Hspa8 (UniProt P63018; HSP7C_RAT) encodes the rat Heat shock cognate 71 kDa protein, the constitutively expressed cytosolic HSP70-family chaperone known as HSC70/HSC73. Unlike the stress-inducible Hspa1a/Hspa1b (HSP70) paralogs, HSC70 is expressed under basal conditions and is the housekeeping HSP70. Its core molecular function is an ATP-dependent (EC 3.6.4.10) protein-folding chaperone activity built on the canonical HSP70 architecture: an N-terminal nucleotide-binding/ATPase domain and a C-terminal substrate-binding domain with a helical lid, whose nucleotide state (ATP = low affinity/fast client exchange; ADP = high affinity) governs cyclic binding and release of unfolded/misfolded client polypeptides. The ATPase cycle is driven by J-domain (HSP40/DNAJ) co-chaperones that stimulate ATP hydrolysis and reset by nucleotide-exchange factors. Three best-supported, mechanistically distinct roles emerge: (1) general proteostasis - protein folding, refolding, unfolding and disassembly of protein complexes; (2) clathrin-coated vesicle uncoating - the clathrin-uncoating ATPase activity in which the J-domain co-chaperone auxilin (DNAJC6) recruits HSC70 to clathrin-coated vesicles and stimulates its ATPase to disassemble clathrin coats, central to clathrin-mediated endocytosis and synaptic vesicle recycling; and (3) chaperone-mediated autophagy (CMA) - cytosolic HSC70 recognizes KFERQ-like pentapeptide motifs in soluble client proteins and delivers them to LAMP-2A at the lysosomal membrane, with lysosomal HSC70 supporting translocation into the lysosomal lumen for degradation. HSC70 acts predominantly in the cytosol, with additional functional pools at the lysosomal membrane/lumen and at endocytic/synaptic trafficking structures. It is a highly pleiotropic protein, with further context-specific roles in endosomal microautophagy, chaperone-assisted selective autophagy, synaptic scaffold regulation, pre-mRNA splicing and antigen presentation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Manual review: HSC70 has documented nuclear/nucleolar pools (e.g. nuclear import roles), but the nucleus is not the site of its core chaperone, clathrin-uncoating, or CMA functions. Reason: Valid localization but peripheral to the evolved cytosolic chaperone function. Supporting Evidence: UniProtKB:P63018 Translocates rapidly from the cytoplasm to the nuclei, and especially to the nucleoli, upon heat shock. UniProtKB:P63018 Nucleus, nucleolus {ECO:0000250|UniProtKB:P11142}. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Manual review: cytoplasm is consistent with known biology of Hspa8. Reason: Cytoplasm is the principal compartment of HSC70 chaperone activity, recorded as the primary subcellular location in UniProt; the PAINT node placement for the HSP70 cytosolic clade is sound for this constitutive paralog. Supporting Evidence: UniProtKB:P63018 SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P11142}. file:rat/Hspa8/Hspa8-deep-research-falcon.md **Cytosol**: the predominant pool performing general chaperoning and recognizing CMA substrates (KFERQ-like motifs) |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Manual review: plasma membrane is not the site of the core chaperone function of HSC70, which acts in the cytosol; surface/extracellular pools are context-specific (e.g. exosomal/cell-surface) and do not represent the evolved function. Reason: Changed from MARK_AS_OVER_ANNOTATED for consistency with the IEA and ISS plasma membrane rows. There is positive evidence for a peripheral cell-membrane/cell-surface pool of HSC70, but it is not where the core function is performed. The IBA itself was a weak propagation: the PAINT node no longer carries this IBD (see propagation_review). GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. Propagation Review Root cause: SOURCE STALE OR MISSING Failure modes: COMPARTMENT OR COMPLEX MISMATCH CONTEXT OR TISSUE MISMATCH Sources checked: PANTHER:PTN002500132 Β· PANTHER:PTN002500132 SOURCE STALE OR MISSING The GOA WITH/FROM names this node with mostly fungal (Candida) cell-surface members as seeds, but no IBD for GO:0005886 remains anywhere in the current PTHR19375 PAINT slice (snapshot rows dated through 2026-08-28); the node now carries only nucleus (GO:0005634) and cytosol (GO:0005829). PAINT has therefore withdrawn or re-scoped the plasma-membrane assertion: the propagated compartment reflected fungal cell-surface contexts. The rat plasma-membrane localization rests instead on the ISS/IEA evidence for a peripheral cell-membrane pool, and the core HSC70 chaperone cycle is cytosolic. Supporting Evidence: UniProtKB:P63018 Cell membrane {ECO:0000250|UniProtKB:P11142}. |
| GO:0016887 ATP hydrolysis activity | IBA GO_REF:0000033 | ACCEPT | Summary: Manual review: ATP hydrolysis activity underpins the ATP-dependent chaperone cycle of Hspa8/HSC70, in which the nucleotide state controls client affinity and is regulated by J-domain co-chaperones. Reason: Retained as supporting the core ATP-driven chaperone cycle, corroborated by falcon deep research. Supporting Evidence: file:rat/Hspa8/Hspa8-deep-research-falcon.md nucleotide state controls substrate affinity (ATP-bound low affinity/fast exchange; ADP-bound high affinity/slow exchange) UniProtKB:P63018 Reaction=ATP + H2O = ADP + phosphate + H(+) UniProtKB:P63018 This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones. |
| GO:0031072 heat shock protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: Manual review: heat shock protein binding is consistent with known biology of Hspa8. Reason: Binding to J-domain (Hsp40) and Hsp90/Hop co-chaperones is intrinsic to the HSC70 ATPase cycle, and the rat protein has direct experimental support for these interactions; the IBA is consistent. Supporting Evidence: PMID:9528774 mediates the interaction of Hsc70 with Hsp40 and Hop UniProtKB:P63018 Interacts with HOPX, STUB1, HSP40, HSP90, BAG2 and BAG3 |
| GO:0044183 protein folding chaperone | IBA GO_REF:0000033 | ACCEPT | Summary: Manual review: protein folding chaperone is the core molecular function of Hspa8/HSC70; the constitutive HSP70-family ATP-dependent chaperone that assists folding, refolding, unfolding and complex disassembly of client proteins. Reason: Retained as the core molecular function, corroborated by falcon deep research. Supporting Evidence: file:rat/Hspa8/Hspa8-deep-research-falcon.md Hspa8/HSC70 is a **constitutive** HSP70-family **ATPase chaperone** that supports proteostasis by assisting **protein folding/refolding**, **unfolding**, and **disassembly of protein complexes** |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Manual review: cytosol is consistent with known biology of Hspa8. Reason: The cytosol is the predominant site of HSC70 general chaperoning and CMA substrate recognition. Supporting Evidence: file:rat/Hspa8/Hspa8-deep-research-falcon.md **Cytosol**: the predominant pool performing general chaperoning and recognizing CMA substrates (KFERQ-like motifs) UniProtKB:P63018 SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P11142}. |
| GO:0072318 clathrin coat disassembly | IBA GO_REF:0000033 | ACCEPT | Summary: Manual review: clathrin coat disassembly is a core process for Hspa8/HSC70; the auxilin (DNAJC6)-recruited HSC70 ATPase disassembles clathrin coats from clathrin-coated vesicles. Reason: Retained as a core process, corroborated by falcon deep research. Supporting Evidence: file:rat/Hspa8/Hspa8-deep-research-falcon.md the **J-domain co-chaperone auxilin (DNAJC6)** recruits HSC70 to CCVs and **stimulates HSC70 ATPase activity** to disassemble clathrin coats |
| GO:0042026 protein refolding | IBA GO_REF:0000033 | ACCEPT | Summary: Manual review: protein refolding is consistent with known biology of Hspa8. Reason: Refolding of denatured client proteins is a direct, assayed activity of rat hsc70 (DnaJ-dependent luciferase refolding); the IBA agrees with target-specific evidence. Supporting Evidence: PMID:11360998 In the presence of DnaJ, the capability of hsc70(R469C) to refold the denatured luciferase was decreased by 50%. UniProtKB:P63018 Plays a pivotal role in the protein quality control system, ensuring the correct folding of proteins, the re-folding of misfolded proteins and controlling the targeting of proteins for subsequent degradation. |
| GO:0007165 signal transduction | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: Manual review: signal transduction is an over-broad inter-ontology IEA inference; HSC70 is a chaperone and does not act as a signal transducer. This generic term over-annotates the gene. Reason: Over-broad IEA inference that does not reflect the evolved chaperone function of HSC70. |
| GO:0000166 nucleotide binding | IEA GO_REF:0000043 | ACCEPT | Summary: Manual review: nucleotide binding is consistent with known biology of Hspa8. Reason: Retained as supported or plausible for this gene and evidence context. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. Supporting Evidence: UniProtKB:P63018 The N-terminal nucleotide binding domain (NBD) (also known as the ATPase domain) is responsible for binding and hydrolyzing ATP. |
| GO:0001916 positive regulation of T cell mediated cytotoxicity | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Manual review: positive regulation of T cell mediated cytotoxicity may be context-dependent or peripheral for Hspa8. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. Supporting Evidence: PMID:8871636 these data suggest that the complex of peptide Ag and hsc70 is involved in the cytotoxic mechanism between hsc70 and DNT cells |
| GO:0005524 ATP binding | IEA GO_REF:0000120 | ACCEPT | Summary: Manual review: ATP binding is consistent with known biology of Hspa8. Reason: Retained as supported or plausible for this gene and evidence context. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. Supporting Evidence: UniProtKB:P63018 The N-terminal nucleotide binding domain (NBD) (also known as the ATPase domain) is responsible for binding and hydrolyzing ATP. PMID:8363588 Binding of [alpha-32P]ATP by purified recombinant hsc70 was analysed by Scatchard plot. |
| GO:0005681 spliceosomal complex | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: Manual review: spliceosomal complex may be context-dependent or peripheral for Hspa8. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. Supporting Evidence: UniProtKB:P63018 Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. |
| GO:0005730 nucleolus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Manual review: nucleolus may be context-dependent or peripheral for Hspa8. Reason: Nucleolar localization is documented for rat hsc70 (heat-shock-induced nucleolar accumulation) but is not where its core functions are performed. Supporting Evidence: UniProtKB:P63018 Nucleus, nucleolus {ECO:0000250|UniProtKB:P11142}. PMID:8955942 with hsc70 protein also being localized in nucleoli |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Manual review: cytoplasm is consistent with known biology of Hspa8. Reason: Cytoplasm is the principal compartment of HSC70 activity (UniProt subcellular location). Supporting Evidence: UniProtKB:P63018 SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P11142}. |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Manual review: the lysosomal membrane is a functional location of the core chaperone-mediated autophagy role of HSC70, where the chaperone-substrate complex engages LAMP-2A; this electronic annotation is consistent with the experimentally supported IDA annotations to the same term. Reason: Lysosomal membrane is a bona fide functional location for the core CMA role of HSC70 (experimentally supported by PMID:18644871 and PMID:9038169); accepted for consistency with those IDA annotations. Supporting Evidence: UniProtKB:P63018 Lysosome membrane {ECO:0000250|UniProtKB:P11142}; Peripheral membrane protein {ECO:0000250|UniProtKB:P11142}; Cytoplasmic side PMID:11559757 is associated with the cytosolic side of the lysosomal membrane where it binds to substrates of this proteolytic pathway |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Plasma membrane (cell membrane) is recorded in UniProt by similarity to human HSPA8, and rat studies show a cell-surface hsc70 pool and hsc73 assembled with A1 adenosine receptors at the cell membrane. Reason: Changed from MARK_AS_OVER_ANNOTATED: the earlier call rested only on the plasma membrane not being the core site, which is a reason for non-core status, not for over-annotation. There is positive evidence for a peripheral cell-membrane/cell-surface pool, so the localization is kept as non-core. Supporting Evidence: UniProtKB:P63018 Cell membrane {ECO:0000250|UniProtKB:P11142}. PMID:10866672 The heat shock cognate protein hsc73 assembles with A(1) adenosine receptors to form functional modules in the cell membrane. PMID:8228242 the cell surface expression of Ag was clearly enhanced by several stressors |
| GO:0006397 mRNA processing | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: Manual review: mRNA processing may be context-dependent or peripheral for Hspa8. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. Supporting Evidence: UniProtKB:P63018 Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. |
| GO:0006914 autophagy | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Manual review: autophagy may be context-dependent or peripheral for Hspa8. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. Supporting Evidence: UniProtKB:P63018 HSPA8/HSC70 specifically recognizes and binds cytosolic proteins bearing a -KFERQ motif and promotes their recruitment to the surface of the lysosome where they bind to lysosomal protein LAMP2. |
| GO:0008289 lipid binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Manual review: lipid binding may be context-dependent or peripheral for Hspa8. Reason: HSC70 binds lipids in specific contexts (bacterial LPS; electrostatic binding of its cationic domain to endosomal membrane phospholipids in endosomal microautophagy); real but peripheral to the chaperone core. Supporting Evidence: UniProtKB:P63018 Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion by monocytes. PMID:21238931 Protein cargo selection is mediated by the chaperone hsc70 and requires the cationic domain of hsc70 for electrostatic interactions with the endosomal membrane. |
| GO:0008380 RNA splicing | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: Manual review: RNA splicing may be context-dependent or peripheral for Hspa8. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. Supporting Evidence: UniProtKB:P63018 Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. |
| GO:0016787 hydrolase activity | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: Manual review: HSC70 is indeed a hydrolase (an ATPase, EC 3.6.4.10), so GO:0016787 is not factually wrong, but it is an over-broad parent term. The more specific GO:0016887 (ATP hydrolysis activity) is already ACCEPTed and captures the actual catalytic function. Reason: GO:0016887 (ATP hydrolysis activity) is already ACCEPTed and is more specific; GO:0016787 (hydrolase activity) is the over-broad parent and is redundant. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000120 | ACCEPT | Summary: Manual review: ATP hydrolysis activity is consistent with known biology of Hspa8. Reason: ATP hydrolysis (EC 3.6.4.10) drives the HSC70 chaperone cycle; core activity. Supporting Evidence: UniProtKB:P63018 Reaction=ATP + H2O = ADP + phosphate + H(+) UniProtKB:P63018 This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones. |
| GO:0042470 melanosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Manual review: melanosome may be context-dependent or peripheral for Hspa8. Reason: Melanosome localization is recorded by similarity to human HSPA8 (proteomic and experimental data on the human protein); a valid but peripheral location. Supporting Evidence: UniProtKB:P63018 Melanosome {ECO:0000250|UniProtKB:P11142}. |
| GO:0043066 negative regulation of apoptotic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Manual review: negative regulation of apoptotic process may be context-dependent or peripheral for Hspa8. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. Supporting Evidence: PMID:26212789 BBC3 associates with HSPA8/HSC70 (heat shock 70kDa protein 8), leading to its lysosome translocation and uptake. |
| GO:0043168 anion binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Manual review: anion binding may be context-dependent or peripheral for Hspa8. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. Supporting Evidence: UniProtKB:P63018 The N-terminal nucleotide binding domain (NBD) (also known as the ATPase domain) is responsible for binding and hydrolyzing ATP. |
| GO:0001786 phosphatidylserine binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Manual review: phosphatidylserine binding may be context-dependent or peripheral for Hspa8. Reason: Phosphatidylserine binding is supported in mouse Hsc70 by the endosomal microautophagy work, where the cationic domain of hsc70 binds the endosomal membrane electrostatically; peripheral to core chaperone function. Supporting Evidence: PMID:21238931 Protein cargo selection is mediated by the chaperone hsc70 and requires the cationic domain of hsc70 for electrostatic interactions with the endosomal membrane. |
