CLU

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.[provided by RefSeq, May 2011]

Clusterin

Isoform 1:
Functions as extracellular chaperone that prevents aggregation of non native proteins (PubMed:11123922, PubMed:19535339).

Prevents stress-induced aggregation of blood plasma proteins (PubMed:11123922, PubMed:12176985, PubMed:17260971, PubMed:19996109).

Inhibits formation of amyloid fibrils by APP, APOC2, B2M, CALCA, CSN3, SNCA and aggregation-prone LYZ variants (in vitro) (PubMed:12047389, PubMed:17412999, PubMed:17407782).

Does not require ATP (PubMed:11123922).

Maintains partially unfolded proteins in a state appropriate for subsequent refolding by other chaperones, such as HSPA8/HSC70 (PubMed:11123922).

Does not refold proteins by itself (PubMed:11123922).

Binding to cell surface receptors triggers internalization of the chaperone-client complex and subsequent lysosomal or proteasomal degradation (PubMed:21505792).

Protects cells against apoptosis and against cytolysis by complement (PubMed: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 (PubMed:20068069).

Promotes proteasomal degradation of COMMD1 and IKBKB (PubMed:20068069).

Modulates NF-kappa-B transcriptional activity (PubMed:12882985).

A mitochondrial form suppresses BAX-dependent release of cytochrome c into the cytoplasm and inhibit apoptosis (PubMed:16113678, PubMed:17689225).

Plays a role in the regulation of cell proliferation (PubMed:19137541).

An intracellular form suppresses stress-induced apoptosis by stabilizing mitochondrial membrane integrity through interaction with HSPA5 (PubMed:22689054).

Secreted form does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity (PubMed:24073260).

Secreted form act as an important modulator during neuronal differentiation through interaction with STMN3 (By similarity).

Plays a role in the clearance of immune complexes that arise during cell injury (By similarity).

Isoform 6:
Does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity.

Isoform 4:
Does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity (PubMed:24073260).

Promotes cell death through interaction with BCL2L1 that releases and activates BAX (PubMed:21567405).

Antimicrobial humoral response Source: Reactome
Cell morphogenesis Source: Alzheimers_University_of_Toronto
Central nervous system myelin maintenance Source: Alzheimers_University_of_Toronto
Chaperone-mediated protein complex assembly Source: Alzheimers_University_of_Toronto
Chaperone-mediated protein folding Source: UniProtKB
Chaperone-mediated protein transport involved in chaperone-mediated autophagy Source: ARUK-UCL
Complement activation Source: ProtInc
Complement activation, classical pathway Source: UniProtKB-KW
Immune complex clearance Source: UniProtKB
Innate immune response Source: UniProtKB-KW
Intrinsic apoptotic signaling pathway Source: UniProtKB
Lipid metabolic process Source: ProtInc
Microglial cell activation Source: Alzheimers_University_of_Toronto
Microglial cell proliferation Source: Alzheimers_University_of_Toronto
Negative regulation of amyloid-beta formation Source: Alzheimers_University_of_Toronto
Negative regulation of amyloid fibril formation Source: ARUK-UCL
Negative regulation of cell death Source: ARUK-UCL
Negative regulation of cellular response to thapsigargin Source: ARUK-UCL
Negative regulation of cellular response to tunicamycin Source: ARUK-UCL
Negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage Source: BHF-UCL
Negative regulation of protein-containing complex assembly Source: ARUK-UCL
Negative regulation of release of cytochrome c from mitochondria Source: ARUK-UCL
Negative regulation of response to endoplasmic reticulum stress Source: ARUK-UCL
Platelet degranulation Source: Reactome
Positive regulation of amyloid-beta formation Source: Alzheimers_University_of_Toronto
Positive regulation of amyloid fibril formation Source: ARUK-UCL
Positive regulation of apoptotic process Source: UniProtKB
Positive regulation of gene expression Source: ARUK-UCL
Positive regulation of intrinsic apoptotic signaling pathway Source: UniProtKB
Positive regulation of neurofibrillary tangle assembly Source: Alzheimers_University_of_Toronto
Positive regulation of neuron death Source: Alzheimers_University_of_Toronto
Positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
Positive regulation of nitric oxide biosynthetic process Source: Alzheimers_University_of_Toronto
Positive regulation of proteasomal ubiquitin-dependent protein catabolic process Source: UniProtKB
Positive regulation of protein-containing complex assembly Source: ARUK-UCL
Positive regulation of receptor-mediated endocytosis Source: ARUK-UCL
Positive regulation of tau-protein kinase activity Source: Alzheimers_University_of_Toronto
Positive regulation of tumor necrosis factor production Source: Alzheimers_University_of_Toronto
Positive regulation of ubiquitin-dependent protein catabolic process Source: UniProtKB
Protein import Source: Alzheimers_University_of_Toronto
Protein stabilization Source: UniProtKB
Protein targeting to lysosome involved in chaperone-mediated autophagy Source: ARUK-UCL
Regulation of amyloid-beta clearance Source: Alzheimers_University_of_Toronto
Regulation of apoptotic process Source: GO_Central
Regulation of cell population proliferation Source: UniProtKB
Regulation of complement activation Source: Reactome
Regulation of neuronal signal transduction Source: Alzheimers_University_of_Toronto
Regulation of neuron death Source: Alzheimers_University_of_Toronto
Release of cytochrome c from mitochondria Source: BHF-UCL
Response to misfolded protein Source: BHF-UCL
Response to virus Source: UniProtKB
Reverse cholesterol transport Source: BHF-UCL

