with reception of an intracellular signal (e.g. DNA damage, endoplasmic reticulum stress, oxidative stress etc.), and ends when the execution phase of apoptosis is triggered. The intrinsic apoptotic signaling pathway is crucially regulated by permeabilization of the mitochondrial outer membrane (MOMP).|The signals that start intrinsic apoptosis may come from extracellular sources (e.g. oxidative stress, UV exposure), but the reception of the signal and thus the signaling pathway start inside the cell (as a result of DNA damage, redox imbalance, etc.). Examples are ZPR9 (ZNF622) and ASK1 (MAP3K5) (UniProt symbols Q969S3 and Q99683) in PMID: 21771788. A diagram of the intrinsic apoptotic pathway including examples of molecular players can be found in Figure 2 in PMID: 21760595. GO:0097193]

microglial cell activation [The change in morphology and behavior of a microglial cell resulting from exposure to a cytokine, chemokine, cellular ligand, or soluble factor. GO:0001774]

microglial cell proliferation [The expansion of a microglial cell population by cell division. GO:0061518]

negative regulation of amyloid fibril formation [Any process that stops, prevents or reduces the frequency, rate or extent of amyloid fibril formation.|Although deposition of amyloid fibrils is associated with diseases, e.g. Alzheimer's disease, amyloid formation is a normal process. Disease occurs when the balance between amyloid formation and clearance is disrupted (reviewed e.g. in PMID: 29654159 and PMID: 28937655). An example of a normal amyloid complex is composed of human RIP1 and RIP3 kinases (PMID: 22817896). GO:1905907]

negative regulation of amyloid-beta formation [Any process that stops, prevents or reduces the frequency, rate or extent of amyloid-beta formation. GO:1902430]

negative regulation of apoptotic process [Any process that stops, prevents, or reduces the frequency, rate or extent of cell death by apoptotic process.|This term should only be used when it is not possible to determine which phase or subtype of the apoptotic process is negatively regulated by a gene product. Whenever detailed information is available, the more granular children terms should be used. GO:0043066]

negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage [Any process that stops, prevents or reduces the frequency, rate or extent of intrinsic apoptotic signaling pathway in response to DNA damage. GO:1902230]

negative regulation of neuron apoptotic process [Any process that stops, prevents, or reduces the frequency, rate or extent of cell death by apoptotic process in neurons. GO:0043524]

negative regulation of protein-containing complex assembly [Any process that stops, prevents, or reduces the frequency, rate or extent of protein complex assembly. GO:0031333]

negative regulation of response to endoplasmic reticulum stress [Any process that stops, prevents or reduces the frequency, rate or extent of a response to endoplasmic reticulum stress. GO:1903573]

neuron projection morphogenesis [The process in which the anatomical structures of a neuron projection are generated and organized. A neuron projection is any process extending from a neural cell, such as axons or dendrites. GO:0048812]

positive regulation of amyloid-beta formation [Any process that activates or increases the frequency, rate or extent of amyloid-beta formation. GO:1902004]

positive regulation of apoptotic process [Any process that activates or increases the frequency, rate or extent of cell death by apoptotic process.|This term should only be used when it is not possible to determine which phase or subtype of the apoptotic process is positively regulated by a gene product. Whenever detailed information is available, the more granular children terms should be used. GO:0043065]

positive regulation of cell differentiation [Any process that activates or increases the frequency, rate or extent of cell differentiation. GO:0045597]

positive regulation of cell population proliferation [Any process that activates or increases the rate or extent of cell proliferation. GO:0008284]

positive regulation of gene expression [Any process that increases the frequency, rate or extent of gene expression. Gene expression is the process in which a gene's coding sequence is converted into a mature gene product (protein or RNA). GO:0010628]

positive regulation of intrinsic apoptotic signaling pathway [Any process that activates or increases the frequency, rate or extent of intrinsic apoptotic signaling pathway. GO:2001244]

positive regulation of neurofibrillary tangle assembly [Any process that activates or increases the frequency, rate or extent of neurofibrillary tangle assembly. GO:1902998]

positive regulation of nitric oxide biosynthetic process [Any process that activates or increases the frequency, rate or extent of the chemical reactions and pathways resulting in the formation of nitric oxide. GO:0045429]

positive regulation of proteasomal ubiquitin-dependent protein catabolic process [Any process that activates or increases the frequency, rate or extent of the breakdown of a protein or peptide by hydrolysis of its peptide bonds, initiated by the covalent attachment of ubiquitin, and mediated by the proteasome. GO:0032436]

