Clusterin (CLU), also known as Apolipoprotein J (ApoJ) and Complement Cytolysis Inhibitor (CLI), is a highly glycosylated secreted chaperone that functions primarily as an extracellular holdase. The predominant secretory isoform (sCLU) prevents aggregation of non-native proteins in the extracellular space, maintaining them in a soluble, folding-competent state for subsequent refolding by ATP-dependent chaperones such as HSPA8/HSC70. CLU does not refold proteins itself and does not require ATP. It inhibits amyloid fibril formation by multiple amyloidogenic proteins (APP, APOC2, SNCA, etc.) and plays a key role in inhibiting complement membrane attack complex (MAC) assembly by preventing C9 polymerization. CLU also facilitates clearance of misfolded proteins via receptor-mediated endocytosis through LRP2/megalin. Intracellular forms of CLU have been implicated in ubiquitin-dependent proteasomal degradation, anti-apoptotic signaling via BAX interaction at mitochondria, and NF-kappa-B modulation. CLU is associated with the HDL particle and is widely expressed, with particular relevance to Alzheimer disease, atherosclerosis, and cancer.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0042981 regulation of apoptotic process | IBA GO_REF:0000033 | ACCEPT | Summary: CLU is well-established as a regulator of apoptosis. The secreted form inhibits apoptosis via complement MAC inhibition (PMID:9200695), the intracellular form inhibits apoptosis by interacting with activated BAX at mitochondria (PMID:16113678), and isoform 4 (nCLU) promotes apoptosis via BCL2L1 interaction (UniProt). The IBA annotation to the broad term "regulation of apoptotic process" is appropriate given the dual pro- and anti-apoptotic roles of different CLU isoforms. Reason: CLU has well-documented roles in both inhibiting and promoting apoptosis depending on isoform and context. The IBA term at this level of specificity is appropriate for the phylogenetically conserved function. Supporting Evidence: PMID:16113678 intracellular clusterin inhibits apoptosis by interfering with Bax activation in mitochondria |
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Nuclear localization of CLU has been reported for intracellular isoforms (isoform 4/nCLU) and under stress conditions (PMID:19137541, PMID:25051234). The predominant secreted form (isoform 1) is not nuclear. The IBA annotation is reasonable given nuclear isoforms exist across species. Multiple IDA annotations also support nuclear localization. Reason: Nuclear localization is real but represents a minor isoform (nCLU/isoform 4) or stress-related redistribution, not the predominant subcellular localization of the main secreted form. Keep as non-core. Supporting Evidence: PMID:19137541 proteasome inhibition by MG132 caused stabilization and accumulation of all CLU protein products, including the nuclear form of CLU (nCLU) |
| GO:0005615 extracellular space | IBA GO_REF:0000033 | ACCEPT | Summary: CLU is a secreted glycoprotein that is a major constituent of the extracellular space, present in plasma, CSF, and other body fluids (PMID:2387851, PMID:11123922). This is the core localization of the predominant secreted isoform. Reason: Extracellular space is the primary site of CLU function as an extracellular chaperone and complement regulator. Well-supported by extensive literature. Supporting Evidence: PMID:11123922 Clusterin represents the first identified secreted mammalian chaperone. |
| GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PMID:20068069 demonstrated that sCLU acts as a ubiquitin-binding protein that enhances COMMD1 and I-kappaB proteasomal degradation by interacting with members of the SCF-betaTrCP E3 ligase family in prostate cancer cells. This is supported by IMP evidence from the same publication. The IBA annotation reflects a conserved intracellular function. Reason: This function is demonstrated for intracellular CLU in cancer cell context (PMID:20068069) and is not the core extracellular chaperone function. The annotation is valid but represents a secondary/intracellular activity. Supporting Evidence: PMID:20068069 sCLU increases NF-kappaB nuclear translocation and transcriptional activity by serving as a ubiquitin-binding protein that enhances COMMD1 and I-kappaB proteasomal degradation by interacting with members of the SCF-betaTrCP E3 ligase family. |
| GO:0051787 misfolded protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: Misfolded protein binding is the core molecular function of CLU as an extracellular holdase chaperone. CLU binds stressed/misfolded proteins to form soluble high molecular weight complexes and prevents their aggregation (PMID:11123922, PMID:19996109). This is the most appropriate MF term for CLU's chaperone activity. Reason: This is the most informative and accurate MF term for CLU's core function. CLU binds misfolded/stressed proteins via exposed hydrophobic surfaces, maintaining them in a soluble state. Well-supported by multiple IDA studies (PMID:11123922, PMID:19996109). Supporting Evidence: PMID:11123922 clusterin (i) inhibits stress-induced precipitation of a very broad range of structurally divergent protein substrates, (ii) binds irreversibly via an ATP-independent mechanism to stressed proteins to form solubilized high molecular weight complexes |
| GO:0002376 immune system process | IEA GO_REF:0000043 | ACCEPT | Summary: CLU participates in immune system processes primarily through complement regulation (inhibition of MAC assembly) and immune complex clearance. The IEA term is very broad but not incorrect. Reason: CLU is a complement regulator that inhibits MAC assembly (PMID:9200695, PMID:34667172). The broad IEA annotation to "immune system process" is acceptable as a high-level summary, though more specific terms are also annotated. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: CLU is a secreted protein found in the extracellular region. This is well-established. The IEA maps correctly from UniProt subcellular location. Reason: Extracellular region is the primary localization of the predominant secreted CLU isoform. Confirmed by multiple experimental methods. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Nuclear localization is documented for the nCLU isoform (isoform 4) and under stress/proteasome inhibition (PMID:19137541). IEA is consistent with IDA and IBA annotations to nucleus. Reason: Nuclear localization is real for minor intracellular isoforms but not the predominant secreted form. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Cytoplasmic localization of CLU occurs via retrotranslocation from the ER under stress (PMID:22689054) and for intracellular isoforms. IEA is consistent with multiple IDA annotations. Reason: Cytoplasmic localization is documented but represents stress-induced or isoform-specific behavior, not the primary localization. |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Mitochondrial localization occurs under ER stress conditions where CLU retrotranslocates to the cytosol and redistributes to mitochondria to inhibit apoptosis (PMID:22689054, PMID:16113678). IEA is consistent with IDA evidence. Reason: Mitochondrial localization is stress-induced and relates to anti-apoptotic function of intracellular CLU, not the primary extracellular chaperone function. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | ACCEPT | Summary: CLU transits through the ER as part of the secretory pathway. The precursor is glycosylated in the ER. IEA mapping from UniProt is appropriate as CLU does transiently reside in the ER. Reason: CLU passes through the ER during biosynthesis. Under stress conditions, ER-resident CLU can retrotranslocate. The annotation is valid. |
| GO:0005829 cytosol | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Cytosolic CLU has been detected by IDA (PMID:22689054) and is associated with stress-induced retrotranslocation. IEA is consistent. Reason: Cytosolic localization is secondary, occurring under stress conditions. Not the primary localization. |
| GO:0006915 apoptotic process | IEA GO_REF:0000043 | ACCEPT | Summary: CLU is involved in apoptotic process regulation. IEA from UniProt keyword "Apoptosis" is appropriate. CLU both inhibits (via BAX interaction, PMID:16113678) and promotes (nCLU isoform) apoptosis. Reason: IEA to the broad term "apoptotic process" is acceptable given CLU's well-documented roles in apoptosis regulation. |
| GO:0006958 complement activation, classical pathway | IEA GO_REF:0000043 | MODIFY | Summary: CLU is a complement regulator but specifically inhibits the terminal pathway (MAC assembly) rather than activating the classical pathway. CLU inhibits C9 polymerization on C5b-8 and C5b-9 complexes (PMID:9200695). The term "complement activation, classical pathway" is misleading for CLU's function, which is inhibitory and acts on the terminal pathway. Reason: CLU does not activate the classical complement pathway. It inhibits terminal complement assembly (MAC). More appropriate terms are already annotated (GO:0001971, GO:0045916). This IEA mapping is inaccurate. Proposed replacements: negative regulation of complement activation Supporting Evidence: PMID:9200695 Clusterin inhibited at three sites and by two modes of action. Clusterin inhibited C9 assembly on C5b-8 and C5b-9 and also bound to C5b-7 to prevent membrane attachment. |
| GO:0031410 cytoplasmic vesicle | IEA GO_REF:0000043 | ACCEPT | Summary: CLU is found in cytoplasmic vesicles (secretory granules, chromaffin granules, platelet alpha granules). IEA from UniProt keyword is reasonable. Reason: CLU transits through the secretory pathway and is found in various vesicular compartments including platelet alpha granules and secretory granules. |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Under stress, intracellular CLU redistributes to mitochondria and stabilizes mitochondrial membrane integrity (PMID:22689054, PMID:17689225). CLU interacts with conformation-altered BAX at the mitochondrial membrane (PMID:16113678). Reason: Mitochondrial membrane localization is stress-induced and related to anti-apoptotic function of intracellular CLU, not the primary function. |
| GO:0042583 chromaffin granule | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: CLU has been detected in chromaffin granules as noted in UniProt subcellular location. The early literature described CLU in endocrine and neuronal granules (PMID:1585460). Reason: Chromaffin granule localization is a minor specialized localization consistent with CLU's role as a secreted glycoprotein in neuroendocrine cells. |
| GO:0045087 innate immune response | IEA GO_REF:0000043 | ACCEPT | Summary: CLU inhibits MAC assembly, a key effector of innate immunity. The IEA annotation to innate immune response is appropriate. Reason: CLU regulates complement, which is a core component of innate immunity. This broad term is acceptable alongside the more specific complement annotations. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Perinuclear localization has been observed for intracellular CLU (PMID:20068069). IEA from UniProt mapping is consistent with IDA data. Reason: Perinuclear localization is documented for intracellular CLU but is not the primary localization. |
| GO:0005515 protein binding | IPI PMID:17043677 Disrupted in Schizophrenia 1 Interactome: evidence for the c... | MARK AS OVER ANNOTATED | Summary: PMID:17043677 reports CLU interaction with DISC1 in a schizophrenia interactome study. "Protein binding" is uninformative for CLU given its known chaperone function; more specific terms like misfolded protein binding already capture this. Reason: Protein binding is too vague. CLU interacts with many proteins via its chaperone activity. More specific MF terms are already annotated. |
