Clu
Developmental stage
Expressed by cells undergoing programmed death as a result of the hormonal stimuli or a traumatic insult.
Function
Functions as extracellular chaperone that prevents aggregation of non native proteins. Prevents stress-induced aggregation of blood plasma proteins. Inhibits formation of amyloid fibrils by APP, APOC2, B2M, CALCA, CSN3, SNCA and aggregation-prone LYZ variants (in vitro). Does not require ATP. Maintains partially unfolded proteins in a state appropriate for subsequent refolding by other chaperones, such as HSPA8/HSC70. Does not refold proteins by itself. Binding to cell surface receptors triggers internalization of the chaperone-client complex and subsequent lysosomal or proteasomal degradation. When secreted, protects cells against apoptosis and against cytolysis by complement. 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. Promotes proteasomal degradation of COMMD1 and IKBKB. Modulates NF-kappa-B transcriptional activity (By similarity). Following stress, promotes apoptosis (By similarity). Inhibits apoptosis when associated with the mitochondrial membrane by interference with BAX-dependent release of cytochrome c into the cytoplasm. Plays a role in the regulation of cell proliferation. An intracellular form suppresses stress-induced apoptosis by stabilizing mitochondrial membrane integrity through interaction with HSPA5. Secreted form does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity (By similarity). Secreted form act as an important modulator during neuronal differentiation through interaction with STMN3 (PubMed:16038898). Plays a role in the clearance of immune complexes that arise during cell injury (By similarity).
Post-translational modifications
Proteolytically cleaved on its way through the secretory system, probably within the Golgi lumen (PubMed:3415696, PubMed:3651384). Proteolytic cleavage is not necessary for its chaperone activity. All non-secreted forms are not proteolytically cleaved. Chaperone activity of uncleaved forms is dependent on a non-reducing environment (By similarity).
Polyubiquitinated, leading to proteasomal degradation. Under cellular stress, the intracellular level of cleaved form is reduced due to proteasomal degradation.
Extensively glycosylated with sulfated N-linked carbohydrates (PubMed:3651384). About 30% of the protein mass is comprised of complex N-linked carbohydrate. Endoplasmic reticulum (ER) stress induces changes in glycosylation status and increases level of hypoglycosylated forms. Core carbohydrates are essential for chaperone activity. Non-secreted forms are hypoglycosylated or unglycosylated (By similarity).
Sequence Similarities
Belongs to the clusterin family.
Tissue Specificity
Detected in Sertoli cells (at protein level). Detected in cultured Sertoli cells, testis, epididymis, liver and brain.
Cellular localization
- Secreted
- Nucleus
- Cytoplasm
- Mitochondrion membrane
- Peripheral membrane protein
- Cytoplasmic side
- Cytoplasm
- Cytosol
- Microsome
- Endoplasmic reticulum
- Mitochondrion
- Mitochondrion membrane
- Cytoplasm
- Perinuclear region
- Cytoplasmic vesicle
- Secretory vesicle
- Chromaffin granule
- Can retrotranslocate from the secretory compartments to the cytosol upon cellular stress. Detected in perinuclear foci that may be aggresomes containing misfolded, ubiquitinated proteins. Detected at the mitochondrion membrane upon induction of apoptosis. 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. ER stress reduces secretion. Under the stress, minor amounts of non-secreted forms accumulate in cytoplasm.
Alternative names
Clusterin, Dimeric acid glycoprotein, Sulfated glycoprotein 2, Testosterone repressed prostate message 2, DAG, SGP-2, TRPM-2, Clu