positive regulation of protein-containing complex assembly [Any process that activates or increases the frequency, rate or extent of protein complex assembly. GO:0031334]

positive regulation of receptor-mediated endocytosis [Any process that activates or increases the frequency, rate or extent of receptor mediated endocytosis, the uptake of external materials by cells, utilizing receptors to ensure specificity of transport. GO:0048260]

positive regulation of tumor necrosis factor production [Any process that activates or increases the frequency, rate or extent of tumor necrosis factor production.|Note that this term refers only to the specific, original 'tumor necrosis factor' protein (TNF) and not other members of the tumor necrosis factor superfamily (those with the gene symbol root 'TNFSF'). GO:0032760]

positive regulation of ubiquitin-dependent protein catabolic process [Any process that activates or increases the frequency, rate or extent of ubiquitin-dependent protein catabolic process. GO:2000060]

protein import [The targeting and directed movement of proteins into a cell or organelle. Not all import involves an initial targeting event. GO:0017038]

protein stabilization [Any process involved in maintaining the structure and integrity of a protein and preventing it from degradation or aggregation. GO:0050821]

protein targeting to lysosome involved in chaperone-mediated autophagy [The targeting of a protein to the lysosome process in which an input protein binds to a chaperone and subsequently to a lysosomal receptor. GO:0061740]

regulation of amyloid-beta clearance [Any process that modulates the frequency, rate or extent of amyloid-beta clearance. GO:1900221]

regulation of apoptotic process [Any process that modulates the occurrence or rate of cell death by apoptotic process.|This term should only be used when it is not possible to determine which phase or subtype of the apoptotic process is regulated by a gene product. Whenever detailed information is available, the more granular children terms should be used. GO:0042981]

regulation of cell population proliferation [Any process that modulates the frequency, rate or extent of cell proliferation. GO:0042127]

regulation of neuronal signal transduction [Any process that modulates the frequency, rate or extent of neuronal signal transduction. GO:1902847]

response to light stimulus [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a light stimulus, electromagnetic radiation of wavelengths classified as infrared, visible or ultraviolet light. GO:0009416]

response to misfolded protein [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a misfolded protein stimulus. GO:0051788]

response to potassium ion [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a potassium ion stimulus. GO:0035864]

response to virus [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus from a virus. GO:0009615]

spermatogenesis [The developmental process by which male germ line stem cells self renew or give rise to successive cell types resulting in the development of a spermatozoa. GO:0007283]

MSigDB Signatures:

REACTOME_HEMOSTASIS: Hemostasis [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_HEMOSTASIS.html]

REACTOME_INNATE_IMMUNE_SYSTEM: Innate Immune System [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_INNATE_IMMUNE_SYSTEM.html]

REACTOME_COMPLEMENT_CASCADE: Complement cascade [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_COMPLEMENT_CASCADE.html]

WP_MALE_INFERTILITY: Male infertility [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_MALE_INFERTILITY.html]

KEGG_MEDICUS_REFERENCE_REGULATION_OF_COMPLEMENT_CASCADE_MAC_INHIBITION: Pathway Definition from KEGG: (CD59,CLU,VTN) -| (C5b+C6+C7+C8+C9) [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_MEDICUS_REFERENCE_REGULATION_OF_COMPLEMENT_CASCADE_MAC_INHIBITION.html]

WP_COMPLEMENT_AND_COAGULATION_CASCADES: Complement and coagulation cascades [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_COMPLEMENT_AND_COAGULATION_CASCADES.html]

REACTOME_TERMINAL_PATHWAY_OF_COMPLEMENT: Terminal pathway of complement [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_TERMINAL_PATHWAY_OF_COMPLEMENT.html]

7. Gene Descriptions

NCBI Gene Summary: The protein encoded by this gene is a secreted chaperone that can under some stress conditions also be found in the cell cytosol. It has been suggested to be involved in several basic biological events such as cell death, tumor progression, and neurodegenerative disorders. Alternate splicing results in both coding and non-coding variants.

GeneCards Summary: CLU (Clusterin) is a Protein Coding gene. Diseases associated with CLU include Anaplastic Large Cell Lymphoma and Ovarian Cystadenoma. Among its related pathways are Response to elevated platelet cytosolic Ca2+ and Immune response Lectin induced complement pathway. Gene Ontology (GO) annotations related to this gene include ubiquitin protein ligase binding and protein-folding chaperone binding. An important paralog of this gene is CLUL1.