| GO:0005515 protein binding | IPI PMID:17170699 ERp57 is essential for efficient folding of glycoproteins sh... | MARK AS OVER ANNOTATED | Summary: PMID:17170699 identifies CLU as an endogenous substrate of ERp57 (PDIA3), an ER oxidoreductase required for disulfide bond formation in glycoproteins. This reflects CLU being a client of the ER folding machinery, not a function of CLU itself. Reason: Protein binding is uninformative. CLU is a substrate of ERp57, not a binding partner in a functional sense relevant to CLU's molecular function. |
| GO:0005515 protein binding | IPI PMID:20195357 A comprehensive resource of interacting protein regions for ... | MARK AS OVER ANNOTATED | Summary: PMID:20195357 is a large-scale interacting protein region resource. Protein binding is uninformative for a known chaperone. Reason: Generic protein binding from a high-throughput study; uninformative for CLU which has more specific MF annotations. |
| GO:0005515 protein binding | IPI PMID:22179788 The extracellular chaperone clusterin sequesters oligomeric ... | MARK AS OVER ANNOTATED | Summary: PMID:22179788 shows CLU sequesters oligomeric Abeta(1-40). This is better captured by the amyloid-beta binding (GO:0001540) annotation from the same publication. Reason: More specific terms (amyloid-beta binding, misfolded protein binding) already capture this interaction. |
| GO:0005515 protein binding | IPI PMID:22528093 Search for amyloid-binding proteins by affinity chromatograp... | MARK AS OVER ANNOTATED | Summary: PMID:22528093 identifies CLU as an amyloid-binding protein by affinity chromatography. Better captured by GO:0001540 amyloid-beta binding. Reason: Uninformative. CLU's binding to amyloid proteins is captured by more specific annotations. |
| GO:0005515 protein binding | IPI PMID:25451228 PACAP inhibits tumor growth and interferes with clusterin in... | MARK AS OVER ANNOTATED | Summary: PMID:25451228 shows PACAP interacts with CLU and downregulates CLU expression in cervical cancer cells. Protein binding is uninformative. Reason: PACAP-CLU interaction in cancer context. Protein binding is too vague. |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | MARK AS OVER ANNOTATED | Summary: PMID:26496610 is a large-scale human interactome study. Protein binding from high-throughput data is uninformative for CLU. Reason: Generic high-throughput protein binding; uninformative. |
| GO:0005515 protein binding | IPI PMID:28887769 Ξ±-Synuclein Interacts with Lipoproteins in Plasma. | MARK AS OVER ANNOTATED | Summary: PMID:28887769 shows alpha-synuclein co-immunoprecipitates with ApoJ from plasma, suggesting association on lipoprotein particles. This reflects CLU's apolipoprotein role rather than direct protein binding. Reason: The interaction is likely indirect, mediated through shared lipoprotein particles. Protein binding is uninformative; CLU's chaperone function already covers its protein-binding activity. |
| GO:0005515 protein binding | IPI PMID:31270237 Ξ±-synuclein-lipoprotein interactions and elevated ApoE level... | MARK AS OVER ANNOTATED | Summary: PMID:31270237 shows alpha-synuclein colocalizes with apolipoproteins including ApoJ on lipoprotein vesicles in CSF. Likely an indirect association on lipoproteins. Reason: Indirect association on lipoproteins; protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:31413325 HENA, heterogeneous network-based data set for Alzheimer's d... | MARK AS OVER ANNOTATED | Summary: PMID:31413325 is a heterogeneous network-based data set for AD. Protein binding from a data-mining resource is uninformative. Reason: Computational dataset; protein binding is uninformative for CLU. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: PMID:32814053 is interactome mapping of neurodegenerative disease proteins. Protein binding is uninformative for CLU which has specific MF annotations. Reason: High-throughput interactome study; uninformative protein binding. |
| GO:0002434 immune complex clearance | IEA GO_REF:0000107 | ACCEPT | Summary: CLU facilitates clearance of immune complexes via receptor-mediated endocytosis through LRP2/megalin and other receptors. This IEA from Ensembl Compara is consistent with ISS evidence also annotated. Reason: Immune complex clearance is a documented function of CLU, consistent with its role as an extracellular chaperone that facilitates clearance of protein complexes via receptor-mediated endocytosis. |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The nCLU isoform (isoform 4) promotes apoptosis by interacting with BCL2L1 (UniProt). The IEA from Ensembl Compara is consistent with orthologue data. Reason: Positive regulation of apoptosis is real but specific to the nuclear isoform (nCLU). The predominant secreted form is anti-apoptotic. |
| GO:0045202 synapse | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: CLU is found at synapses in the brain and has been implicated in synaptic biology through its interactions with amyloid-beta and its association with neurodegeneration. However, CLU is not a synaptic protein per se; it is an extracellular chaperone that is present in the extracellular space including at synapses. Reason: CLU is an extracellular chaperone found throughout the extracellular space. Its presence at synapses reflects general extracellular localization rather than synaptic-specific localization. |
| GO:1902004 positive regulation of amyloid-beta formation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Under certain conditions (low CLU:Abeta ratio), CLU can promote amyloid formation (PMID:17412999). However, at physiological ratios CLU primarily inhibits amyloid formation. The IEA annotation is technically valid but context-dependent. Reason: CLU can promote amyloid-beta formation at very low CLU:substrate ratios (PMID:17412999), but its primary function is inhibitory. This annotation captures a secondary, dose-dependent effect. Supporting Evidence: PMID:17412999 Proamyloidogenic effects of clusterin appear to be restricted to conditions in which the substrate protein is present at a very large molar excess |
| GO:1905907 negative regulation of amyloid fibril formation | IEA GO_REF:0000107 | ACCEPT | Summary: CLU potently inhibits amyloid fibril formation by multiple substrates (PMID:17412999, PMID:12047389, PMID:22179788). This is a core function. IEA is consistent with extensive experimental evidence. Reason: Negative regulation of amyloid fibril formation is a well-established core function of CLU as an extracellular holdase chaperone. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Cytosolic CLU detected by immunofluorescence curation. Consistent with retrotranslocation under stress (PMID:22689054). Reason: Cytosolic localization is stress-induced, not the primary localization. |
| GO:0005576 extracellular region | HDA PMID:20551380 Proteomics characterization of extracellular space component... | ACCEPT | Summary: PMID:20551380 is a proteomics characterization of extracellular space components in human aorta that detected CLU. Confirms core extracellular localization. Reason: Proteomic detection of CLU in extracellular space of human aorta. Consistent with core localization. |
| GO:0005576 extracellular region | HDA PMID:27559042 Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin... | ACCEPT | Summary: PMID:27559042 is a glycoproteomics study of human atrial fibrillation tissue that detected CLU extracellularly. Confirms core localization. Reason: High-throughput proteomic detection confirming CLU in extracellular region. |
| GO:0001971 negative regulation of activation of membrane attack complex | IDA PMID:34667172 Structural basis of soluble membrane attack complex packagin... | ACCEPT | Summary: PMID:34667172 provides structural basis showing how clusterin binds sMAC and inhibits C9 polymerization by obstructing the polymerizing face of C9. This is a core function of CLU. Reason: Cryo-EM structure of sMAC shows how CLU recognizes and inhibits polymerizing complement proteins. Core complement regulatory function. Supporting Evidence: PMID:34667172 clusterin recognizes and inhibits polymerizing complement proteins by binding a negatively charged surface of sMAC |
| GO:0001971 negative regulation of activation of membrane attack complex | IDA PMID:9200695 Potent inhibition of terminal complement assembly by cluster... | ACCEPT | Summary: PMID:9200695 demonstrates CLU is a potent inhibitor of terminal complement assembly, binding to C5b-8 and C5b-9 to prevent C9 polymerization with high affinity. Reason: Definitive biochemical characterization of CLU as a MAC inhibitor. Core function. Supporting Evidence: PMID:9200695 Clusterin inhibited C9 assembly on C5b-8 and C5b-9 and also bound to C5b-7 to prevent membrane attachment |
| GO:0045916 negative regulation of complement activation | IDA PMID:34667172 Structural basis of soluble membrane attack complex packagin... | ACCEPT | Summary: Same study as above, CLU negatively regulates complement by inhibiting MAC. Core function. Reason: Core complement regulatory function demonstrated structurally. |
| GO:0045916 negative regulation of complement activation | IDA PMID:9200695 Potent inhibition of terminal complement assembly by cluster... | ACCEPT | Summary: CLU inhibits terminal complement at multiple steps (PMID:9200695). Core function. Reason: Biochemically validated complement inhibition. Core function. |
| GO:0140311 protein sequestering activity | IDA PMID:34667172 Structural basis of soluble membrane attack complex packagin... | ACCEPT | Summary: PMID:34667172 shows CLU sequesters soluble MAC precursors to prevent bystander damage. CLU traps C9 in an intermediate conformation. This is consistent with CLU's broader role as a protein sequestering agent. Reason: Protein sequestering is a core MF of CLU -- it captures misfolded proteins and complement intermediates to prevent aggregation and inappropriate activity. Structurally demonstrated. |
| GO:0140311 protein sequestering activity | IDA PMID:9200695 Potent inhibition of terminal complement assembly by cluster... | ACCEPT | Summary: PMID:9200695 shows CLU binds C5b-8 and C5b-9 complexes, sequestering them. Consistent with protein sequestering activity. Reason: Core MF of CLU to sequester complement intermediates and misfolded proteins. |
| GO:1903660 negative regulation of complement-dependent cytotoxicity | IDA PMID:34667172 Structural basis of soluble membrane attack complex packagin... | ACCEPT | Summary: CLU prevents complement-dependent cytotoxicity by inhibiting MAC assembly (PMID:34667172). Core function. Reason: Direct consequence of MAC inhibition. Well-supported. |
| GO:1903660 negative regulation of complement-dependent cytotoxicity | IDA PMID:9200695 Potent inhibition of terminal complement assembly by cluster... | ACCEPT | Summary: PMID:9200695 estimates that CLU can reduce complement cytolysis of nucleated cells by 10-fold or more. Core function. Reason: Direct biochemical demonstration of CLU protecting against complement-dependent cytotoxicity. Supporting Evidence: PMID:9200695 the presence of <10% of the circulating clusterin in its heterodimeric, active form could reduce the rate of complement cytolysis of nucleated cells by 10-fold, and under some conditions by 100-fold or more |