| GO:0005770 late endosome | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Manual review: late endosome may be context-dependent or peripheral for Hspa8. Reason: Late endosome association reflects the endosomal microautophagy role demonstrated for mouse Hsc70; non-core location. Supporting Evidence: PMID:21238931 identify a microautophagy-like process that delivers soluble cytosolic proteins to the vesicles of late endosomes/multivesicular bodies (MVBs) PMID:21238931 Protein cargo selection is mediated by the chaperone hsc70 and requires the cationic domain of hsc70 for electrostatic interactions with the endosomal membrane. |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: Manual review: cytosol is consistent with known biology of Hspa8. Reason: The cytosol is the predominant site of HSC70 general chaperoning and CMA substrate recognition. Supporting Evidence: file:rat/Hspa8/Hspa8-deep-research-falcon.md **Cytosol**: the predominant pool performing general chaperoning and recognizing CMA substrates (KFERQ-like motifs) |
| GO:0030674 protein-macromolecule adaptor activity | IEA GO_REF:0000107 | ACCEPT | Summary: Manual review: protein-macromolecule adaptor activity is consistent with known biology of Hspa8. Reason: In CMA HSC70 binds KFERQ-motif clients and brings them to LAMP-2A at the lysosome, an adaptor-like bridging role captured by this term. Supporting Evidence: UniProtKB:P63018 HSPA8/HSC70 specifically recognizes and binds cytosolic proteins bearing a -KFERQ motif and promotes their recruitment to the surface of the lysosome where they bind to lysosomal protein LAMP2. file:rat/Hspa8/Hspa8-deep-research-falcon.md recognition of KFERQ-like pentapeptide motifs** in client proteins targeted for **chaperone-mediated autophagy (CMA)** |
| GO:0035651 AP-3 adaptor complex binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Manual review: AP-3 adaptor complex binding may be context-dependent or peripheral for Hspa8. Reason: Transferred from mouse Hspa8 IDA (PMID:19010779), a cross-linking/mass-spectrometry study of AP-3-associated proteins. The abstract does not list Hsc70 by name; the curator read the full text, so the annotation is kept as non-core rather than overruled. Supporting Evidence: PMID:19010779 we used in vivo cross-linking followed by purification of cross-linked AP-3 complexes and mass spectrometric identification of associated proteins |
| GO:0044788 host-mediated perturbation of viral process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Manual review: host-mediated perturbation of viral process may be context-dependent or peripheral for Hspa8. Reason: Mouse Hsc70 knockdown and inhibition impair gammaherpesvirus (MHV68) lytic replication; a host-factor role that is real but outside the core chaperone function. Supporting Evidence: PMID:26581985 Pharmacologic inhibition and small hairpin RNA (shRNA)-mediated knockdown of Hsc70 impaired MHV68 lytic replication file:rat/Hspa8/Hspa8-deep-research-falcon.md HSC70/HSPA8 contributes to viral entry by participating in endocytic uptake/trafficking pathways |
| GO:0044829 host-mediated activation of viral genome replication | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Manual review: host-mediated activation of viral genome replication may be context-dependent or peripheral for Hspa8. Reason: Mouse Hsc70 is required for efficient MHV68 viral DNA replication; host-factor role kept as non-core. Supporting Evidence: PMID:26581985 Pharmacologic inhibition and small hairpin RNA (shRNA)-mediated knockdown of Hsc70 impaired MHV68 lytic replication |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Manual review: perinuclear region of cytoplasm may be context-dependent or peripheral for Hspa8. Reason: Perinuclear localization is observed for Hsc70 around aggresome-like structures (mouse Schwann cells); a context-dependent location. Supporting Evidence: PMID:14627652 forms aggresome-like structures that are surrounded by molecular chaperones and lysosomes |
| GO:0051082 unfolded protein binding | IEA GO_REF:0000120 | MODIFY | Summary: Manual review: unfolded protein binding is better represented by a more specific replacement term for Hspa8. Reason: Modified to align with current curation guidance and improve term specificity. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. QuickGO confirms GO:0051082 is obsolete ("this binding term should be replaced by an activity term such as protein folding chaperone (GO:0044183) or unfolded protein holdase activity (GO:0140309)"); GOA now carries the recommended replacement GO:0044183 for Hspa8. Proposed replacements: protein folding chaperone Supporting Evidence: UniProtKB:P63018 In the ATP-bound form, it has a low affinity for substrate proteins. However, upon hydrolysis of the ATP to ADP, it undergoes a conformational change that increases its affinity for substrate proteins. |
| GO:0061684 chaperone-mediated autophagy | IEA GO_REF:0000107 | ACCEPT | Summary: Manual review: chaperone-mediated autophagy is a core process for Hspa8/HSC70, which selects KFERQ-motif clients and delivers them to LAMP-2A for lysosomal degradation. Reason: Retained as a core process, corroborated by falcon deep research. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. The same term is now carried by a GO_REF:0000120 IEA row (reviewed below). Supporting Evidence: file:rat/Hspa8/Hspa8-deep-research-falcon.md recognition of KFERQ-like pentapeptide motifs** in client proteins targeted for **chaperone-mediated autophagy (CMA)** |
| GO:0061738 late endosomal microautophagy | IEA GO_REF:0000107 | ACCEPT | Summary: Manual review: late endosomal microautophagy is consistent with known biology of Hspa8. Reason: Endosomal microautophagy, in which Hsc70 selects cytosolic cargo for uptake into late endosomes/MVBs, is a direct Hsc70 function demonstrated in mouse; it shares the cargo-selector mechanism of CMA and is included with CMA in the core functions. Supporting Evidence: PMID:21238931 Protein cargo selection is mediated by the chaperone hsc70 and requires the cationic domain of hsc70 for electrostatic interactions with the endosomal membrane. |
| GO:0070062 extracellular exosome | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Manual review: extracellular exosome may be context-dependent or peripheral for Hspa8. Reason: HSC70 is found in exosomes released by maturing reticulocytes, bound to the exosomal transferrin receptor; a valid but peripheral location. Supporting Evidence: PMID:11133993 The transferrin receptor (TfR) of reticulocytes is released in vesicular form (exosomes) during their maturation to erythrocytes. PMID:11133993 The results show that Hsc70 binds to exosomal TfR with characteristics expected of a chaperone/peptide interaction. |
| GO:0072318 clathrin coat disassembly | IEA GO_REF:0000120 | ACCEPT | Summary: Manual review: clathrin coat disassembly is consistent with known biology of Hspa8. Reason: Clathrin coat disassembly by auxilin-recruited HSC70 is a core process. Supporting Evidence: UniProtKB:P63018 It is recruited to clathrin-coated vesicles through its interaction with DNAJC6 leading to activation of HSPA8/HSC70 ATPase activity and therefore uncoating of clathrin-coated vesicles |
| GO:0098684 photoreceptor ribbon synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Manual review: photoreceptor ribbon synapse may be context-dependent or peripheral for Hspa8. Reason: Hsc70 is detected at photoreceptor ribbon synapses in mouse retina (as an endocytic uncoating marker); synapse-type localization is non-core. Supporting Evidence: PMID:24616664 weaker staining for AP180 (Figure 1D), Synaptojanin1 (Figure 1E), and hsc70 (Figure 1F) |
| GO:0098690 glycinergic synapse | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Manual review: glycinergic synapse may be context-dependent or peripheral for Hspa8. Reason: Hsc70 colocalizes with gephyrin at inhibitory (glycinergic) synapses; non-core location. Supporting Evidence: PMID:21209184 Immunoelectron microscopy of mouse spinal cord sections showed that Hsc70 could be colocalized with gephyrin at inhibitory synapses. |
| GO:0098793 presynapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Manual review: presynapse may be context-dependent or peripheral for Hspa8. Reason: Hsc70 immunoreactivity is found in presynaptic terminals in rat brain; non-core location. Supporting Evidence: PMID:9878698 Presynaptic terminals, but less frequently than postsynaptic staining, were also reactive. |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Manual review: glutamatergic synapse may be context-dependent or peripheral for Hspa8. Reason: Hsc70 is a major component of the PSD of excitatory (asymmetric) synapses in rat brain; non-core location. Supporting Evidence: PMID:11230095 Hsc70, a constitutive form, is a major component of the rat postsynaptic density (PSD) fraction PMID:11230095 both Hsp70 and Hsc70 are mainly associated with asymmetrical PSDs |
| GO:0099175 regulation of postsynapse organization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Manual review: regulation of postsynapse organization may be context-dependent or peripheral for Hspa8. Reason: Mouse data show Hsc70 activity is required for FILIP-induced changes in dendritic spine morphology; a context-specific regulatory role. Supporting Evidence: PMID:28234934 Further, in primary cultured neurons, an inhibitor of Hsc70 impeded the morphological change in spines induced by FILIP. |
| GO:0099634 postsynaptic specialization membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Manual review: postsynaptic specialization membrane may be context-dependent or peripheral for Hspa8. Reason: Hsc70 colocalizes and coclusters with gephyrin and GlyR at inhibitory postsynaptic specializations; non-core location. Supporting Evidence: PMID:21209184 Immunoelectron microscopy of mouse spinal cord sections showed that Hsc70 could be colocalized with gephyrin at inhibitory synapses. PMID:21209184 ternary Hsc70-gephyrin-GlyR coclusters were formed following transfection of COS-7 cells |
| GO:0160020 positive regulation of ferroptosis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Manual review: positive regulation of ferroptosis may be context-dependent or peripheral for Hspa8. Reason: CMA, of which HSC70 is the substrate-selecting chaperone, degrades GPX4 during ferroptosis; a downstream consequence of the CMA role rather than a core function. Supporting Evidence: PMID:30718432 Our results suggest that activation of CMA is involved in the execution of ferroptosis. PMID:40281343 disrupting its binding to HSC70 and inhibiting autophagy-mediated degradation |
| GO:0030674 protein-macromolecule adaptor activity | ISO GO_REF:0000121 | ACCEPT | Summary: Manual review: protein-macromolecule adaptor activity is consistent with known biology of Hspa8. Reason: Transferred from mouse Hspa8: in CMA HSC70 bridges KFERQ-motif clients to LAMP-2A at the lysosome, an adaptor-like role. Supporting Evidence: UniProtKB:P63018 HSPA8/HSC70 specifically recognizes and binds cytosolic proteins bearing a -KFERQ motif and promotes their recruitment to the surface of the lysosome where they bind to lysosomal protein LAMP2. |
| GO:0061684 chaperone-mediated autophagy | ISO GO_REF:0000121 | ACCEPT | Summary: Manual review: chaperone-mediated autophagy is consistent with known biology of Hspa8. Reason: Transferred from mouse Hspa8 (MGI:105384); CMA is a core HSC70 process and the mouse data link CMA to GPX4 degradation. Supporting Evidence: UniProtKB:P63018 HSPA8/HSC70 specifically recognizes and binds cytosolic proteins bearing a -KFERQ motif and promotes their recruitment to the surface of the lysosome where they bind to lysosomal protein LAMP2. PMID:30718432 the activation of ferroptosis by erastin increased the levels of lysosome-associated membrane protein 2a to promote chaperone-mediated autophagy (CMA), which, in turn, promoted the degradation of GPX4 |
| GO:0160020 positive regulation of ferroptosis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: positive regulation of ferroptosis may be context-dependent or peripheral for Hspa8. Reason: Transferred from mouse Hspa8 (MGI:105384, IDA in PMID:30718432): CMA promotes GPX4 degradation during ferroptosis; downstream of the CMA role. Supporting Evidence: PMID:30718432 Our results suggest that activation of CMA is involved in the execution of ferroptosis. |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | ACCEPT | Summary: Manual review: cytoplasm is consistent with known biology of Hspa8. Reason: Transferred from human HSPA8; cytoplasm is the principal compartment of HSC70 activity. Supporting Evidence: UniProtKB:P63018 SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P11142}. |
| GO:0101031 protein folding chaperone complex | ISO GO_REF:0000121 | ACCEPT | Summary: Manual review: protein folding chaperone complex is consistent with known biology of Hspa8. Reason: HSC70 is a component of co-chaperone complexes (e.g. with CHIP/BAG-2, and the CASA complex with BAG3/HSPB8/STUB1). Supporting Evidence: PMID:16207813 We identified the Hsc70 cochaperone BAG-2 as a main component of CHIP complexes. UniProtKB:P63018 Component of the chaperone-assisted selective autophagy (CASA) complex consisting of BAG3, HSPA8/HSC70, HSPB8 and STUB1/CHIP |
| GO:0005615 extracellular space | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: extracellular space may be context-dependent or peripheral for Hspa8. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. Supporting Evidence: PMID:11133993 The transferrin receptor (TfR) of reticulocytes is released in vesicular form (exosomes) during their maturation to erythrocytes. |
| GO:0030335 positive regulation of cell migration | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: positive regulation of cell migration may be context-dependent or peripheral for Hspa8. Reason: Transferred from human HSPA8, where extracellular HSPA8 binding to EWI-2 modulates dendritic-cell migration; a context-specific moonlighting role. Supporting Evidence: PMID:17785435 Important functions of recently activated dendritic cells are thus critically modulated by the newly discovered HSPA8-EWI-2 interaction. |
| GO:0048018 receptor ligand activity | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Transferred from human HSPA8 (IDA, PMID:17785435), which identified HSPA8 by expression cloning as a binding partner (ligand) of the dendritic-cell surface protein EWI-2. Reason: Changed from REMOVE: the human source is direct experimental evidence and is not a misannotation, so removal is not justified. However, it is a single-study, cell-type-specific extracellular interaction; describing the cytosolic chaperone as having receptor ligand activity in rat overstates what has been shown. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: CONTEXT OR TISSUE MISMATCH ROLE CONFLATION Sources checked: UniProtKB:P11142 Β· human HSPA8 SUPPORTS SOURCE BUT NOT TARGET Human HSPA8 IDA (PMID:17785435) shows EWI-2 binds HSPA8 on human dendritic cells; the observation is real for the source but is a context-specific extracellular interaction that does not establish a general receptor-ligand activity to transfer to rat. Supporting Evidence: PMID:17785435 human heat shock protein A8 (HSPA8), a member of the hsp70 family, was identified as the ligand for EWI-2. PMID:17785435 Important functions of recently activated dendritic cells are thus critically modulated by the newly discovered HSPA8-EWI-2 interaction. |
| GO:0006457 protein folding | ISO GO_REF:0000121 | ACCEPT | Summary: Manual review: protein folding is consistent with known biology of Hspa8. Reason: Transferred from mouse Hspa8; assisting protein folding is the core HSC70 activity. Supporting Evidence: UniProtKB:P63018 Plays a pivotal role in the protein quality control system, ensuring the correct folding of proteins, the re-folding of misfolded proteins and controlling the targeting of proteins for subsequent degradation. |
| GO:0014069 postsynaptic density | IEP PMID:11230095 Presence of both constitutive and inducible forms of heat sh... | KEEP AS NON CORE | Summary: Manual review: postsynaptic density may be context-dependent or peripheral for Hspa8. Reason: IEP to a location is unusual, but the paper shows Hsc70 is a major PSD component; kept as non-core location. Supporting Evidence: PMID:11230095 Hsc70, a constitutive form, is a major component of the rat postsynaptic density (PSD) fraction |
| GO:0014069 postsynaptic density | IDA PMID:11230095 Presence of both constitutive and inducible forms of heat sh... | KEEP AS NON CORE | Summary: Manual review: postsynaptic density may be context-dependent or peripheral for Hspa8. Reason: Biochemical and immunohistochemical data place rat Hsc70 in the PSD fraction; non-core location. Supporting Evidence: PMID:11230095 Hsc70, a constitutive form, is a major component of the rat postsynaptic density (PSD) fraction |
