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; testosterone-repressed prostate message 2; TRPM-2; contains: Clusterin beta chain; apoJalpha; complement cytolysis inhibitor a chain; contains: Clusterin alpha chain; apoJbeta; complement cytolysis inhibitor b chain (CLU, APOJ, CLI, KUB1, AAG4)

Function

• isoform 1 functions as extracellular chaperone that prevents aggregation of non-native proteins
• prevents stress-induced aggregation of plasma proteins
• inhibits formation of amyloid fibrils by APP, APOC2, B2M, CALCA, CSN3, SNCA & aggregation-prone LYZ variants (in vitro)
• circulates with HDL
• 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 & subsequent lysosomal or proteasomal degradation
• secreted isoform 1 protects cells against apoptosis & against cytolysis by complement
• intracellular isoforms interact with ubiquitin & SCF E3 ubiquitin-protein ligase complexes & promote the ubiquitination & subsequent proteasomal degradation of target proteins
• promotes proteasomal degradation of COMMD1 & IKBKB
• modulates NF-kappa-B transcriptional activity
• nuclear isoforms promote apoptosis
• mitochondrial isoforms suppress BAX-dependent release of cytochrome c into the cytoplasm & inhibit apoptosis.
• role in regulation of cell proliferation
• isoform 1 is proteolytically cleaved on its way through the secretory system, probably within the Golgi lumen
• polyubiquitinated, leading to proteasomal degradation
• self-associates & forms higher oligomers
• interacts with a broad range of misfolded proteins, including APP, APOC2 & LYZ
• slightly acidic pH promotes interaction with misfolded proteins
• forms high-molecular weight oligomers upon interaction with misfolded proteins
• interacts with APOA1, LRP2, CLUAP1 AND PON1
• interacts with the complement complex
  • inhibits binding of complement C8 & C9 to the C5b67 complex
• interacts (via alpha chain) with XRCC6
• interacts with SYVN1, COMMD1, BTRC, CUL1 & with ubiquitin & SCF E3 ubiquitin-protein ligase complexes
• interacts (via alpha chain) with BAX in stressed cells, where BAX undergoes a conformation change leading to association with the mitochondrial membrane
• does not interact with BAX in unstressed cells

Structure

• heavily N-glycosylated
• ~30% of the protein mass is comprised of complex N-linked carbohydrate
• antiparallel disulfide-linked heterodimer of an alpha chain & a beta chain
• belongs to the clusterin family

Compartment

• isoform 1:
  • secreted
  • can retrotranslocate from the secretory compartments to the cytosol upon cellular stress
• nucleus, cytoplasm, mitochondrial membrane
• peripheral membrane, cytoplasmic side
• microsome, endoplasmic reticulum
• cytoplasmic vesicle, secretory vesicle, chromaffin granule (putative)
• isoforms lacking the N-terminal signal sequence are cytoplasmic &/or nuclear
• secreted isoforms 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 mitochondrial membrane upon induction of apoptosis

Alternative splicing

named isoforms=5

Expression

• ubiquitous
• detected in plasma, cerebrospinal fluid, milk, seminal fluid & colonic mucosa
• detected in the germinal center of colon lymphoid nodules & in colon parasympathetic ganglia of the Auerbach plexus (at protein level)
• detected in brain, testis, ovary, liver & pancreas, & at lower levels in kidney, heart, spleen & lung
• up-regulated in response to enterovirus 71 (EV71) infection (at protein level)
• up-regulated by agents that induce apoptosis, both at mRNA & protein level
• isoform 1 is up-regulated by androgen
• isoform 2 is down-regulated by androgen

Pathology

• clusterin is absent in erythrocytes of patients with paroxysmal nocturnal hemoglobinuria (PNH)
• clusterin may play neuroprotective role in dementia
• a minor isoform that has been detected in a breast cancer cell line, but not in any other tissues or cell lines

Comparative biology

• plasma collected from voluntarily running mice infused into sedentary mice reduces baseline neuroinflammatory gene expression & experimentally-induced neuroinflammation
• increase in complement cascade inhibitors including clusterin*

* persons with mild cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of clusterin

More general terms

• chromogranin; secretogranin;granin
• protease inhibitor
• glycoprotein
• phosphoprotein
• multisubunit protein

Additional terms

• clusterin-associated protein 1 (CLUAP1, KIAA0643)
• Clusterin-like protein 1 precursor (retinal-specific clusterin-like protein, CLUL1)

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=1191
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:1191
• OMIM: https://mirror.omim.org/entry/185430
• UniProt: http://www.uniprot.org/uniprot/P10909.html