| GO:0005886 plasma membrane | IDA PMID:30333625 LILRB4 signalling in leukaemia cells mediates T cell suppres... | KEEP AS NON CORE | Summary: PMID:30333625 reports CLU at the plasma membrane in the context of LILRB4 signaling in leukemia. CLU can bind cell surface receptors. Reason: CLU can associate with the plasma membrane via receptor binding, but it is not an intrinsic membrane protein. This is a minor localization. |
| GO:0010628 positive regulation of gene expression | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS from orthologue data. CLU has been shown to modulate NF-kB transcriptional activity (PMID:20068069), which indirectly regulates gene expression. However, this is very broad. Reason: Very broad term. CLU modulates NF-kB via ubiquitin-mediated degradation of inhibitors, but "positive regulation of gene expression" is too general and nonspecific. |
| GO:0051087 protein-folding chaperone binding | ISS GO_REF:0000024 | ACCEPT | Summary: CLU interacts with ATP-dependent chaperones including HSPA8/HSC70 (PMID:11123922) and HSPA5/GRP78 (PMID:22689054). CLU-client complexes are substrates for refolding by HSP70. The ISS annotation is valid. Reason: CLU stabilizes stressed proteins in a state competent for refolding by HSP70. This functional cooperation requires interaction with protein-folding chaperones. Supporting Evidence: PMID:11123922 stabilizes stressed proteins in a state competent for refolding by heat shock protein 70 (HSP70) |
| GO:0005615 extracellular space | IDA PMID:30333625 LILRB4 signalling in leukaemia cells mediates T cell suppres... | ACCEPT | Summary: PMID:30333625 detects CLU in the extracellular space. Confirms core localization. Reason: Extracellular space is the core localization. |
| GO:0048018 receptor ligand activity | IDA PMID:27477018 TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ,... | ACCEPT | Summary: PMID:27477018 shows CLU is a ligand for TREM2, a microglial receptor. CLU binding to TREM2 facilitates uptake of amyloid-beta by microglia. CLU is also a ligand for LRP2/megalin and VLDLR. Receptor ligand activity is appropriate. Reason: CLU functions as a ligand for multiple receptors (TREM2, LRP2, VLDLR) to mediate clearance of misfolded proteins and lipoproteins. This is a core functional aspect. Supporting Evidence: PMID:27477018 identified a set of lipoprotein particles (including LDL) and apolipoproteins (including CLU/APOJ and APOE) as ligands of TREM2 |
| GO:0097242 amyloid-beta clearance | IDA PMID:27477018 TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ,... | ACCEPT | Summary: PMID:27477018 shows CLU facilitates Abeta uptake by microglia via TREM2 binding. CLU-Abeta complexes are taken up by microglia in a TREM2-dependent manner. This is a key function in AD pathobiology. Reason: Amyloid-beta clearance is a well-supported function of CLU, mediated via receptor binding and endocytosis. Core function in brain proteostasis. Supporting Evidence: PMID:27477018 Ξ²-amyloid (AΞ²) binds to lipoproteins and this complex is efficiently taken up by microglia in a TREM2-dependent fashion |
| GO:0005576 extracellular region | TAS PMID:23164821 Clusterin regulates Ξ²-amyloid toxicity via Dickkopf-1-driven... | ACCEPT | Summary: PMID:23164821 discusses CLU in the context of beta-amyloid toxicity regulation. Confirms extracellular localization. Reason: Consistent with core extracellular localization. |
| GO:0005737 cytoplasm | TAS PMID:23164821 Clusterin regulates Ξ²-amyloid toxicity via Dickkopf-1-driven... | KEEP AS NON CORE | Summary: PMID:23164821 mentions cytoplasmic CLU. Consistent with intracellular forms documented elsewhere. Reason: Cytoplasmic localization is secondary, representing intracellular isoforms or stress-induced redistribution. |
| GO:0043524 negative regulation of neuron apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: CLU protects neurons from apoptosis, consistent with its anti-apoptotic function via BAX interaction (PMID:16113678) and neuroprotective roles documented in AD context (PMID:9560017). Reason: Neuroprotection is a well-supported secondary function of CLU but reflects the general anti-apoptotic activity applied to neurons rather than a neuron-specific mechanism. |
| GO:0061740 protein targeting to lysosome involved in chaperone-mediated autophagy | IDA PMID:9228033 Interaction of apolipoprotein J-amyloid beta-peptide complex... | ACCEPT | Summary: PMID:9228033 shows CLU-Abeta complexes are internalized via LRP2/megalin and targeted to lysosomes for degradation. This is receptor-mediated endocytosis leading to lysosomal degradation, which is a core clearance function of CLU. Reason: CLU facilitates targeting of misfolded protein cargo to lysosomes for degradation via receptor-mediated endocytosis. Core clearance function. |
| GO:0140597 protein carrier chaperone | IDA PMID:9228033 Interaction of apolipoprotein J-amyloid beta-peptide complex... | ACCEPT | Summary: PMID:9228033 shows CLU acts as a carrier chaperone that binds Abeta and delivers it to LRP2/megalin for internalization and degradation. This is an excellent MF term for CLU's carrier function. Reason: Protein carrier chaperone accurately captures CLU's function of binding misfolded proteins and delivering them to receptors for clearance. Core MF. |
| GO:0016887 ATP hydrolysis activity | IDA NOT PMID:11123922 Clusterin is an ATP-independent chaperone with very broad su... | ACCEPT | Summary: PMID:11123922 explicitly demonstrated that CLU lacks detectable ATPase activity. This is a NOT annotation confirming CLU is an ATP-independent chaperone. Reason: Important negative annotation. CLU is definitively established as an ATP-independent chaperone, distinguishing it from classical chaperones like HSP70. Supporting Evidence: PMID:11123922 lacks detectable ATPase activity |
| GO:0048156 tau protein binding | IPI PMID:25051234 Intracellular clusterin interacts with brain isoforms of the... | ACCEPT | Summary: PMID:25051234 shows intracellular CLU (iCLU) interacts with tau in AD. Co-immunoprecipitation from human brain tissue confirmed iCLU association with modified tau species found in AD. Reason: Tau binding is well-supported by co-IP from human brain. Relevant to CLU's role in AD pathobiology and consistent with its broader misfolded protein binding activity. Supporting Evidence: PMID:25051234 By overexpressing iCLU and Tau in cell culture systems we discovered that iCLU was a Tau-interacting protein and that iCLU associated with brain-specific isoforms of BIN1, also recently identified as a Tau-binding protein |
| GO:0001836 release of cytochrome c from mitochondria | IC PMID:16113678 Clusterin inhibits apoptosis by interacting with activated B... | KEEP AS NON CORE | Summary: PMID:16113678 shows intracellular CLU inhibits BAX oligomerization, which leads to release of cytochrome c. The IC annotation infers CLU involvement in cytochrome c release (by inhibiting it). The annotation term itself describes the process, while CLU is a negative regulator. Reason: CLU inhibits cytochrome c release by blocking BAX activation at mitochondria. This is an intracellular anti-apoptotic function, not the primary extracellular chaperone function. |
| GO:0032760 positive regulation of tumor necrosis factor production | IDA PMID:15857407 Apolipoprotein J (clusterin) activates rodent microglia in v... | KEEP AS NON CORE | Summary: PMID:15857407 shows exogenous CLU activates rodent microglia and increases TNF-alpha secretion with EC50 of 55 nM. This is a pro-inflammatory effect in the CNS context. Reason: Microglial activation and TNF induction by CLU is a secondary, context-dependent effect in the CNS, not the core molecular function. Supporting Evidence: PMID:15857407 ApoJ increased the secretion of reactive nitrogen intermediates in a dose-dependent manner (EC(50) 112 nm), which was completely blocked by aminoguanidine (AG), a nitric oxide synthase inhibitor. However, AG did not block the increased secretion of tumor necrosis factor-alpha by apoJ (EC(50) 55 nm). |
| GO:0045429 positive regulation of nitric oxide biosynthetic process | IDA PMID:15857407 Apolipoprotein J (clusterin) activates rodent microglia in v... | KEEP AS NON CORE | Summary: PMID:15857407 shows CLU increases reactive nitrogen intermediate secretion from microglia in a dose-dependent manner. Reason: Microglial NO induction is a secondary inflammatory response to CLU in the CNS, not the core function. |
| GO:0005102 signaling receptor binding | IPI PMID:27477018 TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ,... | ACCEPT | Summary: PMID:27477018 shows CLU binds TREM2 receptor on microglia. CLU also binds LRP2/megalin and VLDLR. Signaling receptor binding is an appropriate MF term. Reason: CLU is a ligand for multiple signaling receptors (TREM2, LRP2, VLDLR). This is integral to its clearance function and a core molecular activity. |
| GO:0031333 negative regulation of protein-containing complex assembly | IMP PMID:16113678 Clusterin inhibits apoptosis by interacting with activated B... | ACCEPT | Summary: PMID:16113678 shows CLU impedes BAX oligomerization, preventing mitochondrial pore formation. This represents negative regulation of protein complex assembly (BAX oligomers). Reason: Although the BAX oligomerization evidence is an intracellular anti-apoptotic context, the GO term itself captures a core CLU activity: preventing harmful protein complex or aggregate assembly. Keeping this term action consistent with the amyloid-oligomer rows. |
| GO:0031333 negative regulation of protein-containing complex assembly | IDA PMID:22179788 The extracellular chaperone clusterin sequesters oligomeric ... | ACCEPT | Summary: PMID:22179788 shows CLU sequesters oligomeric Abeta, preventing further aggregation/complex assembly. This reflects CLU's core holdase chaperone function preventing protein aggregation. Reason: Preventing protein complex/aggregate assembly is a direct consequence of CLU's core holdase chaperone activity. |
| GO:0031333 negative regulation of protein-containing complex assembly | IDA PMID:23106396 Amyloid-Ξ² oligomers are sequestered by both intracellular an... | ACCEPT | Summary: PMID:23106396 shows CLU sequesters Abeta oligomers, preventing further assembly. Same core chaperone function as above. Reason: Core chaperone function preventing misfolded protein complex assembly. |
| GO:0031334 positive regulation of protein-containing complex assembly | IDA PMID:22179788 The extracellular chaperone clusterin sequesters oligomeric ... | KEEP AS NON CORE | Summary: PMID:22179788 shows that at very low CLU:Abeta ratios, CLU can promote Abeta complex formation. This is a dose-dependent effect opposite to the primary inhibitory function. Reason: At substoichiometric levels, CLU can paradoxically promote protein complex assembly. This is a secondary, dose-dependent effect opposite to the core inhibitory function. |
| GO:0002434 immune complex clearance | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from orthologues. CLU facilitates clearance of immune complexes via receptor-mediated endocytosis. Consistent with the IEA annotation from Ensembl Compara. Reason: Immune complex clearance is a documented function of CLU, consistent with its chaperone-carrier function. |
| GO:0048260 positive regulation of receptor-mediated endocytosis | ISS GO_REF:0000024 | ACCEPT | Summary: CLU-cargo complexes are internalized via receptor-mediated endocytosis through LRP2/megalin (PMID:9228033) and TREM2 (PMID:27477018). CLU promotes this process. ISS is consistent. Reason: CLU facilitates receptor-mediated endocytosis of its cargo complexes. Core clearance mechanism. |
