Protein: Clusterin (Aging-associated gene 4 protein) (Apolipoprotein J) (Apo-J) (Complement cytolysis inhibitor) (CLI) (Complement-associated protein SP-40,40) (Ku70-binding protein 1) (NA1/NA2) (Sulfated glycoprotein 2) (SGP-2) (Testosterone-repressed prostate message 2) (TRPM-2) [Cleaved into: Clusterin beta chain (ApoJalpha) (Complement cytolysis inhibitor a chain) (SP-40,40 beta-chain); Clusterin alpha chain (ApoJbeta) (Complement cytolysis inhibitor b chain) (SP-40,40 alpha-chain)] (P10909)
Organism: Homo sapiens (Human)
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. 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. A mitochondrial form suppresses BAX-dependent release of cytochrome c into the cytoplasm and inhibit apoptosis. 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. 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).
Subcellular location: [Isoform 1]: Secreted {ECO:0000269|PubMed:11123922, ECO:0000269|PubMed:17260971, ECO:0000269|PubMed:17412999, ECO:0000269|PubMed:17451556, ECO:0000269|PubMed:2387851, ECO:0000269|PubMed:24073260, ECO:0000269|PubMed:2780565, ECO:0000269|PubMed:3154963, ECO:0000269|PubMed:8292612, ECO:0000269|PubMed:8328966}. Note=Can retrotranslocate from the secretory compartments to the cytosol upon cellular stress. {ECO:0000269|PubMed:17451556}.; SUBCELLULAR LOCATION: [Isoform 4]: Cytoplasm {ECO:0000269|PubMed:24073260}. Note=Keeps cytoplasmic localization in stressed and unstressed cell. {ECO:0000269|PubMed:24073260}.; SUBCELLULAR LOCATION: [Isoform 6]: Cytoplasm {ECO:0000269|PubMed:24073260}. Note=Keeps cytoplasmic localization in stressed and unstressed cell. {ECO:0000269|PubMed:24073260}.; SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:12551933, ECO:0000269|PubMed:19137541}. Cytoplasm {ECO:0000269|PubMed:12551933, ECO:0000269|PubMed:17689225, ECO:0000269|PubMed:19137541, ECO:0000269|PubMed:20068069, ECO:0000269|PubMed:22689054, ECO:0000269|PubMed:24073260}. Mitochondrion membrane; Peripheral membrane protein; Cytoplasmic side {ECO:0000269|PubMed:17689225}. Cytoplasm, cytosol {ECO:0000269|PubMed:17451556, ECO:0000269|PubMed:22689054, ECO:0000269|PubMed:24073260}. Microsome {ECO:0000269|PubMed:22689054}. Endoplasmic reticulum {ECO:0000269|PubMed:16113678, ECO:0000269|PubMed:22689054}. Mitochondrion {ECO:0000269|PubMed:16113678, ECO:0000269|PubMed:22689054}. Mitochondrion membrane {ECO:0000269|PubMed:16113678, ECO:0000269|PubMed:17689225}. Cytoplasm, perinuclear region {ECO:0000250|UniProtKB:P05371}. Cytoplasmic vesicle, secretory vesicle, chromaffin granule {ECO:0000250}. Note=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:17451556, PubMed:22689054, PubMed:24073260). Non-secreted forms emerge mainly from failed translocation, alternative splicing or non-canonical initiation start codon (PubMed:12551933, PubMed:24073260). {ECO:0000269|PubMed:12551933, ECO:0000269|PubMed:17451556, ECO:0000269|PubMed:17689225, ECO:0000269|PubMed:20068069, ECO:0000269|PubMed:22689054, ECO:0000269|PubMed:24073260}.
Interaction partners:
- Apolipoprotein E
- Apolipoprotein A-I
- Amyloid-beta precursor protein
- Serum paraoxonase/arylesterase 1
- Low-density lipoprotein receptor-related protein 2
- Lactotransferrin
- Triggering receptor expressed on myeloid cells 2
- Apolipoprotein A-IV
- X-ray repair cross-complementing protein 6
- Apolipoprotein C-I
Sequence:
MMKTLLLFVGLLLTWESGQVLGDQTVSDNELQEMSNQGSKYVNKEIQNAVNGVKQIKTLIEKTNEERKTLLSNLEEAKKKKEDALNETRESETKLKELPGVCNETMMALWEECKPCLKQTCMKFYARVCRSGSGLVGRQLEEFLNQSSPFYFWMNGDRIDSLLENDRQQTHMLDVMQDHFSRASSIIDELFQDRFFTREPQDTYHYLPFSLPHRRPHFFFPKSRIVRSLMPFSPYEPLNFHAMFQPFLEMIHEAQQAMDIHFHSPAFQHPPTEFIREGDDDRTVCREIRHNSTGCLRMKDQCDKCREILSVDCSTNNPSQAKLRRELDESLQVAERLTRKYNELLKSYQWKMLNTSSLLEQLNEQFNWVSRLANLTQGEDQYYLRVTTVASHTSDSDVPSGVTEVVVKLFDSDPITVTVPVEVSRKNPKFMETVAEKALQEYRKKHREE