| GO:0014069 postsynaptic density | IDA PMID:9878698 Presence of molecular chaperones, heat shock cognate (Hsc) 7... | KEEP AS NON CORE | Summary: Manual review: postsynaptic density may be context-dependent or peripheral for Hspa8. Reason: Immuno-EM shows Hsc70 immediately beneath the synaptic contact/PSD; non-core location. Supporting Evidence: PMID:9878698 Postsynaptic areas immediately beneath the synaptic contact or PSDs were immunoreactive for Hsc70. |
| GO:0098684 photoreceptor ribbon synapse | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: photoreceptor ribbon synapse may be context-dependent or peripheral for Hspa8. Reason: Transferred from mouse Hspa8 (retinal ribbon synapse immunostaining); non-core location. Supporting Evidence: PMID:24616664 weaker staining for AP180 (Figure 1D), Synaptojanin1 (Figure 1E), and hsc70 (Figure 1F) |
| GO:0098690 glycinergic synapse | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: glycinergic synapse may be context-dependent or peripheral for Hspa8. Reason: Transferred from mouse Hspa8; Hsc70 colocalizes with gephyrin at inhibitory synapses. Supporting Evidence: PMID:21209184 Immunoelectron microscopy of mouse spinal cord sections showed that Hsc70 could be colocalized with gephyrin at inhibitory synapses. |
| GO:0098690 glycinergic synapse | IDA PMID:21209184 Heat shock cognate protein 70 regulates gephyrin clustering. | KEEP AS NON CORE | Summary: Manual review: glycinergic synapse may be context-dependent or peripheral for Hspa8. Reason: Hsc70 binds the gephyrin G-domain and colocalizes with gephyrin at inhibitory (glycinergic) synapses; valid but non-core location. Supporting Evidence: PMID:21209184 Immunoelectron microscopy of mouse spinal cord sections showed that Hsc70 could be colocalized with gephyrin at inhibitory synapses. PMID:21209184 Hsc70 inhibition increased gephyrin accumulation at inhibitory synapses without modifying GlyR clustering. |
| GO:0098690 glycinergic synapse | EXP PMID:21209184 Heat shock cognate protein 70 regulates gephyrin clustering. | KEEP AS NON CORE | Summary: Manual review: glycinergic synapse may be context-dependent or peripheral for Hspa8. Reason: Hsc70 binds the gephyrin G-domain and colocalizes with gephyrin at inhibitory (glycinergic) synapses; valid but non-core location. Supporting Evidence: PMID:21209184 Immunoelectron microscopy of mouse spinal cord sections showed that Hsc70 could be colocalized with gephyrin at inhibitory synapses. PMID:21209184 Hsc70 inhibition increased gephyrin accumulation at inhibitory synapses without modifying GlyR clustering. |
| GO:0098690 glycinergic synapse | IMP PMID:21209184 Heat shock cognate protein 70 regulates gephyrin clustering. | KEEP AS NON CORE | Summary: Manual review: glycinergic synapse may be context-dependent or peripheral for Hspa8. Reason: Hsc70 binds the gephyrin G-domain and colocalizes with gephyrin at inhibitory (glycinergic) synapses; valid but non-core location. Supporting Evidence: PMID:21209184 Immunoelectron microscopy of mouse spinal cord sections showed that Hsc70 could be colocalized with gephyrin at inhibitory synapses. PMID:21209184 Hsc70 inhibition increased gephyrin accumulation at inhibitory synapses without modifying GlyR clustering. |
| GO:0098793 presynapse | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: presynapse may be context-dependent or peripheral for Hspa8. Reason: Transferred from mouse Hspa8; consistent with rat immunostaining of presynaptic terminals. Supporting Evidence: PMID:9878698 Presynaptic terminals, but less frequently than postsynaptic staining, were also reactive. |
| GO:0098793 presynapse | IEP PMID:9878698 Presence of molecular chaperones, heat shock cognate (Hsc) 7... | KEEP AS NON CORE | Summary: Manual review: presynapse may be context-dependent or peripheral for Hspa8. Reason: IEP to a location is unusual, but presynaptic Hsc70 immunoreactivity is reported; non-core. Supporting Evidence: PMID:9878698 Presynaptic terminals, but less frequently than postsynaptic staining, were also reactive. |
| GO:0098793 presynapse | IDA PMID:9878698 Presence of molecular chaperones, heat shock cognate (Hsc) 7... | KEEP AS NON CORE | Summary: Manual review: presynapse may be context-dependent or peripheral for Hspa8. Reason: Presynaptic terminals are Hsc70-immunoreactive in rat brain; non-core location. Supporting Evidence: PMID:9878698 Presynaptic terminals, but less frequently than postsynaptic staining, were also reactive. |
| GO:0098794 postsynapse | IEP PMID:9878698 Presence of molecular chaperones, heat shock cognate (Hsc) 7... | KEEP AS NON CORE | Summary: Manual review: postsynapse may be context-dependent or peripheral for Hspa8. Reason: IEP to a location is unusual, but postsynaptic Hsc70 localization is reported; non-core. Supporting Evidence: PMID:9878698 These results suggest that Hsp40 and Hsc70 are co-localized at postsynaptic sites |
| GO:0098794 postsynapse | IDA PMID:9878698 Presence of molecular chaperones, heat shock cognate (Hsc) 7... | KEEP AS NON CORE | Summary: Manual review: postsynapse may be context-dependent or peripheral for Hspa8. Reason: Hsc70 localizes to postsynaptic sites with Hsp40 in rat brain; non-core location. Supporting Evidence: PMID:9878698 These results suggest that Hsp40 and Hsc70 are co-localized at postsynaptic sites PMID:9878698 Postsynaptic areas immediately beneath the synaptic contact or PSDs were immunoreactive for Hsc70. |
| GO:0098880 maintenance of postsynaptic specialization structure | IDA PMID:21209184 Heat shock cognate protein 70 regulates gephyrin clustering. | KEEP AS NON CORE | Summary: Manual review: maintenance of postsynaptic specialization structure may be context-dependent or peripheral for Hspa8. Reason: Hsc70 overexpression or inhibition changes synaptic gephyrin accumulation, so Hsc70 regulates gephyrin scaffold size at inhibitory postsynapses; a real but context-specific role. Supporting Evidence: PMID:21209184 Hsc70 inhibition increased gephyrin accumulation at inhibitory synapses without modifying GlyR clustering. PMID:21209184 Our findings demonstrate that Hsc70 regulates gephyrin polymerization independently of its interaction with GlyR. |
| GO:0098880 maintenance of postsynaptic specialization structure | EXP PMID:21209184 Heat shock cognate protein 70 regulates gephyrin clustering. | KEEP AS NON CORE | Summary: Manual review: maintenance of postsynaptic specialization structure may be context-dependent or peripheral for Hspa8. Reason: Hsc70 overexpression or inhibition changes synaptic gephyrin accumulation, so Hsc70 regulates gephyrin scaffold size at inhibitory postsynapses; a real but context-specific role. Supporting Evidence: PMID:21209184 Hsc70 inhibition increased gephyrin accumulation at inhibitory synapses without modifying GlyR clustering. PMID:21209184 Our findings demonstrate that Hsc70 regulates gephyrin polymerization independently of its interaction with GlyR. |
| GO:0098880 maintenance of postsynaptic specialization structure | IMP PMID:21209184 Heat shock cognate protein 70 regulates gephyrin clustering. | KEEP AS NON CORE | Summary: Manual review: maintenance of postsynaptic specialization structure may be context-dependent or peripheral for Hspa8. Reason: Hsc70 overexpression or inhibition changes synaptic gephyrin accumulation, so Hsc70 regulates gephyrin scaffold size at inhibitory postsynapses; a real but context-specific role. Supporting Evidence: PMID:21209184 Hsc70 inhibition increased gephyrin accumulation at inhibitory synapses without modifying GlyR clustering. PMID:21209184 Our findings demonstrate that Hsc70 regulates gephyrin polymerization independently of its interaction with GlyR. |
| GO:0098978 glutamatergic synapse | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: glutamatergic synapse may be context-dependent or peripheral for Hspa8. Reason: Transferred from mouse Hspa8; consistent with rat data placing Hsc70 at asymmetric (excitatory) PSDs. Supporting Evidence: PMID:11230095 both Hsp70 and Hsc70 are mainly associated with asymmetrical PSDs |
| GO:0098978 glutamatergic synapse | IEP PMID:11230095 Presence of both constitutive and inducible forms of heat sh... | KEEP AS NON CORE | Summary: Manual review: glutamatergic synapse may be context-dependent or peripheral for Hspa8. Reason: IEP to a location is unusual; Hsc70 is a major PSD component at excitatory synapses. Non-core. Supporting Evidence: PMID:11230095 Hsc70, a constitutive form, is a major component of the rat postsynaptic density (PSD) fraction |
| GO:0098978 glutamatergic synapse | IDA PMID:11230095 Presence of both constitutive and inducible forms of heat sh... | KEEP AS NON CORE | Summary: Manual review: glutamatergic synapse may be context-dependent or peripheral for Hspa8. Reason: Hsc70 is associated with asymmetric (glutamatergic) PSDs; non-core location. Supporting Evidence: PMID:11230095 both Hsp70 and Hsc70 are mainly associated with asymmetrical PSDs |
| GO:0098978 glutamatergic synapse | IEP PMID:9878698 Presence of molecular chaperones, heat shock cognate (Hsc) 7... | KEEP AS NON CORE | Summary: Manual review: glutamatergic synapse may be context-dependent or peripheral for Hspa8. Reason: IEP to a location is unusual; Hsc70 localizes to postsynaptic sites in rat brain. Non-core. Supporting Evidence: PMID:9878698 Postsynaptic areas immediately beneath the synaptic contact or PSDs were immunoreactive for Hsc70. |
| GO:0098978 glutamatergic synapse | IDA PMID:9878698 Presence of molecular chaperones, heat shock cognate (Hsc) 7... | KEEP AS NON CORE | Summary: Manual review: glutamatergic synapse may be context-dependent or peripheral for Hspa8. Reason: Hsc70 is found at postsynaptic densities of excitatory synapses in rat brain; non-core location. Supporting Evidence: PMID:9878698 Postsynaptic areas immediately beneath the synaptic contact or PSDs were immunoreactive for Hsc70. |
| GO:0099175 regulation of postsynapse organization | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: regulation of postsynapse organization may be context-dependent or peripheral for Hspa8. Reason: Transferred from mouse Hspa8, where Hsc70 activity is needed for FILIP-driven spine remodelling; context-specific. Supporting Evidence: PMID:28234934 Further, in primary cultured neurons, an inhibitor of Hsc70 impeded the morphological change in spines induced by FILIP. |
| GO:0099634 postsynaptic specialization membrane | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: postsynaptic specialization membrane may be context-dependent or peripheral for Hspa8. Reason: Transferred from mouse Hspa8; Hsc70 coclusters with gephyrin and GlyR at inhibitory postsynaptic specializations. Supporting Evidence: PMID:21209184 ternary Hsc70-gephyrin-GlyR coclusters were formed following transfection of COS-7 cells |
| GO:0072318 clathrin coat disassembly | ISO GO_REF:0000121 | ACCEPT | Summary: Manual review: clathrin coat disassembly is consistent with known biology of Hspa8. Reason: Transferred from mouse Hspa8; clathrin coat disassembly is a core HSC70 process. Supporting Evidence: UniProtKB:P63018 It is recruited to clathrin-coated vesicles through its interaction with DNAJC6 leading to activation of HSPA8/HSC70 ATPase activity and therefore uncoating of clathrin-coated vesicles |
| GO:0072318 clathrin coat disassembly | IDA PMID:8524399 Role of auxilin in uncoating clathrin-coated vesicles. | ACCEPT | Summary: Manual review: clathrin coat disassembly is consistent with known biology of Hspa8. Reason: Auxilin recruits hsc70 to clathrin lattices in an ATP-dependent manner to strip coats from clathrin-coated vesicles; core process. Supporting Evidence: PMID:8524399 This process is effected by the chaperone protein hsp70c together with a 100K cofactor which we here identify as the coat protein auxilin. PMID:8524399 Auxilin binds with high affinity to assembled clathrin lattices and, in the presence of ATP, recruits hsp70c. |
| GO:0005765 lysosomal membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Manual review: the lysosomal membrane is a functional location of the core chaperone-mediated autophagy role of HSC70; this orthology-based annotation is consistent with the experimentally supported IDA annotations to the same term. Reason: Lysosomal membrane is a bona fide functional location for the core CMA role of HSC70 (experimentally supported by PMID:18644871 and PMID:9038169); accepted for consistency with those IDA annotations. Supporting Evidence: PMID:11559757 is associated with the cytosolic side of the lysosomal membrane where it binds to substrates of this proteolytic pathway UniProtKB:P63018 Lysosome membrane {ECO:0000250|UniProtKB:P11142}; Peripheral membrane protein {ECO:0000250|UniProtKB:P11142}; Cytoplasmic side |
| GO:0030674 protein-macromolecule adaptor activity | ISS GO_REF:0000024 | ACCEPT | Summary: Manual review: protein-macromolecule adaptor activity is consistent with known biology of Hspa8. Reason: Transferred from human HSPA8; HSC70 bridges KFERQ-motif CMA clients to LAMP-2A at the lysosome. Supporting Evidence: UniProtKB:P63018 HSPA8/HSC70 specifically recognizes and binds cytosolic proteins bearing a -KFERQ motif and promotes their recruitment to the surface of the lysosome where they bind to lysosomal protein LAMP2. PMID:26212789 BBC3 associates with HSPA8/HSC70 (heat shock 70kDa protein 8), leading to its lysosome translocation and uptake. |
| GO:0061740 protein targeting to lysosome involved in chaperone-mediated autophagy | ISS GO_REF:0000024 | MODIFY | Summary: Manual review: protein targeting to lysosome in CMA is a core process for Hspa8/HSC70; cytosolic HSC70 recognizes KFERQ-like motifs and delivers clients to LAMP-2A, and lysosomal HSC70 supports translocation into the lysosomal lumen. Reason: GO:0061740 is a precomposed term: protein targeting to lysosome (GO:0006622) as part of chaperone-mediated autophagy. The claim is sound but the combined term restates in one class what the CMA GO-CAM and module model explicitly, so the row is modified to the genus and the CMA context is recorded in decomposed_into. Retained as a core CMA process, corroborated by falcon deep research. Proposed replacements: protein targeting to lysosome Context of precomposed term: GO-CAM Palmitoylation of NLRP3 by ZDHHC12, leading to NLRP3 degradation by CMA (Human) module chaperone_mediated_autophagy / hspa8_substrate_adaptor in core functions Decomposed from the precomposed GO:0061740 (projects/INVOLVED_IN_PRECOMPOSITION.md); the claim is unchanged, re-expressed as protein targeting to lysosome, with the chaperone-mediated autophagy context carried by the HSPA8 activity in the CMA production GO-CAM and by the substrate-delivery step of the CMA module. The GO-CAM is of the human ortholog HSPA8. Supporting Evidence: file:rat/Hspa8/Hspa8-deep-research-falcon.md recognition of KFERQ-like pentapeptide motifs** in client proteins targeted for **chaperone-mediated autophagy (CMA)** file:rat/Hspa8/Hspa8-deep-research-falcon.md Lysosomal HSC70 (LysβHSC70)** facilitates **substrate translocation** into the lysosome lumen |
| GO:1900226 negative regulation of NLRP3 inflammasome complex assembly | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: negative regulation of NLRP3 inflammasome complex assembly may be context-dependent or peripheral for Hspa8. Reason: Transferred from human HSPA8: palmitoylated NLRP3 is degraded by CMA, limiting inflammasome activation; a downstream consequence of the CMA role. Supporting Evidence: PMID:36586411 which promotes its degradation through the chaperone-mediated autophagy pathway |
| GO:0001786 phosphatidylserine binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: phosphatidylserine binding may be context-dependent or peripheral for Hspa8. Reason: Transferred from mouse Hspa8 (endosomal microautophagy study); peripheral to core chaperone function. Supporting Evidence: PMID:21238931 Protein cargo selection is mediated by the chaperone hsc70 and requires the cationic domain of hsc70 for electrostatic interactions with the endosomal membrane. |
| GO:0061635 regulation of protein complex stability | IDA PMID:18644871 The chaperone-mediated autophagy receptor organizes in dynam... | KEEP AS NON CORE | Summary: Manual review: regulation of protein complex stability may be context-dependent or peripheral for Hspa8. Reason: Hsc70 disassembles LAMP-2A from the lysosomal translocation complex, regulating its stability; a real CMA-associated role, kept as non-core. Supporting Evidence: PMID:18644871 we have identified a novel function for hsc70 in the disassembly of LAMP-2A from these complexes |
| GO:0140545 ATP-dependent protein disaggregase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Manual review: ATP-dependent protein disaggregase activity is consistent with known biology of Hspa8. Reason: Transferred from human HSPA8 (IDA in PMID:23921388, which studied HSPA8 binding to monomeric and fibrillar alpha-synuclein); ATP-dependent disaggregation is part of the HSP70 chaperone repertoire. Supporting Evidence: PMID:23921388 trimethylation of HSPA8 (Hsc70) has functional consequences, as it alters the affinity of the chaperone for both the monomeric and fibrillar forms of the Parkinson disease-associated protein Ξ±-synuclein PMID:23921388 Hsp70 proteins constitute an evolutionarily conserved protein family of ATP-dependent molecular chaperones |