| GO:0051082 unfolded protein binding | IMP PMID:25402950 The chaperone activity of clusterin is dependent on glycosyl... | MODIFY | Summary: GO:0051082 "unfolded protein binding" is now formally obsolete (go-ontology#30962). The annotation is based on PMID:25402950 (Rohne et al. 2014), which investigated the chaperone activity of clusterin under different glycosylation and redox conditions. The paper demonstrates that CLU has chaperone-like holdase activity -- it prevents aggregation of stressed/unfolded target proteins and maintains them in a soluble state. Critically, CLU does not actively refold proteins (PMID:11123922) and does not require ATP (PMID:11123922). This is consistent with an extracellular holdase function rather than a classical folding chaperone. The best replacement from existing GO terms is GO:0044183 "protein folding chaperone" (defined as binding to a protein to assist the protein folding process), though this is an imperfect fit since CLU prevents aggregation rather than directly assisting folding. The existing IBA annotation to GO:0051787 "misfolded protein binding" and the IDA annotations to GO:0051787 (PMID:11123922, PMID:19996109) more accurately capture the binding aspect of CLU chaperone function. GO:0050821 "protein stabilization" (already annotated via IDA from PMID:11123922 and PMID:12176985) captures the biological process aspect. A holdase-specific MF term would be ideal but does not currently exist in GO. Reason: GO:0051082 "unfolded protein binding" is now formally obsolete. CLU is an extracellular holdase chaperone that prevents protein aggregation rather than actively promoting folding. PMID:25402950 demonstrates that CLU chaperone activity depends on glycosylation and redox environment, confirming holdase function. PMID:11123922 established that CLU does not refold proteins by itself and does not require ATP. GO:0044183 "protein folding chaperone" is proposed as an interim replacement -- it is the closest available MF term for chaperone activity, though CLU functions as a holdase (preventing aggregation and maintaining proteins in a folding-competent state for downstream ATP-dependent chaperones) rather than a foldase. The existing annotations to GO:0051787 "misfolded protein binding" (IBA, IDA) already capture the binding specificity, and GO:0050821 "protein stabilization" (IDA) captures the biological process. A future holdase-specific term in GO would be more appropriate. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:25402950 We show that the PC-cleavage is dispensable for sCLU chaperone activity. Moreover, our data demonstrate that while fully deglycosylated sCLU lacks chaperone activity, partially deglycosylated sCLU is still capable of solubilizing target proteins. PMID:11123922 clusterin (i) inhibits stress-induced precipitation of a very broad range of structurally divergent protein substrates, (ii) binds irreversibly via an ATP-independent mechanism to stressed proteins to form solubilized high molecular weight complexes, (iii) lacks detectable ATPase activity, (iv) when acting alone, does not effect refolding of stressed proteins in vitro, and (v) stabilizes stressed proteins in a state competent for refolding by heat shock protein 70 (HSP70). |
| GO:0005737 cytoplasm | IDA PMID:22689054 GRP78 regulates clusterin stability, retrotranslocation and ... | KEEP AS NON CORE | Summary: PMID:22689054 demonstrates that under ER stress, GRP78 facilitates CLU retrotranslocation from the ER to the cytoplasm in prostate cancer cells. Subcellular fractionation and confocal microscopy confirmed cytoplasmic CLU accumulation under stress. Reason: Cytoplasmic localization of CLU is well-documented under ER stress conditions (PMID:22689054). This is a secondary, stress-induced localization, not the primary extracellular localization. Supporting Evidence: PMID:22689054 ER stress increased association between GRP78 and CLU, which led to increased cytoplasmic CLU levels, while reducing sCLU levels secreted into the culture media. |
| GO:0043065 positive regulation of apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from orthologue data. The nCLU isoform (isoform 4) promotes apoptosis by interacting with BCL2L1 (UniProt). Consistent with the IEA annotation from Ensembl Compara (already reviewed). Reason: Positive regulation of apoptosis is valid for the nuclear isoform (nCLU). The predominant secreted form is anti-apoptotic. This is a minor isoform-specific function. |
| GO:0005634 nucleus | IDA PMID:19137541 Clusterin is a short half-life, poly-ubiquitinated protein, ... | KEEP AS NON CORE | Summary: PMID:19137541 shows that proteasome inhibition by MG132 causes stabilization and accumulation of all CLU protein products including the nuclear form (nCLU). The nuclear localization was directly observed in prostate cancer cells under proteasome inhibition. Reason: Nuclear localization is real for the nCLU isoform and under proteasome inhibition, but is not the predominant localization of the main secreted form. Supporting Evidence: PMID:19137541 Proteasome inhibition by MG132 caused stabilization and accumulation of all CLU protein products, including the nuclear form of CLU (nCLU), and committing cells to caspase-dependent death. |
| GO:0005737 cytoplasm | IDA PMID:17689225 Multiple pathways regulating the anti-apoptotic protein clus... | KEEP AS NON CORE | Summary: PMID:17689225 reports that CLU overexpressed by HDI treatment localizes to cytoplasm and mitochondria in breast cancer cells. The hyper-expressed form localizes to mitochondria and inhibits cytochrome c release. Reason: Cytoplasmic CLU is documented in cancer cells under treatment conditions. This is a secondary localization related to the anti-apoptotic intracellular function. Supporting Evidence: PMID:17689225 The hyper-expressed form of clusterin localizes to mitochondria, inhibits cytochrome c release, and is inhibited by the proteasome. |
| GO:0005743 mitochondrial inner membrane | IDA PMID:17689225 Multiple pathways regulating the anti-apoptotic protein clus... | KEEP AS NON CORE | Summary: PMID:17689225 shows that CLU localizes to mitochondria in breast cancer cells treated with HDIs and inhibits cytochrome c release. UniProt annotates CLU at the mitochondrial membrane as a peripheral membrane protein on the cytoplasmic side. Reason: Mitochondrial inner membrane localization is stress/treatment-induced. CLU is not a constitutive mitochondrial protein. This relates to the anti-apoptotic function of intracellular CLU in cancer cells. Supporting Evidence: PMID:17689225 The hyper-expressed form of clusterin localizes to mitochondria, inhibits cytochrome c release, and is inhibited by the proteasome. |
| GO:0042127 regulation of cell population proliferation | IMP PMID:19137541 Clusterin is a short half-life, poly-ubiquitinated protein, ... | KEEP AS NON CORE | Summary: PMID:19137541 demonstrates that siRNA-mediated depletion of CLU in PC-3 prostate cancer cells induces cell cycle progression and higher expression of proliferation markers (H3, PCNA, cyclins A, B1, D), while CLU overexpression inhibits proliferation and induces apoptosis. Reason: Regulation of cell proliferation by CLU is documented in prostate cancer cells but represents a secondary, context-dependent role in cancer biology, not the core chaperone function. Supporting Evidence: PMID:19137541 Following siRNA targeting all CLU mRNA variants, all protein products quickly disappeared, inducing cell cycle progression and higher expression of specific proliferation markers (i.e., H3 mRNA, PCNA, and cyclins A, B1, and D) as detected by RT-qPCR and Western blot |
| GO:0050821 protein stabilization | IDA PMID:12176985 Mildly acidic pH activates the extracellular molecular chape... | ACCEPT | Summary: PMID:12176985 shows that CLU at mildly acidic pH has enhanced chaperone activity, stabilizing stressed proteins against aggregation. Low pH induces dissociation of CLU aggregates and increases solvent-exposed hydrophobicity, enhancing its ability to stabilize stressed proteins. Reason: Protein stabilization is a core biological process of CLU. The holdase chaperone activity of CLU directly prevents aggregation and maintains proteins in a stable, soluble state. Well-demonstrated by direct assay. Supporting Evidence: PMID:12176985 the chaperone action of clusterin is enhanced at mildly acidic pH. Clusterin is the first chaperone shown to be activated by reduced pH. |
| GO:0005739 mitochondrion | IDA PMID:22689054 GRP78 regulates clusterin stability, retrotranslocation and ... | KEEP AS NON CORE | Summary: PMID:22689054 shows that under ER stress in prostate cancer cells, GRP78 facilitates CLU retrotranslocation and co-localized redistribution to the mitochondria, reducing stress-induced apoptosis by stabilizing mitochondrial membrane integrity. Reason: Mitochondrial localization is stress-induced and occurs in cancer cells under treatment conditions. Not the primary localization of the predominant secreted form. Supporting Evidence: PMID:22689054 GRP78 increased stress-induced CLU retrotranslocation from the ER with co-localized redistribution to the mitochondria, thereby reducing stress-induced apoptosis by cooperatively stabilizing mitochondrial membrane integrity. |
| GO:0005829 cytosol | IDA PMID:22689054 GRP78 regulates clusterin stability, retrotranslocation and ... | KEEP AS NON CORE | Summary: PMID:22689054 demonstrates cytosolic CLU accumulation under ER stress via retrotranslocation from the ER in prostate cancer cells. Reason: Cytosolic localization is secondary and stress-induced, not the primary localization of the secreted form. |
| GO:0043231 intracellular membrane-bounded organelle | IDA PMID:22689054 GRP78 regulates clusterin stability, retrotranslocation and ... | KEEP AS NON CORE | Summary: PMID:22689054 shows CLU in intracellular membrane-bounded organelles (ER, mitochondria) during ER stress in prostate cancer cells. This is a very broad CC term. Reason: Very broad localization term. CLU transits through the ER as part of the secretory pathway and redistributes to mitochondria under stress. More specific CC terms are already annotated. |
| GO:0099020 perinuclear endoplasmic reticulum lumen | IDA PMID:22689054 GRP78 regulates clusterin stability, retrotranslocation and ... | KEEP AS NON CORE | Summary: PMID:22689054 shows CLU in the ER lumen prior to retrotranslocation in prostate cancer cells. CLU is synthesized and glycosylated in the ER as part of its normal secretory processing. Reason: Perinuclear ER lumen localization reflects CLU transit through the secretory pathway. CLU is normally processed through the ER but its functional site is extracellular. |
| GO:0005515 protein binding | IPI PMID:22689054 GRP78 regulates clusterin stability, retrotranslocation and ... | MARK AS OVER ANNOTATED | Summary: PMID:22689054 shows CLU associates with GRP78/BiP under ER stress. This interaction is between CLU as a client/substrate of the ER chaperone machinery and is better captured by the existing annotation to GO:0051087 protein-folding chaperone binding. Reason: Protein binding is uninformative. The CLU-GRP78 interaction is already better captured by the protein-folding chaperone binding annotation (GO:0051087). |