Isoform 1: Secreted. Can retrotranslocate from the secretory compartments to the cytosol upon cellular stress.
Isoform 4: Cytoplasm. Keeps cytoplasmic localization in stressed and unstressed cell.
Isoform 6: Cytoplasm. Keeps cytoplasmic localization in stressed and unstressed cell.
Mitochondrion membrane; Mitochondrion; Nucleus; Cytoplasm; Cytosol; Microsome; Endoplasmic reticulum; Perinuclear region; Chromaffin granule. Secreted isoforms can retrotranslocate from the secretory compartments to the cytosol upon cellular stress (PubMed:17451556). Detected in perinuclear foci that may be aggresomes containing misfolded, ubiquitinated proteins (PubMed:20068069). Detected at the mitochondrion membrane upon induction of apoptosis (PubMed:17689225). Under ER stress, a immaturely glycosylated pre-secreted form retrotranslocates from the endoplasmic reticulum (ER)-Golgi network to the cytoplasm to localize in the mitochondria through HSPA5 interaction (PubMed:22689054). ER stress reduces secretion (PubMed:22689054). Under the stress, minor amounts of non-secreted forms accumulate in cytoplasm (PubMed:24073260, PubMed:22689054, PubMed:17451556). Non-secreted forms emerge mainly from failed translocation, alternative splicing or non-canonical initiation start codon (PubMed:24073260, PubMed:12551933).

Proteolytically cleaved on its way through the secretory system, probably within the Golgi lumen (PubMed:2387851). Proteolytic cleavage is not necessary for its chaperone activity (PubMed:25402950). All non-secreted forms are not proteolytically cleaved (PubMed:24073260). Chaperone activity of uncleaved forms is dependent on a non-reducing envoronment (PubMed:25402950).
Polyubiquitinated, leading to proteasomal degradation (PubMed:17451556, PubMed:19137541). Under cellular stress, the intracellular level of cleaved form is reduced due to proteasomal degradation (PubMed:17451556).
Extensively glycosylated with sulfated N-linked carbohydrates (PubMed:17260971, PubMed:2387851). About 30% of the protein mass is comprised of complex N-linked carbohydrate (PubMed:2387851). Endoplasmic reticulum (ER) stress induces changes in glycosylation status and increases level of hypoglycosylated forms (PubMed:22689054). Core carbohydrates are essential for chaperone activity (PubMed:25402950). Non-secreted forms are hypoglycosylated or unglycosylated (PubMed:24073260).