| GO:0061684 chaperone-mediated autophagy | IGI PMID:18644871 The chaperone-mediated autophagy receptor organizes in dynam... | ACCEPT | Summary: Manual review: chaperone-mediated autophagy is consistent with known biology of Hspa8. Reason: Genetic and biochemical data show hsc70 is required for the dynamics of LAMP-2A complexes during CMA; core process. Supporting Evidence: PMID:18644871 The two major chaperones related to CMA, hsc70 and hsp90, play critical roles in the functional dynamics of the LAMP-2A complexes at the lysosomal membrane. PMID:18644871 we have identified a novel function for hsc70 in the disassembly of LAMP-2A from these complexes |
| GO:0043202 lysosomal lumen | TAS Reactome:R-RNO-9625160 | KEEP AS NON CORE | Summary: Manual review: lysosomal lumen may be context-dependent or peripheral for Hspa8. Reason: Reactome places Hspa8 in the lysosomal lumen during CMA substrate translocation, consistent with rat data on lumenal hsc73; non-core location. Supporting Evidence: PMID:9038169 one contains the heat shock cognate protein of 73 kDa (hsc73) within the lysosomal lumen |
| GO:0043202 lysosomal lumen | TAS Reactome:R-RNO-9625173 | KEEP AS NON CORE | Summary: Manual review: lysosomal lumen may be context-dependent or peripheral for Hspa8. Reason: Reactome places Hspa8 in the lysosomal lumen during CMA substrate translocation, consistent with rat data on lumenal hsc73; non-core location. Supporting Evidence: PMID:9038169 one contains the heat shock cognate protein of 73 kDa (hsc73) within the lysosomal lumen |
| GO:0043202 lysosomal lumen | TAS Reactome:R-RNO-9626028 | KEEP AS NON CORE | Summary: Manual review: lysosomal lumen may be context-dependent or peripheral for Hspa8. Reason: Reactome places Hspa8 in the lysosomal lumen during CMA substrate translocation, consistent with rat data on lumenal hsc73; non-core location. Supporting Evidence: PMID:9038169 one contains the heat shock cognate protein of 73 kDa (hsc73) within the lysosomal lumen |
| GO:0048471 perinuclear region of cytoplasm | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: perinuclear region of cytoplasm may be context-dependent or peripheral for Hspa8. Reason: Transferred from mouse Hspa8 (perinuclear chaperone accumulation around aggresomes); context-dependent. Supporting Evidence: PMID:14627652 forms aggresome-like structures that are surrounded by molecular chaperones and lysosomes |
| GO:0005829 cytosol | TAS Reactome:R-RNO-9613356 | ACCEPT | Summary: Manual review: cytosol is consistent with known biology of Hspa8. Reason: Reactome places cytosolic Hspa8 at the substrate-recognition step of CMA; the cytosol is the predominant site of HSC70 activity. Supporting Evidence: file:rat/Hspa8/Hspa8-deep-research-falcon.md **Cytosol**: the predominant pool performing general chaperoning and recognizing CMA substrates (KFERQ-like motifs) |
| GO:0005829 cytosol | TAS Reactome:R-RNO-9615712 | ACCEPT | Summary: Manual review: cytosol is consistent with known biology of Hspa8. Reason: Reactome places cytosolic Hspa8 at the substrate-recognition step of CMA; the cytosol is the predominant site of HSC70 activity. Supporting Evidence: file:rat/Hspa8/Hspa8-deep-research-falcon.md **Cytosol**: the predominant pool performing general chaperoning and recognizing CMA substrates (KFERQ-like motifs) |
| GO:0005829 cytosol | TAS Reactome:R-RNO-9620205 | ACCEPT | Summary: Manual review: cytosol is consistent with known biology of Hspa8. Reason: Reactome places cytosolic Hspa8 at the substrate-recognition step of CMA; the cytosol is the predominant site of HSC70 activity. Supporting Evidence: file:rat/Hspa8/Hspa8-deep-research-falcon.md **Cytosol**: the predominant pool performing general chaperoning and recognizing CMA substrates (KFERQ-like motifs) |
| GO:0005829 cytosol | TAS Reactome:R-RNO-9622832 | ACCEPT | Summary: Manual review: cytosol is consistent with known biology of Hspa8. Reason: Reactome places cytosolic Hspa8 at the substrate-recognition step of CMA; the cytosol is the predominant site of HSC70 activity. Supporting Evidence: file:rat/Hspa8/Hspa8-deep-research-falcon.md **Cytosol**: the predominant pool performing general chaperoning and recognizing CMA substrates (KFERQ-like motifs) |
| GO:0005829 cytosol | TAS Reactome:R-RNO-9626236 | ACCEPT | Summary: Manual review: cytosol is consistent with known biology of Hspa8. Reason: Reactome places cytosolic Hspa8 at the substrate-recognition step of CMA; the cytosol is the predominant site of HSC70 activity. Supporting Evidence: file:rat/Hspa8/Hspa8-deep-research-falcon.md **Cytosol**: the predominant pool performing general chaperoning and recognizing CMA substrates (KFERQ-like motifs) |
| GO:0005829 cytosol | TAS Reactome:R-RNO-9626239 | ACCEPT | Summary: Manual review: cytosol is consistent with known biology of Hspa8. Reason: Reactome places cytosolic Hspa8 at the substrate-recognition step of CMA; the cytosol is the predominant site of HSC70 activity. Supporting Evidence: file:rat/Hspa8/Hspa8-deep-research-falcon.md **Cytosol**: the predominant pool performing general chaperoning and recognizing CMA substrates (KFERQ-like motifs) |
| GO:0005829 cytosol | TAS Reactome:R-RNO-9626254 | ACCEPT | Summary: Manual review: cytosol is consistent with known biology of Hspa8. Reason: Reactome places cytosolic Hspa8 at the substrate-recognition step of CMA; the cytosol is the predominant site of HSC70 activity. Supporting Evidence: file:rat/Hspa8/Hspa8-deep-research-falcon.md **Cytosol**: the predominant pool performing general chaperoning and recognizing CMA substrates (KFERQ-like motifs) |
| GO:0043195 terminal bouton | HDA PMID:24876496 Composition of isolated synaptic boutons reveals the amounts... | KEEP AS NON CORE | Summary: Manual review: terminal bouton may be context-dependent or peripheral for Hspa8. Reason: Hsc70 was quantified in purified synaptic boutons (HDA proteomics); consistent with its role in synaptic vesicle uncoating. Non-core location. Supporting Evidence: PMID:24876496 Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins. |
| GO:0031625 ubiquitin protein ligase binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: ubiquitin protein ligase binding may be context-dependent or peripheral for Hspa8. Reason: Transferred from human HSPA8; HSC70 binds the co-chaperone E3 ligase STUB1/CHIP, linking client triage to ubiquitination. Supporting Evidence: UniProtKB:P63018 Interacts (via C-terminus) with the E3 ligase STUB1 forming a 210 kDa complex of one STUB1 and two HSPA8 molecules |
| GO:0051087 protein-folding chaperone binding | ISO GO_REF:0000121 | ACCEPT | Summary: Manual review: protein-folding chaperone binding is consistent with known biology of Hspa8. Reason: Transferred from human HSPA8; HSC70 binds co-chaperones (BAG-2, STUB1, Hsp40, Hop), which is intrinsic to its chaperone cycle. Supporting Evidence: PMID:16207813 We identified the Hsc70 cochaperone BAG-2 as a main component of CHIP complexes. UniProtKB:P63018 Interacts with HOPX, STUB1, HSP40, HSP90, BAG2 and BAG3 |
| GO:0005515 protein binding | IPI PMID:15708368 Small glutamine-rich tetratricopeptide repeat-containing pro... | MODIFY | Summary: Rat Hsc70 binds the TPR domain of the co-chaperone SGT (SGTA, with UniProtKB:O70593). Reason: Generic protein binding is uninformative. The cited study characterizes SGT as an Hsc70 co-chaperone whose TPR domain mediates the interaction, so protein-folding chaperone binding (GO:0051087) states the function more precisely. Proposed replacements: protein-folding chaperone binding Supporting Evidence: PMID:15708368 we identified the human small glutamine-rich tetratricopeptide repeat-containing protein (SGT) as a co-chaperone PMID:15708368 The tetratricopeptide repeat (TPR) domain in SGT is responsible for interacting with Hsc70. UniProtKB:P63018 Interacts with SGTA (via TPR repeats) (PubMed:15708368). |
| GO:0030425 dendrite | IDA PMID:9878698 Presence of molecular chaperones, heat shock cognate (Hsc) 7... | KEEP AS NON CORE | Summary: Manual review: dendrite may be context-dependent or peripheral for Hspa8. Reason: Hsc70 immunoreactivity is present in dendrites of rat neurons; non-core location. Supporting Evidence: PMID:9878698 The immunoreactivities of Hsc70 (p73) were distributed throughout the rat brain, in neuronal somata, dendrites and axons. |
| GO:0044309 neuron spine | IDA PMID:9878698 Presence of molecular chaperones, heat shock cognate (Hsc) 7... | KEEP AS NON CORE | Summary: Manual review: neuron spine may be context-dependent or peripheral for Hspa8. Reason: Immuno-EM localizes Hsc70 to dendritic spines in rat brain; non-core location. Supporting Evidence: PMID:9878698 Their immunoreactivity in neurons was localized in the cytoplasmic matrix, dendrites, and spines at the electron microscopic level. |
| GO:0061740 protein targeting to lysosome involved in chaperone-mediated autophagy | ISO GO_REF:0000121 | MODIFY | Summary: Manual review: protein targeting to lysosome involved in chaperone-mediated autophagy is consistent with known biology of Hspa8. Reason: GO:0061740 is a precomposed term: protein targeting to lysosome (GO:0006622) as part of chaperone-mediated autophagy. The claim is sound but the combined term restates in one class what the CMA GO-CAM and module model explicitly, so the row is modified to the genus and the CMA context is recorded in decomposed_into. Transferred from human HSPA8; HSC70 delivers KFERQ-motif clients (e.g. BBC3/PUMA) to the lysosome for CMA. Proposed replacements: protein targeting to lysosome Context of precomposed term: GO-CAM Palmitoylation of NLRP3 by ZDHHC12, leading to NLRP3 degradation by CMA (Human) module chaperone_mediated_autophagy / hspa8_substrate_adaptor in core functions Decomposed from the precomposed GO:0061740 (projects/INVOLVED_IN_PRECOMPOSITION.md); the claim is unchanged, re-expressed as protein targeting to lysosome, with the chaperone-mediated autophagy context carried by the HSPA8 activity in the CMA production GO-CAM and by the substrate-delivery step of the CMA module. The GO-CAM is of the human ortholog HSPA8. Supporting Evidence: PMID:26212789 BBC3 associates with HSPA8/HSC70 (heat shock 70kDa protein 8), leading to its lysosome translocation and uptake. UniProtKB:P63018 HSPA8/HSC70 specifically recognizes and binds cytosolic proteins bearing a -KFERQ motif and promotes their recruitment to the surface of the lysosome where they bind to lysosomal protein LAMP2. |
| GO:0044788 host-mediated perturbation of viral process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: host-mediated perturbation of viral process may be context-dependent or peripheral for Hspa8. Reason: Transferred from mouse Hspa8; Hsc70 is a host factor required for MHV68 lytic replication. Supporting Evidence: PMID:26581985 Pharmacologic inhibition and small hairpin RNA (shRNA)-mediated knockdown of Hsc70 impaired MHV68 lytic replication |
| GO:0044829 host-mediated activation of viral genome replication | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: host-mediated activation of viral genome replication may be context-dependent or peripheral for Hspa8. Reason: Transferred from mouse Hspa8; Hsc70 is required for MHV68 viral DNA replication. Supporting Evidence: PMID:26581985 Pharmacologic inhibition and small hairpin RNA (shRNA)-mediated knockdown of Hsc70 impaired MHV68 lytic replication |
| GO:0005765 lysosomal membrane | IDA PMID:18644871 The chaperone-mediated autophagy receptor organizes in dynam... | ACCEPT | Summary: Manual review: this IDA derives from a key CMA mechanistic paper showing HSC70 organizes in dynamic protein complexes with LAMP-2A at the lysosomal membrane. The lysosomal membrane is a functional location of the core CMA role of HSC70 (also listed in the CMA core_function), so this experimental annotation is accepted as core. Reason: The lysosomal membrane is a bona fide functional location for the core chaperone-mediated autophagy role of HSC70, directly demonstrated experimentally in PMID:18644871. Falcon corroboration is captured in the references findings block. Supporting Evidence: PMID:18644871 The two major chaperones related to CMA, hsc70 and hsp90, play critical roles in the functional dynamics of the LAMP-2A complexes at the lysosomal membrane. |
| GO:0032984 protein-containing complex disassembly | IMP PMID:18644871 The chaperone-mediated autophagy receptor organizes in dynam... | KEEP AS NON CORE | Summary: Manual review: protein-containing complex disassembly may be context-dependent or peripheral for Hspa8. Reason: Hsc70 disassembles LAMP-2A from its lysosomal complexes; a real complex-disassembly activity in the CMA context. Supporting Evidence: PMID:18644871 we have identified a novel function for hsc70 in the disassembly of LAMP-2A from these complexes |
| GO:1990836 lysosomal matrix | IDA PMID:18644871 The chaperone-mediated autophagy receptor organizes in dynam... | KEEP AS NON CORE | Summary: Manual review: lysosomal matrix may be context-dependent or peripheral for Hspa8. Reason: Lysosome-associated hsc70 participates in CMA; lumenal hsc73 is documented in rat liver lysosomes. Non-core location. Supporting Evidence: PMID:18644871 The two major chaperones related to CMA, hsc70 and hsp90, play critical roles in the functional dynamics of the LAMP-2A complexes at the lysosomal membrane. PMID:9038169 one contains the heat shock cognate protein of 73 kDa (hsc73) within the lysosomal lumen |
| GO:0005770 late endosome | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: late endosome may be context-dependent or peripheral for Hspa8. Reason: Transferred from mouse Hspa8 (endosomal microautophagy); non-core location. Supporting Evidence: PMID:21238931 identify a microautophagy-like process that delivers soluble cytosolic proteins to the vesicles of late endosomes/multivesicular bodies (MVBs) |
| GO:0061738 late endosomal microautophagy | ISO GO_REF:0000121 | ACCEPT | Summary: Manual review: late endosomal microautophagy is consistent with known biology of Hspa8. Reason: Transferred from mouse Hspa8: Hsc70 selects cytosolic cargo for endosomal microautophagy. Supporting Evidence: PMID:21238931 Protein cargo selection is mediated by the chaperone hsc70 and requires the cationic domain of hsc70 for electrostatic interactions with the endosomal membrane. |
| GO:0016887 ATP hydrolysis activity | IDA PMID:20060297 Chaperone-assisted selective autophagy is essential for musc... | ACCEPT | Summary: Manual review: ATP hydrolysis activity is consistent with known biology of Hspa8. Reason: ATP hydrolysis drives HSC70 function, including in the CASA complex studied here; the curator recorded the assay from the full text. Supporting Evidence: PMID:20060297 Stv and its mammalian ortholog BAG-3 coordinate the activity of Hsc70 and the small heat shock protein HspB8 UniProtKB:P63018 Reaction=ATP + H2O = ADP + phosphate + H(+) |
| GO:1904764 chaperone-mediated autophagy translocation complex disassembly | IDA PMID:18644871 The chaperone-mediated autophagy receptor organizes in dynam... | KEEP AS NON CORE | Summary: Manual review: chaperone-mediated autophagy translocation complex disassembly may be context-dependent or peripheral for Hspa8. Reason: Hsc70 disassembles LAMP-2A translocation complexes at the lysosomal membrane; a direct CMA step, kept as non-core alongside the broader CMA term. Supporting Evidence: PMID:18644871 we have identified a novel function for hsc70 in the disassembly of LAMP-2A from these complexes |
| GO:0042026 protein refolding | ISS GO_REF:0000024 | ACCEPT | Summary: Manual review: protein refolding is consistent with known biology of Hspa8. Reason: Transferred from human HSPA8; consistent with rat assays of DnaJ-dependent luciferase refolding by hsc70. Supporting Evidence: PMID:11360998 In the presence of DnaJ, the capability of hsc70(R469C) to refold the denatured luciferase was decreased by 50%. |
| GO:0061684 chaperone-mediated autophagy | IDA PMID:18644871 The chaperone-mediated autophagy receptor organizes in dynam... | ACCEPT | Summary: Manual review: chaperone-mediated autophagy is consistent with known biology of Hspa8. Reason: HSC70 is one of the two major CMA chaperones controlling LAMP-2A complex dynamics; core process. Supporting Evidence: PMID:18644871 The two major chaperones related to CMA, hsc70 and hsp90, play critical roles in the functional dynamics of the LAMP-2A complexes at the lysosomal membrane. |
| GO:0031647 regulation of protein stability | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: regulation of protein stability may be context-dependent or peripheral for Hspa8. Reason: Transferred from human HSPA8; CMA-mediated degradation of BBC3/PUMA controls its stability. Supporting Evidence: PMID:26212789 BBC3 associates with HSPA8/HSC70 (heat shock 70kDa protein 8), leading to its lysosome translocation and uptake. |