| GO:0005515 protein binding | IPI PMID:8555189 Interaction of transforming growth factor beta receptors wit... | MARK AS OVER ANNOTATED | Summary: PMID:8555189 demonstrates that CLU interacts directly with both type I (RI/ACVR1) and type II (RII/TGFBR2) TGF-beta receptors via yeast two-hybrid and co-precipitation experiments. The 60 kDa intracellular form of CLU was precipitated by RI and RII fusion proteins. Reason: While the CLU-TGFBR interaction is specific and validated, the generic term protein binding is uninformative. A more specific term such as signaling receptor binding (GO:0005102) would better capture this. The signaling receptor binding annotation is already present from PMID:27477018. |
| GO:0005576 extracellular region | HDA PMID:27068509 Extracellular matrix remodelling in response to venous hyper... | ACCEPT | Summary: PMID:27068509 is a proteomics study of varicose veins detecting CLU in extracellular matrix. Confirms core extracellular localization. Reason: Proteomic detection confirming CLU in the extracellular region, consistent with core localization as a secreted protein. |
| GO:0005615 extracellular space | HDA PMID:20551380 Proteomics characterization of extracellular space component... | ACCEPT | Summary: PMID:20551380 is a proteomics characterization of extracellular space components in human aorta that detected CLU. Confirms core localization. Reason: Proteomic detection in human aorta extracellular space. Consistent with core localization. Note this is a duplicate of the already-reviewed HDA annotation for extracellular region from same PMID but for the more specific extracellular space term. |
| GO:0050750 low-density lipoprotein particle receptor binding | IPI PMID:9228033 Interaction of apolipoprotein J-amyloid beta-peptide complex... | ACCEPT | Summary: PMID:9228033 demonstrates that CLU-Abeta complex binds LRP-2/megalin (a member of the LDL receptor family) with high affinity. The interaction was shown by ELISA, and CLU-mediated binding to LRP-2 promotes cellular uptake and degradation of Abeta. Reason: LDL receptor family binding is a core molecular function of CLU. CLU serves as a carrier chaperone that delivers misfolded protein cargo to LRP-2/megalin and other LDL receptor family members for receptor-mediated endocytosis and clearance. Supporting Evidence: PMID:9228033 Abeta alone did not bind directly to LRP-2; however, when Abeta1-40 was combined with apoJ to form a complex, binding to LRP-2 took place. |
| GO:0005515 protein binding | IPI PMID:25051234 Intracellular clusterin interacts with brain isoforms of the... | MARK AS OVER ANNOTATED | Summary: PMID:25051234 shows intracellular CLU (iCLU) interacts with tau and BIN1 by co-immunoprecipitation. The tau binding is already captured by the more specific GO:0048156 tau protein binding annotation. Reason: Protein binding is uninformative. The iCLU-tau interaction is better captured by the tau protein binding (GO:0048156) annotation from the same publication. |
| GO:0005634 nucleus | IDA PMID:25051234 Intracellular clusterin interacts with brain isoforms of the... | KEEP AS NON CORE | Summary: PMID:25051234 reports intracellular CLU (iCLU) localization including nuclear localization in cell culture systems overexpressing iCLU, and in human AD brain tissue. Reason: Nuclear localization is real for intracellular CLU isoforms, particularly in the context of AD pathology, but is not the primary localization of the predominant secreted form. |
| GO:0005737 cytoplasm | IDA PMID:25051234 Intracellular clusterin interacts with brain isoforms of the... | KEEP AS NON CORE | Summary: PMID:25051234 shows iCLU in the cytoplasm of cells and human brain tissue. The intracellular form interacts with tau and BIN1 in the cytoplasm. Reason: Cytoplasmic localization for the intracellular CLU form. Secondary to the core extracellular localization. |
| GO:0005856 cytoskeleton | IDA PMID:25051234 Intracellular clusterin interacts with brain isoforms of the... | KEEP AS NON CORE | Summary: PMID:25051234 shows iCLU associates with tau, a microtubule-associated protein. Cytoskeletal localization likely reflects iCLU interaction with tau on microtubules. Reason: Cytoskeletal localization of iCLU is secondary and likely reflects its interaction with tau on microtubules in the context of AD pathology. |
| GO:0016020 membrane | IDA PMID:25051234 Intracellular clusterin interacts with brain isoforms of the... | KEEP AS NON CORE | Summary: PMID:25051234 reports iCLU at membranes. This is a very broad CC term and likely reflects iCLU association with ER membranes or other intracellular membrane compartments. Reason: Very broad term. More specific membrane-associated localizations are already annotated (ER, mitochondrial membrane). This adds little information beyond existing annotations. |
| GO:0001540 amyloid-beta binding | IDA PMID:22179788 The extracellular chaperone clusterin sequesters oligomeric ... | ACCEPT | Summary: PMID:22179788 demonstrates that CLU sequesters oligomeric forms of Abeta(1-40) peptide. CLU binds Abeta oligomers with high efficiency, forming stable CLU-Abeta complexes that prevent further aggregation. Reason: Amyloid-beta binding is a well-established core molecular function of CLU, representing a specific instance of its broader misfolded protein binding chaperone activity. Directly demonstrated by biophysical assays. |
| GO:0001540 amyloid-beta binding | IPI PMID:23106396 Amyloid-Ξ² oligomers are sequestered by both intracellular an... | ACCEPT | Summary: PMID:23106396 shows CLU sequesters Abeta oligomers both extracellularly and intracellularly, demonstrating amyloid-beta binding activity. Reason: Additional evidence for amyloid-beta binding, a core MF of CLU. Consistent with the IDA evidence from PMID:22179788. |
| GO:0044877 protein-containing complex binding | IPI PMID:22179788 The extracellular chaperone clusterin sequesters oligomeric ... | ACCEPT | Summary: PMID:22179788 shows CLU binds to oligomeric Abeta complexes. CLU specifically targets prefibrillar oligomeric species rather than monomers, consistent with binding to protein-containing complexes. Reason: CLU preferentially binds oligomeric protein complexes (prefibrillar species) rather than monomers. This is mechanistically important for its holdase chaperone function and is distinct from simple protein binding. |
| GO:0044877 protein-containing complex binding | IPI PMID:23106396 Amyloid-Ξ² oligomers are sequestered by both intracellular an... | ACCEPT | Summary: PMID:23106396 confirms CLU binds Abeta oligomeric complexes. Consistent with the IPI evidence from PMID:22179788. Reason: Additional evidence for CLU binding to protein-containing complexes (Abeta oligomers). Core MF. |
| GO:0048260 positive regulation of receptor-mediated endocytosis | IGI PMID:9228033 Interaction of apolipoprotein J-amyloid beta-peptide complex... | ACCEPT | Summary: PMID:9228033 shows that CLU-Abeta complex is internalized and degraded by LRP-2-expressing cells. CLU promotes cellular uptake of Abeta via LRP-2/megalin, and this was blocked by LRP-2 antibodies. The IGI annotation reflects genetic interaction evidence. Reason: CLU promotes receptor-mediated endocytosis of its cargo through LRP-2. This is a core clearance mechanism and is well-supported by biochemical evidence. Supporting Evidence: PMID:9228033 When LRP-2-expressing cells were given 125I-Abeta1-40, cellular uptake of the radiolabeled peptide was promoted by co-incubation with apoJ. |
| GO:1905908 positive regulation of amyloid fibril formation | TAS PMID:20005821 Overexpression of low-density lipoprotein receptor in the br... | KEEP AS NON CORE | Summary: PMID:20005821 concerns LDLR overexpression and Abeta clearance in mice. CLU can promote amyloid formation at very low CLU:substrate ratios (PMID:17412999), but its primary function is inhibitory. Reason: CLU can paradoxically promote amyloid formation at substoichiometric concentrations (PMID:17412999). This is a secondary, dose-dependent effect opposite to the core inhibitory function. The TAS reference indirectly supports this. |
| GO:0001540 amyloid-beta binding | IPI PMID:9228033 Interaction of apolipoprotein J-amyloid beta-peptide complex... | ACCEPT | Summary: PMID:9228033 demonstrates that CLU (apoJ) binds Abeta1-40 with a dissociation constant (Kd) of 4.8 nM and forms CLU-Abeta complexes that can be taken up via LRP-2/megalin. Reason: Core MF of CLU. High-affinity amyloid-beta binding (Kd 4.8 nM) demonstrated by quantitative ELISA. Supporting Evidence: PMID:9228033 an estimated dissociation constant (Kd) of 4.8 nM was derived for the interaction between Abeta1-40 and apoJ. |
| GO:0032991 protein-containing complex | IDA PMID:9228033 Interaction of apolipoprotein J-amyloid beta-peptide complex... | ACCEPT | Summary: PMID:9228033 shows CLU forms complexes with Abeta peptide that are recognized by LRP-2/megalin. These CLU-Abeta complexes represent protein-containing complexes. Reason: CLU forms high-molecular-weight complexes with client proteins as part of its core chaperone function. The CLU-Abeta complex is a well-characterized example. |
| GO:1905907 negative regulation of amyloid fibril formation | TAS PMID:9228033 Interaction of apolipoprotein J-amyloid beta-peptide complex... | ACCEPT | Summary: PMID:9228033 shows CLU inhibits formation of Abeta1-40 aggregates when incubated together. CLU-Abeta complex formation prevents Abeta aggregation. Reason: Core function of CLU. Inhibition of amyloid fibril formation is a direct consequence of its holdase chaperone activity. Supporting Evidence: PMID:9228033 incubation of apoJ with Abeta1-40 resulted in the formation of Abeta1-40-apoJ complex and the inhibition of the formation of Abeta1-40 aggregates. |
| GO:1905907 negative regulation of amyloid fibril formation | IDA PMID:22179788 The extracellular chaperone clusterin sequesters oligomeric ... | ACCEPT | Summary: PMID:22179788 shows CLU sequesters oligomeric Abeta, preventing further fibril formation. Direct assay evidence. Reason: Core function. Additional IDA evidence supporting CLU-mediated inhibition of amyloid fibril formation. |
| GO:1905907 negative regulation of amyloid fibril formation | TAS PMID:23106396 Amyloid-Ξ² oligomers are sequestered by both intracellular an... | ACCEPT | Summary: PMID:23106396 demonstrates that both intracellular and extracellular chaperones including CLU sequester Abeta oligomers, preventing further fibril assembly. Reason: Core function. Consistent with multiple other lines of evidence supporting CLU inhibition of amyloid fibril formation. |
| GO:0071944 cell periphery | IDA PMID:21803450 The APP intracellular domain (AICD) potentiates ER stress-in... | KEEP AS NON CORE | Summary: PMID:21803450 studies the APP intracellular domain (AICD) and its effects on ER stress-induced apoptosis. CLU detected at cell periphery may reflect extracellular CLU bound to cell surface receptors or in the process of secretion. Reason: Cell periphery localization is minor and likely reflects CLU binding to cell surface receptors or being in the process of secretion. More specific localizations are already annotated. |
| GO:0090201 negative regulation of release of cytochrome c from mitochondria | TAS PMID:21803450 The APP intracellular domain (AICD) potentiates ER stress-in... | KEEP AS NON CORE | Summary: PMID:21803450 studies AICD-mediated ER stress and CLU's protective role. CLU inhibits cytochrome c release by interacting with activated BAX at mitochondria (PMID:16113678, PMID:17689225). Reason: Negative regulation of cytochrome c release is a consequence of intracellular CLU's anti-apoptotic function via BAX interaction. This is a secondary intracellular function, not the core extracellular chaperone activity. Supporting Evidence: PMID:16113678 intracellular clusterin inhibits apoptosis by interfering with Bax activation in mitochondria |