UniProtKB/Swiss-Prot Summary: Functions as extracellular chaperone that prevents aggregation of non native proteins [PMID: 11123922, PMID: 19535339]. Prevents stress-induced aggregation of blood plasma proteins [PMID: 11123922, PMID: 12176985, PMID: 17260971, PMID: 19996109]. Inhibits formation of amyloid fibrils by APP, APOC2, B2M, CALCA, CSN3, SNCA and aggregation-prone LYZ variants (in vitro) [PMID: 12047389, PMID: 17412999, PMID: 17407782]. Does not require ATP [PMID: 11123922]. Maintains partially unfolded proteins in a state appropriate for subsequent refolding by other chaperones, such as HSPA8/HSC70 [PMID: 11123922]. Does not refold proteins by itself [PMID: 11123922]. Binding to cell surface receptors triggers internalization of the chaperone-client complex and subsequent lysosomal or proteasomal degradation [PMID: 21505792]. Protects cells against apoptosis and against cytolysis by complement [PMID: 2780565]. Intracellular forms interact with ubiquitin and SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes and promote the ubiquitination and subsequent proteasomal degradation of target proteins [PMID: 20068069]. Promotes proteasomal degradation of COMMD1 and IKBKB [PMID: 20068069]. Modulates NF-kappa-B transcriptional activity [PMID: 12882985]. A mitochondrial form suppresses BAX-dependent release of cytochrome c into the cytoplasm and inhibit apoptosis [PMID: 16113678, PMID: 17689225]. Plays a role in the regulation of cell proliferation [PMID: 19137541]. An intracellular form suppresses stress-induced apoptosis by stabilizing mitochondrial membrane integrity through interaction with HSPA5 [PMID: 22689054]. Secreted form does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity [PMID: 24073260]. Secreted form act as an important modulator during neuronal differentiation through interaction with STMN3. Plays a role in the clearance of immune complexes that arise during cell injury. Does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity. Does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity [PMID: 24073260]. Promotes cell death through interaction with BCL2L1 that releases and activates BAX [PMID: 21567405].

8. Cellular Location of Gene Product

General cytoplasmic protein expression most tissues. Localized to the cytosol. Predicted location: Secreted, Intracellular (different isoforms) [https://www.proteinatlas.org/ENSG00000120885/subcellular]

9. Mechanistic Information

Summary

The CLU gene, which encodes the clusterin protein, plays a significant role in kidney diseases and toxicities due to its diverse functions in cellular protection, apoptosis regulation, and response to stress [CS: 9]. In cases of renal damage or toxicity, such as those caused by diseases like diabetic nephropathy or toxic events like ischemia-reperfusion injury, the body triggers protective mechanisms to counteract these harmful effects [CS: 8]. CLU expression is upregulated in response to these stressors, a response likely mediated by factors such as NF-kappaB, growth factors, and apoptosis-inducing agents like ionizing radiation and oxidative stress [CS: 8].

Clusterin, the protein product of the CLU gene, then performs several critical functions in response to this upregulation [CS: 9]. As an extracellular chaperone, clusterin prevents the aggregation of non-native proteins, a common occurrence in stressed or damaged cells, thereby maintaining cellular integrity and preventing further damage [CS: 9]. In the context of renal injury, this chaperone function helps to stabilize proteins that might otherwise aggregate and exacerbate cellular dysfunction [CS: 8]. Moreover, clusterin has a dual role in apoptosis regulation: the secretory form (sCLU) acts as an anti-apoptotic molecule [CS: 7], while the nuclear form (nCLU) has pro-apoptotic effects [CS: 7]. In the kidneys, where cell turnover and regeneration are vital for recovery from injury, these opposing roles of clusterin could facilitate the removal of irreparably damaged cells (through nCLU) and the protection of recoverable cells (through sCLU), thus aiding in the overall recovery and maintenance of kidney function [CS: 8].

10. Upstream Regulators

11. Tissues/Cell Type Where Genes are Overexpressed

Tissue type enchanced: liver (tissue enhanced) [https://www.proteinatlas.org/ENSG00000120885/tissue]

Cell type enchanced: basal prostatic cells, cholangiocytes, collecting duct cells, hepatocytes, muller glia cells, secretory cells (cell type enhanced) [https://www.proteinatlas.org/ENSG00000120885/single+cell+type]

12. Role of Gene in Other Tissues

13. Chemicals Known to Elicit Transcriptional Response of Biomarker in Tissue of Interest

Compounds that increase expression of the gene:

Compounds that decrease expression of the gene:

14. DisGeNet Biomarker Associations to Disease in Organ of Interest