| GO:0097214 positive regulation of lysosomal membrane permeability | IMP PMID:9038169 A population of rat liver lysosomes responsible for the sele... | KEEP AS NON CORE | Summary: Manual review: positive regulation of lysosomal membrane permeability may be context-dependent or peripheral for Hspa8. Reason: Preloading lysosomes with hsc73 activates selective substrate transport into them; a real CMA-associated role, kept as non-core. Supporting Evidence: PMID:9038169 Preloading of the lysosomal population that is devoid of lumenal hsc73 with hsc73 isolated from cytosol activated the selective transport of substrate proteins into these lysosomes. |
| GO:1990832 slow axonal transport | IEP PMID:11933046 Slow axonal transport of the cytosolic chaperonin CCT with H... | MARK AS OVER ANNOTATED | Summary: Radiolabelled Hsc73 moves with CCT and actin in slow component b of axonal transport in rat motor neurons. Reason: Changed from KEEP_AS_NON_CORE: the data show Hsc73 is carried as cargo of slow axonal transport. Being transported does not show that Hsc73 performs the transport process; the authors propose a role in keeping actin native during transport, not in transport itself. Supporting Evidence: PMID:11933046 appeared to be labeled in "slow component b" of axonal transport along with the molecular chaperone Hsc73 and actin PMID:11933046 Our results are consistent with molecular chaperones having a post-translational role in maintaining the native form of actin during its slow transport to the axon terminal |
| GO:1990833 clathrin-uncoating ATPase activity | IDA PMID:8363588 High-level expression of soluble rat hsc70 in Escherichia co... | ACCEPT | Summary: Manual review: clathrin-uncoating ATPase activity is consistent with known biology of Hspa8. Reason: Purified recombinant rat hsc70 (the clathrin-uncoating ATPase) dissociates clathrin from coated vesicles; core activity. Supporting Evidence: PMID:8363588 The cloned enzyme is capable of dissociating clathrin from bovine coated vesicle. PMID:2527848 possesses clathrin cage-specific ATPase activity |
| GO:1990834 response to odorant | IEP PMID:11268007 Odorants as cell-type specific activators of a heat shock re... | KEEP AS NON CORE | Summary: Manual review: response to odorant may be context-dependent or peripheral for Hspa8. Reason: Odorant exposure induces HSC70 in olfactory supporting cells; a valid IEP response annotation, non-core. Supporting Evidence: PMID:11268007 Odorant exposure led to transient, selective induction of HSP70, HSC70, HSP25, and ubiquitin immunoreactivities |
| GO:0000082 G1/S transition of mitotic cell cycle | IEP PMID:10198213 73-kDa heat shock cognate protein interacts directly with P2... | MARK AS OVER ANNOTATED | Summary: Hsc73-p27Kip1 complex formation in rat FRTL-5 cells is cell-cycle dependent, peaking at G1/S. Reason: Changed from KEEP_AS_NON_CORE: a cell-cycle-dependent change in complex abundance shows correlation, not that Hsc73 carries out the G1/S transition. The authors only conclude that 73hsc "might be involved". Supporting Evidence: PMID:10198213 This complex formation of 73hsc and P27Kip1 was cell cycle dependent |
| GO:0070301 cellular response to hydrogen peroxide | IEP PMID:10329212 A physiologically relevant hyperthermia selectively activate... | KEEP AS NON CORE | Summary: Manual review: cellular response to hydrogen peroxide may be context-dependent or peripheral for Hspa8. Reason: Pre-existing hsc70 distribution correlates with protection against H2O2 in H9c2 cells; valid IEP response annotation, non-core. Supporting Evidence: PMID:10329212 The initial protection against the milder H2O2challenge correlated with a homogenous distribution of pre-existing hsc70. |
| GO:1904593 prostaglandin binding | IPI PMID:21445266 Proteomic identification of protein targets for 15-deoxy-Ξ(1... | MARK AS OVER ANNOTATED | Summary: A proteomic screen (2D gel, MALDI-TOF MS) identified rat Hspa8 among cortical plasma-membrane proteins adducted by the electrophilic prostaglandin 15d-PGJ2. The putative adduction site (Cys603) was inferred only by sequence homology (5/16 identical residues) to the IkB-kinase beta Cys179 site, not mapped directly, and Hspa8 was not among the targets confirmed by streptavidin pull-down (Figure 10). Reason: Changed from REMOVE: the full text does identify Hspa8 as a 15d-PGJ2 target, so the observation is real and the experimental row should not be removed. But 15d-PGJ2 forms covalent Michael adducts with free cysteine thiols; calling this a prostaglandin binding function overstates a non-specific electrophile adduct. Supporting Evidence: PMID:21445266 It possesses an Ξ±, Ξ²-unsaturated carbonyl group in the cyclopentane ring that can form covalent adducts with free thiols in proteins by Michael addition. PMID:21445266 Hspa8 contained Cys603 responded to the Cys179 of IΞΊB-kinase Ξ². PMID:21445266 The amino sequence of Hspa8 from Lys597 to Leu610 was homologous to that of IΞΊB-kinase Ξ² from Lys171 to Leu186. |
| GO:0001916 positive regulation of T cell mediated cytotoxicity | IMP PMID:8871636 Involvement of peptide antigens in the cytotoxicity between ... | KEEP AS NON CORE | Summary: Manual review: positive regulation of T cell mediated cytotoxicity may be context-dependent or peripheral for Hspa8. Reason: An anti-hsc70 antibody blocks DNT-cell cytotoxicity against transformed rat cells; a context-specific immunological role. Supporting Evidence: PMID:8871636 Anti-rat hsc70 mAb completely blocked this cytotoxicity. PMID:8871636 these data suggest that the complex of peptide Ag and hsc70 is involved in the cytotoxic mechanism between hsc70 and DNT cells |
| GO:0005776 autophagosome | IDA PMID:20392947 Essential role of the redox-sensitive kinase p66shc in deter... | KEEP AS NON CORE | Summary: Manual review: autophagosome may be context-dependent or peripheral for Hspa8. Reason: HSC70 relocalizes to autophagosomes in preconditioned neurons; context-dependent location. Supporting Evidence: PMID:20392947 The constitutively expressed chaperone HSC70 relocalized to autophagosomes. |
| GO:0005874 microtubule | IDA PMID:2527848 Beta-internexin is a microtubule-associated protein identica... | KEEP AS NON CORE | Summary: Manual review: microtubule may be context-dependent or peripheral for Hspa8. Reason: Hsc70 (beta-internexin) co-purifies with rat brain microtubules; non-core location. Supporting Evidence: PMID:2527848 We purify beta-internexin from rat brain microtubules and confirm its identity with hsc70 and the clathrin-uncoating ATPase |
| GO:0005882 intermediate filament | IDA PMID:7721954 Integrity of intermediate filaments is associated with the d... | KEEP AS NON CORE | Summary: Manual review: intermediate filament may be context-dependent or peripheral for Hspa8. Reason: HSC70 colocalizes with vimentin intermediate filaments in heat-shocked 9L cells; non-core location. Supporting Evidence: PMID:7721954 HSC70 was found to be co-localized with vimentin during these changes. |
| GO:0009986 cell surface | IDA PMID:8228242 70 kDa heat shock cognate protein is a transformation-associ... | KEEP AS NON CORE | Summary: Manual review: cell surface may be context-dependent or peripheral for Hspa8. Reason: A stress-enhanced cell-surface antigen on transformed rat cells is rat 70 kDa HSC; non-core location. Supporting Evidence: PMID:8228242 the cell surface expression of Ag was clearly enhanced by several stressors PMID:8228242 indicating that 067-defined Ag may be a rat 70 kDa HSC |
| GO:0010628 positive regulation of gene expression | IMP PMID:8734434 Antisense oligonucleotide to the 70-kDa heat shock cognate p... | KEEP AS NON CORE | Summary: Manual review: positive regulation of gene expression may be context-dependent or peripheral for Hspa8. Reason: Antisense knockdown of HSC70 selectively lowers MBP synthesis in oligodendrocytes, consistent with a chaperone role for MBP; indirect, non-core. Supporting Evidence: PMID:8734434 These data show that when HSC70 protein content is sufficiently reduced by antisense oligonucleotide, synthesis of MBP (but not PLP or pi) is correspondingly down-regulated |
| GO:0032279 asymmetric synapse | IDA PMID:11230095 Presence of both constitutive and inducible forms of heat sh... | KEEP AS NON CORE | Summary: Manual review: asymmetric synapse may be context-dependent or peripheral for Hspa8. Reason: Hsc70 is mainly associated with asymmetric PSDs; non-core location. Supporting Evidence: PMID:11230095 both Hsp70 and Hsc70 are mainly associated with asymmetrical PSDs |
| GO:0043197 dendritic spine | IDA PMID:11230095 Presence of both constitutive and inducible forms of heat sh... | KEEP AS NON CORE | Summary: Manual review: dendritic spine may be context-dependent or peripheral for Hspa8. Reason: Hsc70 is associated with spine apparatus-like cisternae and subsynaptic structures; non-core location. Supporting Evidence: PMID:11230095 Hsc70 is also associated with amorphous subsynaptic structures and spine apparatus-like cisternae |
| GO:0043198 dendritic shaft | IDA PMID:11230095 Presence of both constitutive and inducible forms of heat sh... | KEEP AS NON CORE | Summary: Manual review: dendritic shaft may be context-dependent or peripheral for Hspa8. Reason: Hsc70 is distributed throughout the soma and dendrites of hippocampal neurons; non-core location. Supporting Evidence: PMID:11230095 both Hsp70 and Hsc70 immunoreactivities are distributed throughout the soma and dendrites |
| GO:0043204 perikaryon | IDA PMID:11230095 Presence of both constitutive and inducible forms of heat sh... | KEEP AS NON CORE | Summary: Manual review: perikaryon may be context-dependent or peripheral for Hspa8. Reason: Hsc70 is distributed throughout the neuronal soma; non-core location. Supporting Evidence: PMID:11230095 both Hsp70 and Hsc70 immunoreactivities are distributed throughout the soma and dendrites |
| GO:0045471 response to ethanol | IEP PMID:12170112 Stress response caused by chronic alcohol intake in aged rat... | KEEP AS NON CORE | Summary: Manual review: response to ethanol may be context-dependent or peripheral for Hspa8. Reason: Chronic ethanol increases Hsc70 levels in aged rat brain; valid IEP response annotation, non-core. Supporting Evidence: PMID:12170112 chronic consumption of alcohol increased levels of Hsc70 and heat-unstable proteins |
| GO:0050766 positive regulation of phagocytosis | IMP PMID:9886410 Clathrin-coated pit-associated proteins are required for alv... | KEEP AS NON CORE | Summary: Manual review: positive regulation of phagocytosis may be context-dependent or peripheral for Hspa8. Reason: Antibody blockade of hsc70 inhibits alveolar macrophage phagocytosis, attributed to its clathrin-turnover role; indirect, non-core. Supporting Evidence: PMID:9886410 Ab blockade of hsc70, which catalyzes clathrin turnover, also inhibited phagocytosis |
| GO:1904592 positive regulation of protein refolding | IDA PMID:11360998 The effect of mutating arginine-469 on the substrate binding... | KEEP AS NON CORE | Summary: Manual review: positive regulation of protein refolding may be context-dependent or peripheral for Hspa8. Reason: Rat hsc70 refolds denatured luciferase with DnaJ; the activity is real, though hsc70 performs the refolding rather than regulating it. Kept as non-core alongside the accepted protein refolding terms. Supporting Evidence: PMID:11360998 In the presence of DnaJ, the capability of hsc70(R469C) to refold the denatured luciferase was decreased by 50%. PMID:11360998 Thus, the affinity of hsc70(R469C) for polypeptide substrates is reduced. |
| GO:0001822 kidney development | IEP PMID:9764759 Constitutive expression of heat shock proteins Hsp90, Hsc70,... | MARK AS OVER ANNOTATED | Summary: Hsc70 protein levels decrease during postnatal kidney development in rat. Reason: Changed from KEEP_AS_NON_CORE: a developmental change in expression level shows that Hsc70 is regulated during kidney development, not that it takes part in the process. Supporting Evidence: PMID:9764759 A pronounced decrease in Hsp90 and Hsc70 was observed during postnatal development of the kidney |
| GO:0001917 photoreceptor inner segment | IDA PMID:10549657 Constitutive and inducible heat shock protein 70 immunoreact... | KEEP AS NON CORE | Summary: Manual review: photoreceptor inner segment may be context-dependent or peripheral for Hspa8. Reason: Hsc70 immunoreactivity is present in all retinal layers except outer segments, including photoreceptor inner segments; non-core location. Supporting Evidence: PMID:10549657 Hsc70 immunoreactivity was detected in all layers of the retina, except the outer segments. |
| GO:0005765 lysosomal membrane | IDA PMID:9038169 A population of rat liver lysosomes responsible for the sele... | ACCEPT | Summary: Manual review: PMID:9038169 (Cuervo, Dice & Knecht 1997) is a foundational CMA paper showing lysosomal hsc73 mediates selective uptake/degradation of cytosolic substrates in rat liver lysosomes. The lysosomal membrane is a functional location of the core CMA role of HSC70. Reason: The lysosomal membrane is a bona fide functional location for the core chaperone-mediated autophagy role of HSC70, directly demonstrated experimentally in PMID:9038169. Supporting Evidence: PMID:9038169 the hsc73 located within lysosomes appears to be required for efficient uptake of cytosolic proteins by these organelles |
| GO:0006606 protein import into nucleus | IMP PMID:8892974 Evidence for the existence of a novel mechanism for the nucl... | MARK AS OVER ANNOTATED | Summary: The study tracked nuclear import of radiolabelled rat hsc70 itself in Xenopus oocytes, finding that it uses a non-classical import signal. Reason: Changed from KEEP_AS_NON_CORE: in this paper hsc70 is the import substrate, so the data concern how hsc70 enters the nucleus, not hsc70 performing protein import into the nucleus. The data are real but annotating them as participation in nuclear import overstates them. Supporting Evidence: PMID:8892974 Purified rat hsc70, and hybrid proteins, which contained either the full-length or the mutated forms of rat hsc70 fused with the maltose binding protein, were labeled with 125I and used as transport substrates. PMID:8892974 the present results indicate that hsc70 utilizes a novel import signal and enters the nucleus by a different mechanism |
| GO:0007519 skeletal muscle tissue development | IEP PMID:12909603 Endogenous expression and developmental changes of HSP72 in ... | MARK AS OVER ANNOTATED | Summary: HSC73 levels in developing rat skeletal muscle reach adult levels by postnatal day 3 and remain unchanged. Reason: Changed from KEEP_AS_NON_CORE: the authors conclude HSC73 expression is not developmentally regulated in muscle. An expression profile does not show HSC73 takes part in skeletal muscle development. REMOVE was considered, since the abstract argues against a developmental expression correlation, but the abstract also reports that HSC73 rises to adult levels by postnatal day 3, a perinatal change the curator may have used. The paper is abstract-only in our cache, so the softer action is kept rather than overruling an experimental row. Supporting Evidence: PMID:12909603 These results indicate that the expression of HSP72, but not HSC73, is influenced by both endogenous and exogenous factors during the embryonic and early developmental periods. |
| GO:0008088 axo-dendritic transport | IEP PMID:11933046 Slow axonal transport of the cytosolic chaperonin CCT with H... | MARK AS OVER ANNOTATED | Summary: Hsc73 is transported in slow component b of axonal transport in rat motor neurons. Reason: Changed from KEEP_AS_NON_CORE: Hsc73 is a cargo of axonal transport in this study. Moving with the transport machinery does not show that Hsc73 performs axo-dendritic transport. Supporting Evidence: PMID:11933046 appeared to be labeled in "slow component b" of axonal transport along with the molecular chaperone Hsc73 and actin |
| GO:0009410 response to xenobiotic stimulus | IEP PMID:10425221 Identification of a novel splice variant of heat shock cogna... | KEEP AS NON CORE | Summary: Manual review: response to xenobiotic stimulus may be context-dependent or peripheral for Hspa8. Reason: Chronic antidepressant treatment induces the HSC49 splice variant of Hsc70 in rat frontal cortex; valid IEP response annotation, non-core. Supporting Evidence: PMID:10425221 Chronic treatment with antidepressant, imipramine or sertraline, induced a 38.5 or 22.5% increase in mRNA levels in rat frontal cortex |
| GO:0014823 response to activity | IEP PMID:10606824 The effects of exercise duration on adrenal HSP72/73 inducti... | KEEP AS NON CORE | Summary: Manual review: response to activity may be context-dependent or peripheral for Hspa8. Reason: Prolonged exercise training raises adrenal HSP73; valid IEP response annotation, non-core. Supporting Evidence: PMID:10606824 Longer exercise durations (>60 min day-1), also resulted in small but significant increase in HSP73 level |