| GO:1903573 negative regulation of response to endoplasmic reticulum stress | IMP PMID:21803450 The APP intracellular domain (AICD) potentiates ER stress-in... | KEEP AS NON CORE | Summary: PMID:21803450 studies the role of CLU in mitigating ER stress-induced apoptosis. CLU upregulation under ER stress (PMID:22689054) and its protective effects suggest involvement in negative regulation of ER stress response. Reason: CLU mitigates ER stress-induced apoptosis, but this represents a secondary stress-protective function of intracellular CLU, not the primary extracellular chaperone activity. |
| GO:0005794 Golgi apparatus | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from orthologue data. CLU transits through the Golgi as part of the secretory pathway where it undergoes proteolytic cleavage into alpha and beta chains. This is expected for a secreted glycoprotein. Reason: CLU is processed in the Golgi where the precursor is cleaved into alpha and beta chains. Golgi transit is part of the normal biosynthetic pathway for this secreted protein. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6810643 | ACCEPT | Summary: Reactome R-HSA-6810643 describes the EPPIN protein complex binding bacteria. CLU is part of the EPPIN complex on spermatozoa (PMID:17567961). Extracellular region localization is consistent. Reason: Core extracellular localization confirmed by Reactome pathway annotation. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8852580 | ACCEPT | Summary: Reactome R-HSA-8852580 describes CLU binding C5b-C7, C8, C9 complement components. This is the core complement regulatory function occurring in the extracellular space. Reason: Core extracellular localization confirmed by Reactome pathway for complement regulation. |
| GO:0005515 protein binding | IPI PMID:17567961 Characterization of an eppin protein complex from human seme... | MARK AS OVER ANNOTATED | Summary: PMID:17567961 identifies CLU as a component of the EPPIN protein complex (EPC) on spermatozoa, also containing lactotransferrin and semenogelin. The interaction was confirmed by immunoprecipitation. Reason: Protein binding is uninformative. The EPPIN complex interaction is specific but protein binding is too vague. A more informative term would be needed, though no specific GO MF term exists for this complex. |
| GO:0005615 extracellular space | IDA PMID:17567961 Characterization of an eppin protein complex from human seme... | ACCEPT | Summary: PMID:17567961 detects CLU in seminal plasma and on spermatozoa surface. Confirms extracellular space localization in the male reproductive tract. Reason: Core extracellular localization confirmed in seminal plasma. |
| GO:0009986 cell surface | IDA PMID:17567961 Characterization of an eppin protein complex from human seme... | KEEP AS NON CORE | Summary: PMID:17567961 shows CLU localizes to the surface of ejaculate spermatozoa as part of the EPPIN protein complex. CLU, LTF, and EPPIN colocalize on the sperm tail. Reason: Cell surface localization on spermatozoa is a specialized localization as part of the EPPIN complex. Not the primary localization but demonstrates CLU's presence at cell surfaces in specific tissue contexts. Supporting Evidence: PMID:17567961 On ejaculate spermatozoa eppin, LTF, and CLU colocalize on the tail. |
| GO:0032991 protein-containing complex | IDA PMID:17567961 Characterization of an eppin protein complex from human seme... | ACCEPT | Summary: PMID:17567961 identifies CLU as part of the EPPIN protein complex (EPC) containing CLU, lactotransferrin, semenogelin, and EPPIN. Confirmed by immunoprecipitation and mass spectrometry. Reason: CLU forms protein-containing complexes both as part of the EPPIN complex on spermatozoa and as chaperone-client complexes with misfolded proteins. Valid CC annotation. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | ACCEPT | Summary: PMID:23533145 is a proteomics study of exosomes from prostatic secretions in urine that detected CLU. High-throughput proteomic detection. Reason: CLU detection in extracellular exosomes is consistent with its secreted nature. CLU is found in various extracellular vesicle preparations. |
| GO:0005615 extracellular space | HDA PMID:16502470 Human colostrum: identification of minor proteins in the aqu... | ACCEPT | Summary: PMID:16502470 identifies CLU in human colostrum by proteomics. Confirms extracellular space localization in a body fluid. Reason: Core extracellular localization confirmed in human colostrum by proteomics. |
| GO:1902004 positive regulation of amyloid-beta formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from orthologue data. CLU can promote amyloid-beta formation at very low CLU:substrate ratios (PMID:17412999). Consistent with the IEA annotation from Ensembl Compara already reviewed. Reason: Dose-dependent secondary effect. At substoichiometric levels, CLU can paradoxically promote amyloid formation, but its primary function is inhibitory. |
| GO:1902998 positive regulation of neurofibrillary tangle assembly | IMP PMID:15897157 Association of apolipoprotein J-positive beta-amyloid plaque... | KEEP AS NON CORE | Summary: PMID:15897157 shows that apoJ-containing conditioned media and hippocampal injection of apoJ increases levels of tau and phosphorylated tau, and apoJ immunopositivity correlates with neuritic dystrophy in AD brain. This suggests CLU facilitates the conversion of diffuse Abeta deposits into amyloid and enhances tau phosphorylation. Reason: This is an indirect, disease-associated effect in the AD brain. CLU promotes tangle assembly through complex mechanisms involving Abeta aggregation and tau phosphorylation. This is a pathological consequence, not a primary molecular function. Supporting Evidence: PMID:15897157 apoJ immunopositivity strongly correlates with the presence of amyloid and associated neuritic dystrophy in the neuropil of AD temporal cortex, and supports a model where extracellular apoJ facilitates the conversion of diffuse Abeta deposits into amyloid and enhances tau phosphorylation in neurites surrounding these of plaques. |
| GO:1902847 regulation of neuronal signal transduction | IMP PMID:21397462 Neural hyperactivation in carriers of the Alzheimer's risk v... | MARK AS OVER ANNOTATED | Summary: PMID:21397462 is an fMRI study showing that carriers of the CLU AD risk variant (rs11136000) have neural hyperactivation during working memory tasks. This is a GWAS variant association study, not a direct demonstration of CLU function in neuronal signal transduction. Reason: This is a GWAS variant association study showing altered brain activation patterns in CLU risk allele carriers. It does not demonstrate a direct molecular role for CLU in neuronal signal transduction. The neural hyperactivation may reflect indirect effects via CLU's roles in Abeta clearance, complement regulation, or lipid transport. |
| GO:0017038 protein import | IDA PMID:24446231 Apolipoproteins E and J interfere with amyloid-beta uptake b... | MODIFY | Summary: PMID:24446231 shows that ApoJ (CLU) interferes with Abeta uptake by primary human astrocytes and microglia. Specifically, ApoJ reduced Abeta oligomer uptake by astrocytes but not microglia. This is more about regulating protein import/clearance than performing the import itself. Reason: PMID:24446231 actually shows CLU reduces Abeta uptake by astrocytes, not promotes it. The term protein import is misleading. CLU regulates Abeta clearance by glial cells but the direction is inhibitory in this study. The annotation to GO:1900221 regulation of amyloid-beta clearance from the same publication is more appropriate. Proposed replacements: regulation of amyloid-beta clearance Supporting Evidence: PMID:24446231 Upon exposure to AΞ² combined with ApoE, ApoJ, Ξ±1-antichymotrypsin (ACT) and a combination of serum amyloid P and complement C1q (SAP-C1q), a clear reduction in astrocytic but not microglial AΞ²oligo uptake, was observed |
| GO:1900221 regulation of amyloid-beta clearance | IDA PMID:24446231 Apolipoproteins E and J interfere with amyloid-beta uptake b... | ACCEPT | Summary: PMID:24446231 demonstrates that CLU modulates Abeta clearance by glial cells. ApoJ reduces astrocytic Abeta oligomer uptake but fibrillar Abeta clearance by microglia is reduced in the presence of AAPs including ApoJ. This demonstrates CLU regulation of Abeta clearance. Reason: Regulation of amyloid-beta clearance is a well-established function of CLU. While PMID:24446231 shows the relationship is complex (CLU can both promote and interfere with clearance depending on cell type and aggregation state), regulation of Abeta clearance is a core function consistent with CLU's chaperone-carrier role. Supporting Evidence: PMID:24446231 Abeta clearance by glial cells is negatively affected by AAPs like ApoE and ApoJ. Thus, targeting the association of Abeta with AAPs, such as ApoE and ApoJ, could serve as a therapeutic strategy to increase Abeta clearance by glial cells. |
| GO:0000902 cell morphogenesis | IDA PMID:15857407 Apolipoprotein J (clusterin) activates rodent microglia in v... | MARK AS OVER ANNOTATED | Summary: PMID:15857407 shows that exogenous CLU activates rodent microglia with changes in morphology, including enlarged cell bodies and processes. Microglial morphological changes are a consequence of activation, not a primary CLU function in cell morphogenesis. Reason: Cell morphogenesis is an over-annotation. The microglial morphological changes observed are secondary to CLU-mediated microglial activation, not a primary function of CLU in cell morphogenesis. CLU is not a morphogen. |
| GO:0001774 microglial cell activation | IDA PMID:15857407 Apolipoprotein J (clusterin) activates rodent microglia in v... | KEEP AS NON CORE | Summary: PMID:15857407 demonstrates that exogenous CLU activates rodent microglia both in vivo (ICV infusion) and in vitro, with enlarged cell bodies, MHCII induction, and increased secretion of NO and TNF-alpha. Reason: Microglial activation by CLU is a well-demonstrated secondary function in the CNS. While not the core chaperone function, it is relevant to CLU's role in neuroinflammation and AD pathobiology. Supporting Evidence: PMID:15857407 exogenous apoJ activates rodent microglia in vivo and in vitro |
| GO:0005737 cytoplasm | IDA PMID:9560017 Possible neuroprotective role of clusterin in Alzheimer's di... | KEEP AS NON CORE | Summary: PMID:9560017 is an immunocytochemical study of CLU in AD brain showing clusterin immunoreactivity in NFT-free neurons of affected cortical areas. Cytoplasmic localization in neurons was observed by immunohistochemistry. Reason: Cytoplasmic CLU immunoreactivity in AD brain neurons. This is a secondary localization, likely reflecting internalized extracellular CLU or intracellular isoforms. |
| GO:0061518 microglial cell proliferation | IDA PMID:15857407 Apolipoprotein J (clusterin) activates rodent microglia in v... | KEEP AS NON CORE | Summary: PMID:15857407 shows CLU activates microglia with morphological changes and inflammatory responses. While activation can include proliferation, the paper primarily demonstrates activation phenotype rather than proliferation specifically. Reason: Microglial proliferation induced by CLU is a secondary effect related to its role in neuroinflammation. Not the core molecular function. |