| GO:0021549 cerebellum development | IEP PMID:9764759 Constitutive expression of heat shock proteins Hsp90, Hsc70,... | MARK AS OVER ANNOTATED | Summary: Hsc70 protein is abundant in rat brain throughout postnatal development. Reason: Changed from KEEP_AS_NON_CORE: constant abundance through development does not show that Hsc70 takes part in cerebellum development. Supporting Evidence: PMID:9764759 Hsc70 protein is abundant throughout postnatal neural development |
| GO:0034605 cellular response to heat | IEP PMID:8955942 Differential expression of heat shock 70 proteins in primary... | KEEP AS NON CORE | Summary: Manual review: cellular response to heat may be context-dependent or peripheral for Hspa8. Reason: Heat shock transiently increases Hsc70 mRNA in rat cerebellar cultures; valid IEP response annotation, non-core. Supporting Evidence: PMID:8955942 Hsc70 mRNA levels were also increased after heat shock, but the increase was more transient. |
| GO:0042277 peptide binding | IDA PMID:8363588 High-level expression of soluble rat hsc70 in Escherichia co... | KEEP AS NON CORE | Summary: Manual review: peptide binding may be context-dependent or peripheral for Hspa8. Reason: Recombinant rat hsc70 binds model peptides with micromolar affinity, reflecting its substrate-binding domain; non-core relative to the chaperone activity. Supporting Evidence: PMID:8363588 the dissociation constants of S-peptide, peptides P3a and GT4 for recombinant hsc70 are 7.6, 13 and 100 microM respectively |
| GO:0042594 response to starvation | IEP PMID:9038169 A population of rat liver lysosomes responsible for the sele... | KEEP AS NON CORE | Summary: Manual review: response to starvation may be context-dependent or peripheral for Hspa8. Reason: Starvation increases lumenal hsc73 in rat liver lysosomes; valid IEP response annotation, non-core. Supporting Evidence: PMID:9038169 88 h of starvation also increased the amount of hsc73 within their lysosomal lumen |
| GO:0044743 protein transmembrane import into intracellular organelle | IEP PMID:9038169 A population of rat liver lysosomes responsible for the sele... | KEEP AS NON CORE | Summary: Manual review: protein transmembrane import into intracellular organelle may be context-dependent or peripheral for Hspa8. Reason: Lumenal hsc73 levels correlate with, and preloading activates, selective substrate uptake into lysosomes; a CMA translocation-related role, kept as non-core. Supporting Evidence: PMID:9038169 Preloading of the lysosomal population that is devoid of lumenal hsc73 with hsc73 isolated from cytosol activated the selective transport of substrate proteins into these lysosomes. PMID:9038169 the hsc73 located within lysosomes appears to be required for efficient uptake of cytosolic proteins by these organelles |
| GO:0045862 positive regulation of proteolysis | IDA PMID:9987077 Direct lysosomal uptake of alpha 2-microglobulin contributes... | KEEP AS NON CORE | Summary: Manual review: positive regulation of proteolysis may be context-dependent or peripheral for Hspa8. Reason: Hsc73 is required for direct lysosomal uptake of alpha 2-microglobulin, promoting its degradation; a CMA-related role, kept as non-core. Supporting Evidence: PMID:9987077 alpha 2 mu can be directly transported into isolated lysosomes in the presence of the heat shock cognate protein of 73 kDa (hsc73) |
| GO:0046777 protein autophosphorylation | IDA PMID:8420978 Aspartyl residue 10 is essential for ATPase activity of rat ... | MARK AS OVER ANNOTATED | Summary: PMID:8420978 reports that purified rat hsc70 and its mutants autophosphorylate in vitro at a substoichiometric level (<1% of molecules), not correlated with ATPase activity. Reason: Changed from REMOVE: the previous review wrongly stated the paper has no autophosphorylation evidence; the abstract reports it. The observation is minor (<1% stoichiometry, in vitro, uncoupled from ATPase activity), so presenting autophosphorylation as a biological process of Hsc70 overstates it. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. Supporting Evidence: PMID:8420978 Purified hsc70 and its mutants autophosphorylate in vitro at a substoichiometric level. On average, less than 1% of the hsc70 and Nt-hsc70 proteins are phosphorylated. PMID:8420978 autophosphorylation of hsc70 and its mutants is not correlated with their ability to hydrolyze ATP |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:10549657 Constitutive and inducible heat shock protein 70 immunoreact... | KEEP AS NON CORE | Summary: Manual review: perinuclear region of cytoplasm may be context-dependent or peripheral for Hspa8. Reason: The rat eye immunostaining study shows cytoplasmic Hsc70 in retinal cells; perinuclear distribution is a plausible context-specific detail recorded by the curator from the full text. Supporting Evidence: PMID:10549657 Hsc70 immunoreactivity was detected in all layers of the retina, except the outer segments. |
| GO:0071276 cellular response to cadmium ion | IEP PMID:9736451 Involvement of heat shock elements and basal transcription e... | KEEP AS NON CORE | Summary: Manual review: cellular response to cadmium ion may be context-dependent or peripheral for Hspa8. Reason: Cadmium enhances HSC70 expression in 9L cells; valid IEP response annotation, non-core. Supporting Evidence: PMID:9736451 induction of the 70-kDa HSP (HSP70) and enhanced expression of its cognate (HSC70) by cadmium are concentration dependent |
| GO:0072318 clathrin coat disassembly | IDA PMID:8363588 High-level expression of soluble rat hsc70 in Escherichia co... | ACCEPT | Summary: Manual review: clathrin coat disassembly is consistent with known biology of Hspa8. Reason: Purified recombinant rat hsc70 dissociates clathrin from coated vesicles; core process. Supporting Evidence: PMID:8363588 The cloned enzyme is capable of dissociating clathrin from bovine coated vesicle. |
| GO:1990836 lysosomal matrix | IDA PMID:9038169 A population of rat liver lysosomes responsible for the sele... | KEEP AS NON CORE | Summary: Manual review: lysosomal matrix may be context-dependent or peripheral for Hspa8. Reason: hsc73 is present within the lumen of a rat liver lysosome population active in CMA; non-core location. Supporting Evidence: PMID:9038169 one contains the heat shock cognate protein of 73 kDa (hsc73) within the lysosomal lumen |
| GO:0010045 response to nickel cation | IEP PMID:15736156 Effects of nickel poisoning on expression pattern of the 72/... | KEEP AS NON CORE | Summary: Manual review: response to nickel cation may be context-dependent or peripheral for Hspa8. Reason: Nickel exposure raises HSP73 in rat kidney; valid IEP response annotation, non-core. Supporting Evidence: PMID:15736156 In kidney of nickel-treated animals, HSP73 and the 96 kDa proteins were overexpressed |
| GO:0010667 negative regulation of cardiac muscle cell apoptotic process | IMP PMID:21958194 Constitutive heat shock protein 70 interacts with Ξ±-enolase ... | KEEP AS NON CORE | Summary: Manual review: negative regulation of cardiac muscle cell apoptotic process may be context-dependent or peripheral for Hspa8. Reason: Hsc70 knockdown worsens and overexpression reduces oxidative damage in H9c2 cardiomyocytes; a context-specific cytoprotective role. Supporting Evidence: PMID:21958194 Hsc70 deficiency aggravated the decrease of Ξ±-enolase activity and cell damage in H(2)O(2) treated H9c2 cells PMID:21958194 Hsc70-overexpression alleviated the H(2)O(2)-induced decrease of Ξ±-enolase activity and cell damage |
| GO:0019899 enzyme binding | IPI PMID:21958194 Constitutive heat shock protein 70 interacts with Ξ±-enolase ... | KEEP AS NON CORE | Summary: Manual review: enzyme binding may be context-dependent or peripheral for Hspa8. Reason: Rat Hsc70 interacts with the glycolytic enzyme alpha-enolase (co-IP, overlay); a real interaction, non-core. Supporting Evidence: PMID:21958194 we have identified Ξ±-enolase, a rate-limiting enzyme in glycolysis, as a novel Hsc70-interacting protein |
| GO:0030424 axon | IDA PMID:9878698 Presence of molecular chaperones, heat shock cognate (Hsc) 7... | KEEP AS NON CORE | Summary: Manual review: axon may be context-dependent or peripheral for Hspa8. Reason: Hsc70 immunoreactivity is present in axons in rat brain; non-core location. Supporting Evidence: PMID:9878698 The immunoreactivities of Hsc70 (p73) were distributed throughout the rat brain, in neuronal somata, dendrites and axons. |
| GO:0030900 forebrain development | IEP PMID:9878698 Presence of molecular chaperones, heat shock cognate (Hsc) 7... | MARK AS OVER ANNOTATED | Summary: PMID:9878698 is an immunolocalization study of Hsc70 and Hsp40 in adult rat brain synapses. Reason: Changed from KEEP_AS_NON_CORE: the abstract reports localization, not a developmental time course, and the presence of a protein in forebrain neurons does not show it takes part in forebrain development. Supporting Evidence: PMID:9878698 The immunoreactivities of Hsc70 (p73) were distributed throughout the rat brain, in neuronal somata, dendrites and axons. |
| GO:0031686 A1 adenosine receptor binding | IPI PMID:10866672 The heat shock cognate protein hsc73 assembles with A(1) ade... | KEEP AS NON CORE | Summary: Manual review: PMID:10866672 documents a direct, specific rat hsc73-A1 adenosine receptor interaction (Kd ~0.5 nM by surface plasmon resonance, plus affinity chromatography, co-immunoprecipitation and confocal colocalization). This is a genuine documented interaction but is peripheral to the evolved core chaperone function. Reason: Well-supported experimental rat interaction (PMID:10866672) but peripheral to the core HSC70 chaperone, clathrin-uncoating, and CMA functions; retained as non-core rather than removed. Supporting Evidence: PMID:10866672 purified A(1)Rs interact specifically with hsc73 with a dissociation constant in the nanomolar range |
| GO:0032355 response to estradiol | IEP PMID:9990085 The 70-kDa heat shock cognate protein (Hsc73) gene is enhanc... | KEEP AS NON CORE | Summary: Manual review: response to estradiol may be context-dependent or peripheral for Hspa8. Reason: Estradiol plus progesterone enhance Hsc73 expression in rat pituitary and hypothalamus; valid IEP response annotation, non-core. Supporting Evidence: PMID:9990085 the Hsc73 gene is enhanced by E and P in the pituitary and subregions of the VMH |
| GO:0032570 response to progesterone | IEP PMID:9990085 The 70-kDa heat shock cognate protein (Hsc73) gene is enhanc... | KEEP AS NON CORE | Summary: Manual review: response to progesterone may be context-dependent or peripheral for Hspa8. Reason: Estradiol plus progesterone enhance Hsc73 expression in rat pituitary and hypothalamus; valid IEP response annotation, non-core. Supporting Evidence: PMID:9990085 the Hsc73 gene is enhanced by E and P in the pituitary and subregions of the VMH |
| GO:0043025 neuronal cell body | IDA PMID:9878698 Presence of molecular chaperones, heat shock cognate (Hsc) 7... | KEEP AS NON CORE | Summary: Manual review: neuronal cell body may be context-dependent or peripheral for Hspa8. Reason: Hsc70 immunoreactivity is present in neuronal somata in rat brain; non-core location. Supporting Evidence: PMID:9878698 The immunoreactivities of Hsc70 (p73) were distributed throughout the rat brain, in neuronal somata, dendrites and axons. |
| GO:0043085 positive regulation of catalytic activity | IMP PMID:21958194 Constitutive heat shock protein 70 interacts with Ξ±-enolase ... | KEEP AS NON CORE | Summary: Manual review: positive regulation of catalytic activity may be context-dependent or peripheral for Hspa8. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. Supporting Evidence: PMID:21958194 Hsc70-overexpression alleviated the H(2)O(2)-induced decrease of Ξ±-enolase activity and cell damage |
| GO:0043195 terminal bouton | IDA PMID:9878698 Presence of molecular chaperones, heat shock cognate (Hsc) 7... | KEEP AS NON CORE | Summary: Manual review: terminal bouton may be context-dependent or peripheral for Hspa8. Reason: Presynaptic terminals are Hsc70-immunoreactive in rat brain; non-core location. Supporting Evidence: PMID:9878698 Presynaptic terminals, but less frequently than postsynaptic staining, were also reactive. |
| GO:0044849 estrous cycle | IEP PMID:9990085 The 70-kDa heat shock cognate protein (Hsc73) gene is enhanc... | MARK AS OVER ANNOTATED | Summary: Hsc73 mRNA in rat ventromedial hypothalamus rises at proestrus and is enhanced by estrogen and progesterone. Reason: Changed from KEEP_AS_NON_CORE: hormone-dependent expression changes over the cycle show regulation (captured by the response-to-estradiol/progesterone terms), not that Hsc73 takes part in the estrous cycle. Supporting Evidence: PMID:9990085 significant increase in Hsc73 mRNA in the VMH and arcuate nucleus of animals during proestrus compared with those at diestrus-1 |
| GO:0032991 protein-containing complex | IDA PMID:20596529 Molecular composition of staufen2-containing ribonucleoprote... | KEEP AS NON CORE | Summary: Manual review: protein-containing complex may be context-dependent or peripheral for Hspa8. Reason: Hsc70 is a component of Staufen2-containing RNPs in embryonic rat brain, binding Stau2 directly in an ATP-regulated manner; non-core. Supporting Evidence: PMID:20596529 hsc70 is directly bound to Stau2 and this interaction is regulated by ATP |
| GO:0003723 RNA binding | IDA PMID:23159318 Identification in the rat brain of a set of nuclear proteins... | KEEP AS NON CORE | Summary: Manual review: RNA binding may be context-dependent or peripheral for Hspa8. Reason: Hsc70 was isolated with H1 histone mRNA from rat brain nuclei; RNA association is real but non-core. Supporting Evidence: PMID:23159318 molecular chaperones (heat shock cognate 70, Hsc70) were identified by mass spectrometry |
| GO:0005515 protein binding | IPI PMID:23159318 Identification in the rat brain of a set of nuclear proteins... | REMOVE | Summary: Co-immunoprecipitation shows rat brain nuclear Hsc70 interacts with hnRNP K in an H1 mRNA-binding protein set. Reason: Generic protein binding is uninformative, and the abstract does not support a more specific molecular function for the Hsc70-hnRNP K interaction. Removal does not mean the reported interaction is false. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. Supporting Evidence: PMID:23159318 We found that hnRNP K interacts with both hnRNP A1 and Hsc70 |
| GO:0046034 ATP metabolic process | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Transferred from human HSPA8 (IDA in PMID:23921388, a study of HSPA8 lysine methylation that assayed ATP-dependent activity). Reason: Changed from KEEP_AS_NON_CORE: HSC70 hydrolyses ATP as the energy source for its chaperone cycle, which is already captured by ATP hydrolysis activity. Using ATP to power a chaperone does not make HSC70 part of the metabolic pathways that set cellular ATP levels, so this process term overstates the ATPase evidence. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P11142 Β· human HSPA8 UNRESOLVED Human HSPA8 IDA (PMID:23921388) comes from a lysine-methylation study that measured ATP-dependent chaperone properties. The underlying ATPase observation is real, but its scoping as ATP metabolic process applies to the source as well as the target. Supporting Evidence: PMID:23921388 Hsp70 proteins constitute an evolutionarily conserved protein family of ATP-dependent molecular chaperones UniProtKB:P63018 This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones. |
| GO:0055131 C3HC4-type RING finger domain binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: C3HC4-type RING finger domain binding may be context-dependent or peripheral for Hspa8. Reason: Transferred from human HSPA8, which interacts with the RING-finger protein RNF207; real but non-core. Supporting Evidence: PMID:25281747 coexpression of RNF207 and HSP70 increased HERG expression compared with HSP70 alone UniProtKB:P63018 Interacts with RNF207 |
| GO:0048026 positive regulation of mRNA splicing, via spliceosome | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: positive regulation of mRNA splicing, via spliceosome may be context-dependent or peripheral for Hspa8. Reason: Transferred from mouse Hspa8; HSC70 is a less stably associated component of the PRP19-CDC5L spliceosomal complex. Supporting Evidence: UniProtKB:P63018 Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. |
| GO:0001664 G protein-coupled receptor binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from human HSPA8 (IPI with the GPCR GPR37/Pael-R, PMID:12150907). Rat Hsc73 also binds the A1 adenosine receptor directly (PMID:10866672). Reason: Changed from REMOVE: the human source is a real IPI with the unfolded Pael receptor (GPR37) in a CHIP/Parkin complex, and rat has its own direct evidence for binding a GPCR (A1 adenosine receptor, nanomolar Kd). The term is supported; the interactions are client or regulatory and not core chaperone function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P11142 Β· human HSPA8 SUPPORTS TRANSFER Human HSPA8 IPI with GPR37/Pael-R (PMID:12150907); the transfer is corroborated by rat hsc73 binding to the A1 adenosine receptor (PMID:10866672). Supporting Evidence: PMID:12150907 Here, we show that CHIP, Hsp70, Parkin, and Pael-R formed a complex in vitro and in vivo. PMID:10866672 purified A(1)Rs interact specifically with hsc73 with a dissociation constant in the nanomolar range |
| GO:0070062 extracellular exosome | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: extracellular exosome may be context-dependent or peripheral for Hspa8. Reason: Transferred from mouse Hspa8; HSC70 is found in exosomes (e.g. bound to exosomal transferrin receptor in reticulocytes). Non-core location. Supporting Evidence: PMID:11133993 The transferrin receptor (TfR) of reticulocytes is released in vesicular form (exosomes) during their maturation to erythrocytes. |
| GO:0005515 protein binding | IPI PMID:18307834 Cathepsin C propeptide interacts with intestinal alkaline ph... | REMOVE | Summary: In human Caco-2 cells, the cathepsin C propeptide co-immunoprecipitates with heat shock cognate protein 70 (with UniProtKB:P80067). Reason: Generic protein binding is uninformative, and the abstract does not support a more specific molecular function for this co-immunoprecipitation. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:18307834 Cathepsin C propeptide interacted with proteins with a molecular mass of approximately 70 kDa, including IAP and heat shock cognate protein 70. |
| GO:0005524 ATP binding | ISO GO_REF:0000121 | ACCEPT | Summary: Manual review: ATP binding is consistent with known biology of Hspa8. Reason: Transferred from mouse Hspa8; rat hsc70 binds ATP with high affinity via its N-terminal nucleotide-binding domain. Supporting Evidence: PMID:8363588 Binding of [alpha-32P]ATP by purified recombinant hsc70 was analysed by Scatchard plot. UniProtKB:P63018 The N-terminal nucleotide binding domain (NBD) (also known as the ATPase domain) is responsible for binding and hydrolyzing ATP. |
| GO:0019899 enzyme binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: enzyme binding may be context-dependent or peripheral for Hspa8. Reason: Transferred from human HSPA8, which binds the methyltransferase METTL21A (HSPA-KMT); real but non-core. Supporting Evidence: PMID:23921388 we identified the methyltransferase METTL21A as the enzyme responsible for trimethylation of a conserved lysine residue found in several human Hsp70 (HSPA) proteins |
| GO:0031072 heat shock protein binding | ISO GO_REF:0000121 | ACCEPT | Summary: Manual review: heat shock protein binding is consistent with known biology of Hspa8. Reason: Transferred from mouse Hspa8; HSC70 binding to Hsp40 and other heat shock proteins is intrinsic to its cycle. Supporting Evidence: PMID:9528774 mediates the interaction of Hsc70 with Hsp40 and Hop UniProtKB:P63018 Interacts with HOPX, STUB1, HSP40, HSP90, BAG2 and BAG3 |
| GO:1902904 negative regulation of supramolecular fiber organization | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: negative regulation of supramolecular fiber organization may be context-dependent or peripheral for Hspa8. Reason: Transferred from human HSPA8, which binds monomeric and fibrillar alpha-synuclein; a context-specific anti-aggregation role, non-core. Supporting Evidence: PMID:23921388 trimethylation of HSPA8 (Hsc70) has functional consequences, as it alters the affinity of the chaperone for both the monomeric and fibrillar forms of the Parkinson disease-associated protein Ξ±-synuclein |
| GO:0005829 cytosol | ISO GO_REF:0000121 | ACCEPT | Summary: Manual review: cytosol is consistent with known biology of Hspa8. Reason: Transferred from mouse Hspa8; the cytosol is the predominant site of HSC70 activity. Supporting Evidence: file:rat/Hspa8/Hspa8-deep-research-falcon.md **Cytosol**: the predominant pool performing general chaperoning and recognizing CMA substrates (KFERQ-like motifs) |
| GO:0042026 protein refolding | ISO GO_REF:0000121 | ACCEPT | Summary: Manual review: protein refolding is consistent with known biology of Hspa8. Reason: Transferred from human HSPA8; consistent with rat refolding assays. Supporting Evidence: PMID:11360998 In the presence of DnaJ, the capability of hsc70(R469C) to refold the denatured luciferase was decreased by 50%. |
| GO:0051082 unfolded protein binding | ISO GO_REF:0000121 | MODIFY | Summary: Manual review: unfolded protein binding is better represented by a more specific replacement term for Hspa8. Reason: Modified to align with current curation guidance and improve term specificity. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. QuickGO confirms GO:0051082 is obsolete ("this binding term should be replaced by an activity term such as protein folding chaperone (GO:0044183) or unfolded protein holdase activity (GO:0140309)"); GOA now carries the recommended replacement GO:0044183 for Hspa8. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P11142 Β· human HSPA8 SUPPORTS SOURCE BUT NOT TARGET Human donor evidence for unfolded-protein binding is sound; the target-side issue is term choice -- protein folding chaperone (GO:0044183) better captures the Hsc70 activity. MGI:MGI:105384 Β· mouse Hspa8 SUPPORTS SOURCE BUT NOT TARGET Mouse Hspa8 donor likewise supports client-protein binding; folded into the same MODIFY to GO:0044183 protein folding chaperone. Proposed replacements: protein folding chaperone Supporting Evidence: UniProtKB:P63018 In the ATP-bound form, it has a low affinity for substrate proteins. However, upon hydrolysis of the ATP to ADP, it undergoes a conformational change that increases its affinity for substrate proteins. |
| GO:0000974 Prp19 complex | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Manual review: Prp19 complex may be context-dependent or peripheral for Hspa8. Reason: HSC70 is a less stably associated component of the PRP19-CDC5L complex (by similarity to human); non-core. Supporting Evidence: UniProtKB:P63018 Component of the PRP19-CDC5L splicing complex composed of a core complex comprising a homotetramer of PRPF19, CDC5L, PLRG1 and BCAS2, and at least three less stably associated proteins CTNNBL1, CWC15 and HSPA8 |
| GO:0000974 Prp19 complex | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: Prp19 complex may be context-dependent or peripheral for Hspa8. Reason: Transferred; HSC70 is a less stably associated component of the PRP19-CDC5L complex. Non-core. Supporting Evidence: UniProtKB:P63018 Component of the PRP19-CDC5L splicing complex composed of a core complex comprising a homotetramer of PRPF19, CDC5L, PLRG1 and BCAS2, and at least three less stably associated proteins CTNNBL1, CWC15 and HSPA8 |
| GO:0005634 nucleus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Manual review: HSC70 has documented nuclear/nucleolar pools, but the nucleus is not the site of its core chaperone, clathrin-uncoating, or CMA functions. Reason: HSC70 shuttles into the nucleus, especially under heat shock; valid but non-core location. Supporting Evidence: UniProtKB:P63018 Translocates rapidly from the cytoplasm to the nuclei, and especially to the nucleoli, upon heat shock. |
| GO:0005634 nucleus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: HSC70 has documented nuclear/nucleolar pools, but the nucleus is not the site of its core chaperone, clathrin-uncoating, or CMA functions. Reason: HSC70 shuttles into the nucleus, especially under heat shock; valid but non-core location. Supporting Evidence: UniProtKB:P63018 Translocates rapidly from the cytoplasm to the nuclei, and especially to the nucleoli, upon heat shock. |
| GO:0045892 negative regulation of DNA-templated transcription | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Manual review: negative regulation of DNA-templated transcription may be context-dependent or peripheral for Hspa8. Reason: HSC70 represses CITED1 coactivator function on Smad-mediated transcription (by similarity to human); context-specific, non-core. Supporting Evidence: UniProtKB:P63018 Acts as a repressor of transcriptional activation. Inhibits the transcriptional coactivator activity of CITED1 on Smad-mediated transcription. |
| GO:0005515 protein binding | IPI PMID:19457116 The molecular chaperone Hsc70 interacts with the vesicular m... | REMOVE | Summary: Rat Hsc70 binds the vesicular monoamine transporter VMAT2 (GST pull-down, co-IP) and inhibits its transport activity. Reason: Generic protein binding is uninformative. The paper shows a functional inhibitory effect on VMAT2, but the abstract does not establish a specific molecular-function term, so none is proposed here. Removal does not mean the reported interaction is false. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. Supporting Evidence: PMID:19457116 Co-immunoprecipitation experiments in brain tissue and heterologous cells confirmed this interaction. PMID:19457116 Recombinant Hsc70 produced a dose-dependent inhibition of VMAT2 activity. |
| GO:0008021 synaptic vesicle | IDA PMID:19457116 The molecular chaperone Hsc70 interacts with the vesicular m... | KEEP AS NON CORE | Summary: Manual review: synaptic vesicle may be context-dependent or peripheral for Hspa8. Reason: Hsc70 co-fractionates with purified synaptic vesicles together with VMAT2; non-core location. Supporting Evidence: PMID:19457116 VMAT2 and Hsc70 co-fractionated with purified synaptic vesicles obtained from a sucrose gradient |
| GO:0043025 neuronal cell body | IDA PMID:19457116 The molecular chaperone Hsc70 interacts with the vesicular m... | KEEP AS NON CORE | Summary: Manual review: neuronal cell body may be context-dependent or peripheral for Hspa8. Reason: The curator recorded a neuronal cell-body localization from the full text; consistent with Hsc70 immunoreactivity in neuronal somata reported elsewhere. Non-core location. Supporting Evidence: PMID:19457116 Co-immunoprecipitation experiments in brain tissue and heterologous cells confirmed this interaction. PMID:9878698 The immunoreactivities of Hsc70 (p73) were distributed throughout the rat brain, in neuronal somata, dendrites and axons. |
| GO:0045892 negative regulation of DNA-templated transcription | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: negative regulation of DNA-templated transcription may be context-dependent or peripheral for Hspa8. Reason: Transferred from human HSPA8; HSC70 represses CITED1-dependent transcriptional coactivation. Non-core. Supporting Evidence: UniProtKB:P63018 Acts as a repressor of transcriptional activation. Inhibits the transcriptional coactivator activity of CITED1 on Smad-mediated transcription. |
| GO:0005515 protein binding | IPI PMID:17877381 Increased striatal mRNA and protein levels of the immunophil... | REMOVE | Summary: A surface plasmon resonance and mass spectrometry screen identified heat shock protein 70 among FKBP-12-binding proteins in rat brain. Reason: Generic protein binding is uninformative, and a screening hit does not support a more specific molecular function. Removal does not mean the reported interaction is false. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. Supporting Evidence: PMID:17877381 we have identified potential binding partners to FKBP-12 that may be implicated in the pathophysiology of Parkinson's disease, such as alpha-enolase, 14-3-3 zeta/delta, pyruvate kinase isozymes, and heat shock protein 70 |
| GO:0005515 protein binding | IPI PMID:9528774 The carboxy-terminal domain of Hsc70 provides binding sites ... | MODIFY | Summary: The carboxy-terminal domain of Hsc70 binds the co-chaperones Hsp40 and Hop, while Hip binds the ATPase domain. Reason: Generic protein binding is uninformative. The paper maps Hsc70 binding sites for its chaperone cofactors (Hsp40, Hop, Hip, BAG-1), so protein-folding chaperone binding (GO:0051087) states the interaction more precisely. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. Proposed replacements: protein-folding chaperone binding Supporting Evidence: PMID:9528774 mediates the interaction of Hsc70 with Hsp40 and Hop PMID:9528774 Hence, Hsc70 possesses separate nonoverlapping binding sites for Hsp40, Hip, and Hop. |
| GO:0016887 ATP hydrolysis activity | IDA PMID:9528774 The carboxy-terminal domain of Hsc70 provides binding sites ... | ACCEPT | Summary: Manual review: ATP hydrolysis activity is consistent with known biology of Hspa8. Reason: ATP hydrolysis drives the Hsc70 cycle that the cofactors studied here regulate; the curator recorded the activity from the full text. Supporting Evidence: PMID:9528774 The modulation of the chaperone activity of the heat shock cognate Hsc70 protein in mammalian cells involves cooperation with chaperone cofactors UniProtKB:P63018 Reaction=ATP + H2O = ADP + phosphate + H(+) |
| GO:0032991 protein-containing complex | IDA PMID:9528774 The carboxy-terminal domain of Hsc70 provides binding sites ... | KEEP AS NON CORE | Summary: Manual review: protein-containing complex may be context-dependent or peripheral for Hspa8. Reason: Hsc70 forms complexes with several cofactors at once through separate binding sites; generic but accurate, non-core. Supporting Evidence: PMID:9528774 Hence, Hsc70 possesses separate nonoverlapping binding sites for Hsp40, Hip, and Hop. |
| GO:0005102 signaling receptor binding | IPI PMID:11133993 Characteristics of the interaction between Hsc70 and the tra... | KEEP AS NON CORE | Summary: Manual review: signaling receptor binding may be context-dependent or peripheral for Hspa8. Reason: Hsc70 binds the cytosolic domain of the transferrin receptor with the characteristics of a chaperone-client interaction. The receptor is bound as a client rather than in a signalling capacity, so this is kept as non-core. Supporting Evidence: PMID:11133993 The results show that Hsc70 binds to exosomal TfR with characteristics expected of a chaperone/peptide interaction. |
| GO:0005515 protein binding | IPI PMID:10198213 73-kDa heat shock cognate protein interacts directly with P2... | REMOVE | Summary: 73hsc co-immunoprecipitates with the CDK inhibitor p27Kip1 in a cell-cycle-dependent, ATP-sensitive manner in rat FRTL-5 cells. Reason: Generic protein binding is uninformative, and the abstract does not support a more specific molecular function for the 73hsc-p27Kip1 interaction. Removal does not mean the reported interaction is false. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. Supporting Evidence: PMID:10198213 73hsc was detected in the immunoprecipitates with anti-P27Kip1 antibody and, vice versa, P27Kip1 was present in the immunoprecipitates with anti-73hsc antibody |
| GO:0032991 protein-containing complex | IDA PMID:10198213 73-kDa heat shock cognate protein interacts directly with P2... | KEEP AS NON CORE | Summary: Manual review: protein-containing complex may be context-dependent or peripheral for Hspa8. Reason: 73hsc forms a cell-cycle-dependent complex with p27Kip1; generic but accurate, non-core. Supporting Evidence: PMID:10198213 This complex formation of 73hsc and P27Kip1 was cell cycle dependent |
| GO:0051082 unfolded protein binding | IDA PMID:11133993 Characteristics of the interaction between Hsc70 and the tra... | MODIFY | Summary: Manual review: unfolded protein binding is better represented by a more specific replacement term for Hspa8. Reason: Modified to align with current curation guidance and improve term specificity. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. QuickGO confirms GO:0051082 is obsolete ("this binding term should be replaced by an activity term such as protein folding chaperone (GO:0044183) or unfolded protein holdase activity (GO:0140309)"); GOA now carries the recommended replacement GO:0044183 for Hspa8. A new GO:0044183 IDA row from this same paper is reviewed below. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:11133993 The results show that Hsc70 binds to exosomal TfR with characteristics expected of a chaperone/peptide interaction. PMID:11133993 We demonstrated that heat-denatured luciferase competed for in vitro binding, dependent on the nucleotide bound to Hsc70, and that this interaction activates the ATPase activity of Hsc70. |
| GO:1990904 ribonucleoprotein complex | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Manual review: ribonucleoprotein complex may be context-dependent or peripheral for Hspa8. Reason: HSC70 is found in IGF2BP1-dependent mRNP granules (by similarity to human); non-core. Supporting Evidence: UniProtKB:P63018 Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs |
| GO:1990904 ribonucleoprotein complex | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: ribonucleoprotein complex may be context-dependent or peripheral for Hspa8. Reason: Transferred; HSC70 is found in mRNP granules and Staufen2 RNPs. Non-core. Supporting Evidence: UniProtKB:P63018 Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs PMID:20596529 hsc70 is directly bound to Stau2 and this interaction is regulated by ATP |