| GO:0097418 neurofibrillary tangle | IDA PMID:9560017 Possible neuroprotective role of clusterin in Alzheimer's di... | KEEP AS NON CORE | Summary: PMID:9560017 shows clusterin immunoreactivity in neuropil threads and neurofibrillary tangles (NFTs) in AD brain by immunocytochemistry. CLU was detected in NFT-containing neurons and in neuropil threads. Reason: CLU localization to neurofibrillary tangles is a disease-associated pathological finding in AD brain, not a normal functional localization. Reflects CLU's association with aggregated tau. |
| GO:0097440 apical dendrite | IDA PMID:9560017 Possible neuroprotective role of clusterin in Alzheimer's di... | KEEP AS NON CORE | Summary: PMID:9560017 is an immunocytochemical study in AD brain. Clusterin immunoreactivity was observed in neurons of affected cortical areas including apical dendrites. This likely reflects CLU association with degenerating neuronal processes. Reason: Apical dendrite localization is a disease-associated finding in AD brain. CLU is not normally a dendritic protein; this reflects its association with degenerating neuronal compartments in AD. |
| GO:1902430 negative regulation of amyloid-beta formation | IDA PMID:12047389 Suppression of apolipoprotein C-II amyloid formation by the ... | ACCEPT | Summary: PMID:12047389 demonstrates that substoichiometric levels of CLU potently inhibit amyloid formation by apolipoprotein C-II. CLU inhibits fibril growth by interacting with transient amyloid nuclei. While the substrate is apoC-II rather than Abeta, the mechanism is analogous. Reason: While PMID:12047389 specifically studies apoC-II amyloid, CLU inhibits amyloid formation by diverse substrates including Abeta. Negative regulation of amyloid-beta formation is a core function. Supporting Evidence: PMID:12047389 Sub-stoichiometric levels of clusterin, derived from either plasma or semen, potently inhibit amyloid formation by apoC-II. |
| GO:1902430 negative regulation of amyloid-beta formation | IDA PMID:17412999 The extracellular chaperone clusterin influences amyloid for... | ACCEPT | Summary: PMID:17412999 directly demonstrates that CLU at substoichiometric levels (e.g., CLU:substrate=1:10) potently inhibits amyloid formation by Abeta peptide and provides cytoprotection. Reason: Core function of CLU. Direct demonstration that CLU inhibits Abeta amyloid formation at physiologically relevant ratios. Supporting Evidence: PMID:17412999 when clusterin is present at much higher but still substoichiometric levels (e.g., a molar ratio of clusterin:substrate=1:10), it potently inhibits amyloid formation and provides substantial cytoprotection. |
| GO:0032286 central nervous system myelin maintenance | IMP PMID:21543606 Common Alzheimer's disease risk variant within the CLU gene ... | MARK AS OVER ANNOTATED | Summary: PMID:21543606 is an imaging genetics study showing that the CLU AD risk variant (rs11136000 C allele) is associated with lower white matter integrity (fractional anisotropy) in young healthy adults. This is a genetic association, not a direct demonstration of CLU function in myelin maintenance. Reason: This is a GWAS variant association with brain imaging measures, not a direct demonstration of CLU function in CNS myelin maintenance. The association between CLU genotype and white matter integrity may reflect indirect effects through lipid transport, complement regulation, or other mechanisms. |
| GO:0051131 chaperone-mediated protein complex assembly | IDA PMID:17412999 The extracellular chaperone clusterin influences amyloid for... | KEEP AS NON CORE | Summary: PMID:17412999 shows that CLU interacts with prefibrillar species and can co-incorporate into insoluble aggregates at low CLU:substrate ratios. At very low ratios, CLU can promote complex assembly, but this is a secondary dose-dependent effect. The term chaperone-mediated protein complex assembly could also reflect CLU forming HMW complexes with client proteins as part of its holdase function. Reason: CLU forms high-molecular-weight complexes with client proteins as part of its holdase chaperone function. At substoichiometric ratios it can also promote assembly of amyloid complexes. This annotation captures a secondary aspect of CLU chaperone activity. |
| GO:0097418 neurofibrillary tangle | IDA PMID:15897157 Association of apolipoprotein J-positive beta-amyloid plaque... | KEEP AS NON CORE | Summary: PMID:15897157 shows apoJ immunoreactivity at the core of beta-amyloid plaques associated with dystrophic neurites in AD brain. ApoJ co-localizes with thioflavine-S-positive amyloid cores and phospho-tau-positive neuritic deposits. Reason: CLU localization to neurofibrillary tangles is a disease-associated pathological finding. Reflects CLU's co-localization with amyloid and tau pathology in AD, consistent with its chaperone function but not a normal subcellular localization. Supporting Evidence: PMID:15897157 Of Abeta deposits with apoJ immunopositivity, 71% were associated with phospho-tau-positive dystrophic neurites in the surrounding tissue. |
| GO:0072562 blood microparticle | HDA PMID:22516433 Proteomic analysis of microvesicles from plasma of healthy d... | ACCEPT | Summary: PMID:22516433 is a proteomic analysis of microvesicles from healthy donor plasma that detected CLU. High-throughput proteomic detection. Reason: CLU is found in blood microparticles, consistent with its presence in various extracellular compartments as a secreted glycoprotein. |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | ACCEPT | Summary: PMID:19199708 is a proteomic analysis of human parotid gland exosomes that detected CLU. High-throughput proteomic detection. Reason: CLU detection in exosomes is consistent with its secreted nature and broad extracellular distribution. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | ACCEPT | Summary: PMID:19056867 is a proteomics study of urinary exosomes that detected CLU. High-throughput proteomic detection. Reason: CLU detection in urinary exosomes is consistent with its presence in body fluids and extracellular vesicles. |
| GO:1902230 negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage | IMP PMID:16113678 Clusterin inhibits apoptosis by interacting with activated B... | KEEP AS NON CORE | Summary: PMID:16113678 shows that intracellular CLU inhibits apoptosis by interacting with activated BAX in mitochondria, preventing BAX oligomerization and cytochrome c release. CLU inhibits chemotherapeutic drug-mediated and c-Myc-mediated apoptosis. Reason: Negative regulation of intrinsic apoptotic signaling is a well-supported secondary function of intracellular CLU, but represents the cancer-related anti-apoptotic activity, not the core extracellular chaperone function. Supporting Evidence: PMID:16113678 intracellular clusterin inhibits apoptosis by interfering with Bax activation in mitochondria |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-481007 | ACCEPT | Summary: Reactome R-HSA-481007 describes exocytosis of platelet alpha granule contents. CLU is released from platelet alpha granules into the extracellular space upon platelet activation. Reason: Core extracellular localization confirmed by Reactome pathway for platelet alpha granule exocytosis. |
| GO:0031093 platelet alpha granule lumen | TAS Reactome:R-HSA-481007 | KEEP AS NON CORE | Summary: Reactome R-HSA-481007 describes CLU as a component of platelet alpha granule contents that are released upon platelet activation. Reason: Platelet alpha granule lumen is a specialized storage localization for CLU prior to secretion upon platelet activation. Valid but specialized localization, not the primary functional site. |
| GO:0031625 ubiquitin protein ligase binding | IDA PMID:20068069 Clusterin facilitates COMMD1 and I-kappaB degradation to enh... | KEEP AS NON CORE | Summary: PMID:20068069 demonstrates that sCLU interacts with members of the SCF-betaTrCP E3 ubiquitin ligase family to enhance COMMD1 and I-kappaB proteasomal degradation. CLU acts as a ubiquitin-binding protein that bridges substrates to the E3 ligase complex. Reason: Ubiquitin protein ligase binding is a validated MF for intracellular CLU in the cancer context. This is a secondary intracellular function demonstrated in prostate cancer cells, not the core extracellular chaperone activity. Supporting Evidence: PMID:20068069 sCLU increases NF-kappaB nuclear translocation and transcriptional activity by serving as a ubiquitin-binding protein that enhances COMMD1 and I-kappaB proteasomal degradation by interacting with members of the SCF-betaTrCP E3 ligase family. |
| GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process | IMP PMID:20068069 Clusterin facilitates COMMD1 and I-kappaB degradation to enh... | KEEP AS NON CORE | Summary: PMID:20068069 demonstrates that sCLU enhances COMMD1 and I-kappaB proteasomal degradation. Knockdown of sCLU stabilizes COMMD1 and I-kappaB, confirming CLU promotes proteasomal degradation. Reason: This function is demonstrated for intracellular CLU in prostate cancer cells. Consistent with the IBA annotation already reviewed. Secondary intracellular activity. |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:20068069 Clusterin facilitates COMMD1 and I-kappaB degradation to enh... | KEEP AS NON CORE | Summary: PMID:20068069 detects CLU in perinuclear foci in prostate cancer cells, potentially representing aggresomes containing misfolded ubiquitinated proteins. UniProt notes perinuclear foci that may be aggresomes. Reason: Perinuclear localization in cancer cells is documented but represents a secondary intracellular localization, not the primary extracellular site. |
| GO:2000060 positive regulation of ubiquitin-dependent protein catabolic process | IMP PMID:20068069 Clusterin facilitates COMMD1 and I-kappaB degradation to enh... | KEEP AS NON CORE | Summary: PMID:20068069 shows CLU promotes ubiquitin-dependent degradation of COMMD1 and I-kappaB. This is the parent term of GO:0032436. Both annotations from the same paper are valid. Reason: Broader term covering the same intracellular function as GO:0032436. Valid but secondary to the core extracellular chaperone function. |
| GO:0005615 extracellular space | IDA PMID:11123922 Clusterin is an ATP-independent chaperone with very broad su... | ACCEPT | Summary: PMID:11123922 is the landmark study establishing CLU as the first identified secreted mammalian chaperone. CLU inhibits stress-induced precipitation of proteins in undiluted human serum, confirming extracellular space as the primary functional site. Reason: Core localization. This is the definitive study establishing CLU as an extracellular chaperone functioning in the extracellular space. Supporting Evidence: PMID:11123922 at physiological levels, clusterin inhibits stress-induced precipitation of proteins in undiluted human serum. Clusterin represents the first identified secreted mammalian chaperone. |
| GO:0006457 protein folding | IDA PMID:11123922 Clusterin is an ATP-independent chaperone with very broad su... | ACCEPT | Summary: PMID:11123922 shows CLU stabilizes stressed proteins in a folding-competent state for subsequent refolding by HSP70. CLU itself does not refold proteins. The annotation to protein folding is appropriate as CLU participates in the protein folding process by preventing irreversible aggregation and maintaining proteins in a refolding-competent state. Reason: CLU participates in the protein folding process as a holdase chaperone that maintains misfolded proteins in a state competent for refolding by downstream ATP-dependent chaperones. Core biological process. Supporting Evidence: PMID:11123922 stabilizes stressed proteins in a state competent for refolding by heat shock protein 70 (HSP70) |