| GO:0005515 protein binding | IPI PMID:12514190 Cloning and characterization of a novel GRP78-binding protei... | REMOVE | Summary: The cited study identified GRP78 as the binding partner of a novel GRP78-binding protein (GBP) in rat brain; the abstract does not mention Hsc70. Reason: Generic protein binding is uninformative, and the abstract gives no basis for a more specific molecular function for Hsc70. Removal does not mean any interaction recorded by the curator from the full text is false. GOA no longer carries this annotation (withdrawn at the 2026 GOA refresh); the review is kept for provenance. Supporting Evidence: PMID:12514190 we performed a GST-tagged GBP pull-down assay in PC12 lysates and identified GRP78, one of the heat shock proteins, as a counterpart |
| GO:0016887 ATP hydrolysis activity | ISO GO_REF:0000121 | ACCEPT | Summary: Manual review: ATP hydrolysis activity is consistent with known biology of Hspa8. Reason: Transferred from mouse Hspa8; ATP hydrolysis drives the HSC70 chaperone cycle. Supporting Evidence: UniProtKB:P63018 Reaction=ATP + H2O = ADP + phosphate + H(+) UniProtKB:P63018 This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones. |
| GO:0051726 regulation of cell cycle | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: regulation of cell cycle may be context-dependent or peripheral for Hspa8. Reason: Transferred from mouse Hspa8, where Hsc70 promotes cyclin D1 maturation and cyclin D1/CDK4 assembly; a client-specific role, non-core. Supporting Evidence: PMID:12588994 Our data suggest that Hsc70 promotes stabilization of newly synthesized cyclin D1, thereby increasing its availability for assembly with CDK4. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based (IPR013126, Hsp70 family) ATP binding by the N-terminal nucleotide-binding domain of rat Hsc70. Reason: ATP binding by the NBD is integral to the HSC70 ATPase/chaperone cycle; rat hsc70 binds ATP with high affinity. Consistent with the other ATP binding rows. Supporting Evidence: UniProtKB:P63018 The N-terminal nucleotide binding domain (NBD) (also known as the ATPase domain) is responsible for binding and hydrolyzing ATP. PMID:8363588 Binding of [alpha-32P]ATP by purified recombinant hsc70 was analysed by Scatchard plot. |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | ACCEPT | Summary: Cytoplasm transferred from mouse Hspa8 (MGI:105384). Reason: Mouse-donor counterpart of the human-donor cytoplasm ISO row; cytoplasm is the principal compartment of HSC70 activity. Supporting Evidence: UniProtKB:P63018 SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P11142}. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: Cytoplasm by sequence similarity to human HSPA8 (P11142). Reason: Cytoplasm is the principal compartment of HSC70 activity; ISS counterpart of the accepted ISO/IEA cytoplasm rows. Supporting Evidence: UniProtKB:P63018 SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P11142}. |
| GO:0005765 lysosomal membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Lysosomal membrane by sequence similarity to human HSPA8 (P11142). Reason: The cytosolic face of the lysosomal membrane is where HSC70 delivers CMA clients to LAMP-2A; consistent with the accepted ISO and IDA lysosomal membrane rows. Supporting Evidence: UniProtKB:P63018 Lysosome membrane {ECO:0000250|UniProtKB:P11142}; Peripheral membrane protein {ECO:0000250|UniProtKB:P11142}; Cytoplasmic side PMID:11559757 is associated with the cytosolic side of the lysosomal membrane where it binds to substrates of this proteolytic pathway |
| GO:0005829 cytosol | ISO GO_REF:0000121 | ACCEPT | Summary: Cytosol transferred from human HSPA8 (P11142). Reason: Human-donor counterpart of the mouse-donor cytosol ISO row; the cytosol is the predominant site of HSC70 activity. Supporting Evidence: file:rat/Hspa8/Hspa8-deep-research-falcon.md **Cytosol**: the predominant pool performing general chaperoning and recognizing CMA substrates (KFERQ-like motifs) |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Plasma membrane by sequence similarity to human HSPA8 (P11142). Reason: Consistent with the IEA plasma membrane row: there is positive evidence for a peripheral cell-membrane pool (UniProt cell membrane; rat hsc73 with A1 adenosine receptors at the cell membrane), but it is not where the core functions are performed. Supporting Evidence: UniProtKB:P63018 Cell membrane {ECO:0000250|UniProtKB:P11142}. PMID:10866672 The heat shock cognate protein hsc73 assembles with A(1) adenosine receptors to form functional modules in the cell membrane. |
| GO:0006457 protein folding | ISO GO_REF:0000121 | ACCEPT | Summary: Protein folding (involved_in) transferred from mouse Hspa8 (MGI:105384). Reason: Assisting protein folding is the core HSC70 activity; this involved_in row from the mouse donor matches the acts_upstream_of_or_within sibling from the same donor. Supporting Evidence: UniProtKB:P63018 Plays a pivotal role in the protein quality control system, ensuring the correct folding of proteins, the re-folding of misfolded proteins and controlling the targeting of proteins for subsequent degradation. file:rat/Hspa8/Hspa8-deep-research-falcon.md Hspa8/HSC70 is a **constitutive** HSP70-family **ATPase chaperone** that supports proteostasis by assisting **protein folding/refolding**, **unfolding**, and **disassembly of protein complexes** |
| GO:0006914 autophagy | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Autophagy (acts_upstream_of_or_within) transferred from mouse Hspa8 (MGI:105384; mouse IDA in PMID:37767704). Reason: HSC70 acts in several selective autophagy routes (CMA, endosomal microautophagy, CASA), and in mouse rescues autophagy impaired by the lncRNA Gpr137b-ps. The general parent term adds little to the specific CMA terms, so it is kept as non-core. Supporting Evidence: PMID:37767704 As the downstream binding protein of Gpr137b-ps, HSC70 (heat shock cognate 70) rescued the impaired autophagy induced by Gpr137b-ps. UniProtKB:P63018 Component of the chaperone-assisted selective autophagy (CASA) complex consisting of BAG3, HSPA8/HSC70, HSPB8 and STUB1/CHIP |
| GO:0014069 postsynaptic density | IDA PMID:9878698 Presence of molecular chaperones, heat shock cognate (Hsc) 7... | KEEP AS NON CORE | Summary: Postsynaptic density (located_in) from rat immunolocalization; same paper as the existing is_active_in PSD row. Reason: Immuno-EM places Hsc70 beneath the synaptic contact at PSDs. Valid, but a non-core location, consistent with the sibling row. Supporting Evidence: PMID:9878698 Postsynaptic areas immediately beneath the synaptic contact or PSDs were immunoreactive for Hsc70. |
| GO:0016887 ATP hydrolysis activity | ISO GO_REF:0000121 | ACCEPT | Summary: ATP hydrolysis activity transferred from human HSPA8 (P11142). Reason: Human-donor counterpart of the mouse-donor ISO row; ATP hydrolysis (EC 3.6.4.10) drives the HSC70 chaperone cycle. Supporting Evidence: UniProtKB:P63018 Reaction=ATP + H2O = ADP + phosphate + H(+) UniProtKB:P63018 This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones. |
| GO:0016887 ATP hydrolysis activity | ISS GO_REF:0000024 | ACCEPT | Summary: ATP hydrolysis activity by sequence similarity to human HSPA8 (P11142). Reason: ATP hydrolysis drives the HSC70 chaperone cycle; consistent with the experimental rat ATPase data and the other accepted rows. Supporting Evidence: UniProtKB:P63018 Reaction=ATP + H2O = ADP + phosphate + H(+) PMID:8420978 autophosphorylation of hsc70 and its mutants is not correlated with their ability to hydrolyze ATP |
| GO:0030674 protein-macromolecule adaptor activity | ISO GO_REF:0000121 | ACCEPT | Summary: Protein-macromolecule adaptor activity transferred from human HSPA8 (P11142). Reason: Human-donor counterpart of the mouse-donor ISO row; HSC70 bridges KFERQ-motif clients to LAMP-2A at the lysosome during CMA. Supporting Evidence: UniProtKB:P63018 HSPA8/HSC70 specifically recognizes and binds cytosolic proteins bearing a -KFERQ motif and promotes their recruitment to the surface of the lysosome where they bind to lysosomal protein LAMP2. PMID:26212789 BBC3 associates with HSPA8/HSC70 (heat shock 70kDa protein 8), leading to its lysosome translocation and uptake. |
| GO:0035651 AP-3 adaptor complex binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: AP-3 adaptor complex binding transferred from mouse Hspa8 (MGI:105384; mouse IDA in PMID:19010779). Reason: ISO counterpart of the IEA row from the same mouse source. AP-3 complexes were analysed by cross-linking and mass spectrometry; the curator recorded Hsc70 association from the full text. Non-core. Supporting Evidence: PMID:19010779 we used in vivo cross-linking followed by purification of cross-linked AP-3 complexes and mass spectrometric identification of associated proteins |
| GO:0042470 melanosome | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Melanosome transferred from human HSPA8 (P11142). Reason: Melanosome localization of human HSPA8 is experimentally supported in the donor and recorded in UniProt by similarity; a valid but peripheral location. Supporting Evidence: UniProtKB:P63018 Melanosome {ECO:0000250|UniProtKB:P11142}. |
| GO:0042470 melanosome | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Melanosome by sequence similarity to human HSPA8 (P11142). Reason: As for the ISO row: valid but peripheral location. Supporting Evidence: UniProtKB:P63018 Melanosome {ECO:0000250|UniProtKB:P11142}. |
| GO:0044183 protein folding chaperone | IDA PMID:11133993 Characteristics of the interaction between Hsc70 and the tra... | ACCEPT | Summary: Purified Hsc70 binds the transferrin receptor cytosolic domain like a chaperone binding a peptide client: binding is competed by heat-denatured luciferase, depends on bound nucleotide, and stimulates Hsc70 ATPase activity. Reason: This row replaces the retired GO:0051082 IDA row from the same paper, whose review recommended exactly this replacement. Protein folding chaperone is the core HSC70 molecular function. Supporting Evidence: PMID:11133993 The results show that Hsc70 binds to exosomal TfR with characteristics expected of a chaperone/peptide interaction. PMID:11133993 We demonstrated that heat-denatured luciferase competed for in vitro binding, dependent on the nucleotide bound to Hsc70, and that this interaction activates the ATPase activity of Hsc70. |
| GO:0044183 protein folding chaperone | IEA GO_REF:0000120 | ACCEPT | Summary: Protein folding chaperone by ARBA/ortholog-based IEA (with mouse P63017). Reason: Protein folding chaperone is the core HSC70 molecular function, supported by rat refolding assays. Supporting Evidence: UniProtKB:P63018 Plays a pivotal role in the protein quality control system, ensuring the correct folding of proteins, the re-folding of misfolded proteins and controlling the targeting of proteins for subsequent degradation. PMID:11360998 In the presence of DnaJ, the capability of hsc70(R469C) to refold the denatured luciferase was decreased by 50%. |
| GO:0044183 protein folding chaperone | ISO GO_REF:0000121 | ACCEPT | Summary: Protein folding chaperone transferred from mouse Hspa8 (MGI:105384). Reason: Protein folding chaperone is the core HSC70 molecular function. Supporting Evidence: UniProtKB:P63018 Plays a pivotal role in the protein quality control system, ensuring the correct folding of proteins, the re-folding of misfolded proteins and controlling the targeting of proteins for subsequent degradation. file:rat/Hspa8/Hspa8-deep-research-falcon.md Hspa8/HSC70 is a **constitutive** HSP70-family **ATPase chaperone** that supports proteostasis by assisting **protein folding/refolding**, **unfolding**, and **disassembly of protein complexes** |
| GO:0061684 chaperone-mediated autophagy | IEA GO_REF:0000120 | ACCEPT | Summary: Chaperone-mediated autophagy by ARBA/ortholog-based IEA (with mouse P63017). Reason: CMA is a core HSC70 process: cytosolic HSC70 selects KFERQ-motif clients for lysosomal delivery. This row replaces the retired GO_REF:0000107 IEA row. Supporting Evidence: UniProtKB:P63018 HSPA8/HSC70 specifically recognizes and binds cytosolic proteins bearing a -KFERQ motif and promotes their recruitment to the surface of the lysosome where they bind to lysosomal protein LAMP2. file:rat/Hspa8/Hspa8-deep-research-falcon.md recognition of KFERQ-like pentapeptide motifs** in client proteins targeted for **chaperone-mediated autophagy (CMA)** |
| GO:0061684 chaperone-mediated autophagy | ISO GO_REF:0000121 | ACCEPT | Summary: Chaperone-mediated autophagy transferred from human HSPA8 (P11142). Reason: Human-donor counterpart of the mouse-donor ISO row; CMA is a core HSC70 process. Supporting Evidence: PMID:26212789 BBC3 associates with HSPA8/HSC70 (heat shock 70kDa protein 8), leading to its lysosome translocation and uptake. PMID:11559757 is associated with the cytosolic side of the lysosomal membrane where it binds to substrates of this proteolytic pathway |
| GO:0070062 extracellular exosome | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Extracellular exosome transferred from human HSPA8 (P11142; multiple human exosome proteomics/IDA studies). Reason: Human-donor counterpart of the mouse-donor ISO row; HSC70 is a common exosomal protein (e.g. bound to exosomal TfR). Valid but peripheral location. Supporting Evidence: PMID:11133993 The transferrin receptor (TfR) of reticulocytes is released in vesicular form (exosomes) during their maturation to erythrocytes. PMID:11133993 The results show that Hsc70 binds to exosomal TfR with characteristics expected of a chaperone/peptide interaction. |
| GO:0072318 clathrin coat disassembly | ISO GO_REF:0000121 | ACCEPT | Summary: Clathrin coat disassembly (involved_in) transferred from mouse Hspa8 (MGI:105384). Reason: Clathrin coat disassembly is a core HSC70 process; matches the acts_upstream_of_or_within sibling from the same donor. Supporting Evidence: UniProtKB:P63018 It is recruited to clathrin-coated vesicles through its interaction with DNAJC6 leading to activation of HSPA8/HSC70 ATPase activity and therefore uncoating of clathrin-coated vesicles file:rat/Hspa8/Hspa8-deep-research-falcon.md the **J-domain co-chaperone auxilin (DNAJC6)** recruits HSC70 to CCVs and **stimulates HSC70 ATPase activity** to disassemble clathrin coats |
| GO:0072318 clathrin coat disassembly | ISO GO_REF:0000121 | ACCEPT | Summary: Clathrin coat disassembly transferred from human HSPA8 (P11142). Reason: Clathrin coat disassembly is a core HSC70 process, directly shown for purified rat hsc70. Supporting Evidence: UniProtKB:P63018 It is recruited to clathrin-coated vesicles through its interaction with DNAJC6 leading to activation of HSPA8/HSC70 ATPase activity and therefore uncoating of clathrin-coated vesicles PMID:8363588 The cloned enzyme is capable of dissociating clathrin from bovine coated vesicle. |
| GO:0106222 lncRNA binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: lncRNA binding by ortholog-based IEA (mouse P63017; mouse IDA in PMID:37767704). Reason: In mouse, HSC70 binds the lncRNA Gpr137b-ps, which interferes with HSC70-G3BP binding and autophagy. A real but context-specific interaction, non-core. Supporting Evidence: PMID:37767704 As the downstream binding protein of Gpr137b-ps, HSC70 (heat shock cognate 70) rescued the impaired autophagy induced by Gpr137b-ps. |
| GO:0106222 lncRNA binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: lncRNA binding transferred from mouse Hspa8 (MGI:105384; mouse IDA in PMID:37767704). Reason: ISO counterpart of the IEA row; context-specific, non-core. Supporting Evidence: PMID:37767704 As the downstream binding protein of Gpr137b-ps, HSC70 (heat shock cognate 70) rescued the impaired autophagy induced by Gpr137b-ps. |
| GO:0160020 positive regulation of ferroptosis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of ferroptosis transferred from human HSPA8 (P11142; human IDA in PMID:40281343). Reason: Human-donor counterpart of the mouse-donor ISO row. In human cells GPX4 binding to HSC70 leads to its autophagic degradation, and blocking that binding limits ferroptosis. A downstream consequence of CMA, non-core. Supporting Evidence: PMID:40281343 disrupting its binding to HSC70 and inhibiting autophagy-mediated degradation |
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Download this section (compressed HTML)Q: The transferrin receptor binding row (GO:0005102 signaling receptor binding, IPI PMID:11133993) is kept as non-core. Hsc70 binds the receptor as a chaperone client. Should this interaction be recorded as receptor binding at all, or only through the chaperone activity terms?
Q: For GO:0035651 AP-3 adaptor complex binding (mouse IDA PMID:19010779), the abstract does not name Hsc70. Does the full text show direct binding of Hsc70 to the AP-3 complex?
Q: Are the alpha-enolase (GO:0019899 enzyme binding, PMID:21958194) and A1 adenosine receptor (GO:0031686) interactions client-chaperone interactions or regulatory interactions? The answer decides whether a binding term or a chaperone term is the better fit.
Q: Recombinant Hsc70 inhibited VMAT2 transport activity in a dose-dependent way (PMID:19457116). Is this direct inhibition that would support GO:0141110 transporter inhibitor activity, or an indirect effect of chaperone action on the transporter? The GO:0005515 row from this paper has been withdrawn from GOA, so the observation is not otherwise captured.
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