| GO:0050821 protein stabilization | IDA PMID:11123922 Clusterin is an ATP-independent chaperone with very broad su... | ACCEPT | Summary: PMID:11123922 directly demonstrates that CLU stabilizes stressed proteins by forming soluble high-molecular-weight complexes, preventing irreversible precipitation. This is the core holdase function. Reason: Protein stabilization is the most accurate BP term for CLU's core holdase chaperone function. CLU prevents irreversible aggregation by binding and stabilizing misfolded proteins. Supporting Evidence: PMID:11123922 binds irreversibly via an ATP-independent mechanism to stressed proteins to form solubilized high molecular weight complexes |
| GO:0051787 misfolded protein binding | IDA PMID:11123922 Clusterin is an ATP-independent chaperone with very broad su... | ACCEPT | Summary: PMID:11123922 demonstrates that CLU binds a very broad range of structurally divergent stressed/misfolded protein substrates via ATP-independent mechanism. This is the core MF of CLU. Reason: Core molecular function. CLU binds misfolded/stressed proteins with very broad substrate specificity. Definitive direct assay evidence. Supporting Evidence: PMID:11123922 In this study, we demonstrate that clusterin (i) inhibits stress-induced precipitation of a very broad range of structurally divergent protein substrates |
| GO:0005615 extracellular space | IDA PMID:19996109 Identification of human plasma proteins as major clients for... | ACCEPT | Summary: PMID:19996109 identifies major plasma protein clients for CLU by studying CLU-client complexes formed under physiologically relevant shear stress. Confirms CLU functions in the extracellular space (plasma). Reason: Core extracellular localization. CLU forms chaperone-client complexes with plasma proteins under physiological stress conditions. |
| GO:0051787 misfolded protein binding | IPI PMID:19996109 Identification of human plasma proteins as major clients for... | ACCEPT | Summary: PMID:19996109 identifies ceruloplasmin, fibrinogen, and albumin as major plasma clients for CLU under shear stress. CLU-client complexes were detected by co-purification and sandwich ELISA. Reason: Core MF. Identifies specific plasma protein clients for CLU chaperone activity, demonstrating misfolded protein binding in a physiological context. Supporting Evidence: PMID:19996109 These proteins were identified by mass spectrometry as ceruloplasmin, fibrinogen, and albumin. |
| GO:0051788 response to misfolded protein | IDA PMID:19996109 Identification of human plasma proteins as major clients for... | ACCEPT | Summary: PMID:19996109 shows CLU responds to misfolded proteins in plasma by forming soluble HMW complexes with stressed clients, preventing their aggregation. This BP captures CLU's role in the cellular/organismal response to misfolded proteins. Reason: Core biological process. CLU is a primary responder to misfolded proteins in the extracellular space, forming complexes to prevent aggregation and facilitate clearance. |
| GO:0009615 response to virus | IEP PMID:16548883 Transcriptomic and proteomic analyses of rhabdomyosarcoma ce... | MARK AS OVER ANNOTATED | Summary: PMID:16548883 shows CLU is differentially expressed in response to enterovirus 71 infection in rhabdomyosarcoma cells. This is an expression pattern observation (IEP), not a functional demonstration. Reason: IEP evidence showing CLU expression changes during viral infection. CLU is a stress-response protein whose expression changes under many stress conditions. Differential expression during viral infection does not demonstrate a specific role in antiviral response. |
| GO:0005515 protein binding | IPI PMID:16113678 Clusterin inhibits apoptosis by interacting with activated B... | MARK AS OVER ANNOTATED | Summary: PMID:16113678 shows CLU interacts with activated BAX at mitochondria. Protein binding is uninformative; the specific interaction with BAX is functionally important for CLU's anti-apoptotic activity. Reason: Protein binding is uninformative. The CLU-BAX interaction is specific and functionally important but the generic term adds no value. More specific annotations already capture this activity. |
| GO:0005615 extracellular space | IDA PMID:16113678 Clusterin inhibits apoptosis by interacting with activated B... | ACCEPT | Summary: PMID:16113678 detects secreted CLU in the extracellular space (culture media) of cancer cells. Confirms core localization. Reason: Core extracellular localization confirmed in cell culture media. |
| GO:0005739 mitochondrion | IDA PMID:16113678 Clusterin inhibits apoptosis by interacting with activated B... | KEEP AS NON CORE | Summary: PMID:16113678 shows intracellular CLU localizes to mitochondria in response to chemotherapeutic drugs and interacts with activated BAX to inhibit apoptosis. Reason: Mitochondrial localization is stress-induced and relates to the anti-apoptotic function of intracellular CLU. Not the primary extracellular localization. Supporting Evidence: PMID:16113678 intracellular clusterin inhibits apoptosis by interfering with Bax activation in mitochondria |
| GO:0034366 spherical high-density lipoprotein particle | IDA PMID:16682745 Isolation and characterization of human apolipoprotein M-con... | ACCEPT | Summary: PMID:16682745 identifies apoJ (CLU) among proteins in apoM-containing HDL particles by mass spectrometry. CLU is a well-known component of HDL particles in plasma (PMID:2387851). Reason: CLU is a core component of HDL particles, where it functions as apolipoprotein J. This is a well-established localization consistent with its dual role as chaperone and apolipoprotein. Supporting Evidence: PMID:16682745 Mass spectrometry showed that the apoM-containing lipoproteins also contained apoJ, apoA-I, apoA-II, apoC-I, apoC-II, apoC-III, paraoxonase 1, and apoB. |
| GO:0043691 reverse cholesterol transport | TAS PMID:16682745 Isolation and characterization of human apolipoprotein M-con... | KEEP AS NON CORE | Summary: PMID:16682745 characterizes apoM-containing HDL particles and their role in cholesterol efflux. CLU is present on HDL particles that stimulate cholesterol efflux from THP-1 foam cells. CLU's role in reverse cholesterol transport is secondary to its primary chaperone function. Reason: CLU associates with HDL particles and may participate in reverse cholesterol transport as an apolipoprotein, but this is a secondary function. CLU's primary role on HDL is likely chaperone-related rather than lipid transport per se. |
| GO:0006629 lipid metabolic process | NAS PMID:2387851 Purification and characterization of apolipoprotein J. | KEEP AS NON CORE | Summary: PMID:2387851 is the original characterization of apolipoprotein J (CLU) as a component of HDL. CLU is an apolipoprotein that associates with lipid particles, but its primary function is protein chaperoning rather than lipid metabolism. Reason: CLU is an apolipoprotein associated with HDL, but its primary molecular function is as a holdase chaperone, not lipid metabolism. The NAS evidence code reflects a non-traceable statement. Lipid metabolic process is a very broad term. |
| GO:0006956 complement activation | TAS PMID:1585460 Clusterin: the intriguing guises of a widely expressed glyco... | MODIFY | Summary: PMID:1585460 is the early review describing CLU's participation in the terminal complement reaction. CLU inhibits complement rather than activating it, so the term complement activation is technically inaccurate for CLU's role. More specific terms (GO:0045916 negative regulation of complement activation) are already annotated. Reason: CLU is a complement inhibitor, not an activator. The term complement activation is misleading. While CLU participates in complement biology, its role is inhibitory. The more accurate term GO:0045916 negative regulation of complement activation is already annotated via IDA. Proposed replacements: negative regulation of complement activation Supporting Evidence: PMID:1585460 participates in the terminal complement reaction |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: Which endogenous CLU glycoforms, proteolytic states, redox states, pH ranges, and hydrophobic-tail conformations determine extracellular holdase strength, client selectivity, and receptor engagement in vivo?
Suggested experts: extracellular proteostasis expert, clusterin structural biochemist, glycoprotein biology expert
Q: Which receptors dominate CLU-client clearance in different tissues and cell types, including LRP2/megalin, VLDLR, LRP8/ApoER2, TREM2, and any additional receptors?
Suggested experts: lipoprotein receptor biologist, microglia biology expert, epithelial protein-clearance expert
Q: What determines the substrate-ratio-dependent switch between CLU-mediated inhibition and promotion of amyloid assembly, and how often does the pro-assembly state occur under physiological extracellular conditions?
Suggested experts: amyloid biophysicist, extracellular chaperone expert
Q: Which intracellular or nuclear CLU isoforms have evolved in-vivo functions, rather than representing rare translation products, failed translocation, or stress-induced relocalization?
Suggested experts: CLU isoform expert, cell stress and trafficking expert
Experiment: Generate endogenous CLU alleles or knock-in rescue systems that separate secreted CLU, hydrophobic-tail mutants, glycosylation-site mutants, and cleavage-state variants, then measure client binding, aggregation suppression, complement MAC inhibition, receptor uptake, and extracellular localization.
Hypothesis: CLU's extracellular holdase, complement-regulatory, and receptor-carrier activities depend on separable structural features and post-translational states.
Type: endogenous mutagenesis and biochemical rescue
Experiment: Use cell-type-specific receptor perturbation in brain, kidney, and vascular models to quantify uptake and degradation of defined CLU-client complexes through LRP2, VLDLR, LRP8, TREM2, and candidate receptors.
Hypothesis: CLU-client clearance uses different receptor hierarchies in distinct extracellular compartments and cell types.
Type: receptor knockout or knockdown with labeled client-clearance assays
Experiment: Titrate CLU and structurally defined client proteins at physiological concentrations in extracellular matrix, CSF-like, plasma-like, and mildly acidic microenvironments, then measure soluble complex formation, amyloid nucleation, fibril growth, and receptor uptake.
Hypothesis: The apparent pro-amyloid versus anti-amyloid effect of CLU is governed by local CLU:client ratio, client conformation, pH, and clearance capacity.
Type: quantitative in-vitro and ex-vivo extracellular proteostasis assay
Experiment: Build isoform-specific CLU reporters and rescue alleles that distinguish secreted, cytosolic, nuclear, and mitochondrial CLU forms under physiological and stress conditions in vivo.
Hypothesis: Most CLU function is carried by the secreted isoform, while intracellular forms have narrower stress- or cell-state-specific roles.
Type: isoform-specific reporter and rescue genetics
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)