Hspa8

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: Hspa8 is found in the nucleus, consistent with its role as a component of the PRP19-CDC5L spliceosomal complex and its stress-induced nuclear/nucleolar translocation (UniProt CC). Reason: Nuclear localization is well-supported by IBA across HSP70 orthologs and consistent with Hspa8's role in splicing and stress response. UniProt notes it translocates to nuclei upon heat shock. Supporting Evidence: GO_REF:0000033 IBA from multiple orthologs including human P11142, yeast SSA1/SSA2, S. pombe
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Hspa8 is primarily cytoplasmic as the constitutive HSP70 chaperone. This is its main subcellular compartment. Reason: Cytoplasmic localization is a core feature of Hspa8/Hsc70, the constitutive cytosolic HSP70 family member. Supported by IBA across many orthologs. Supporting Evidence: GO_REF:0000033 IBA from diverse orthologs including yeast, fly, worm, human
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: Hspa8 localizes to the plasma membrane. UniProt confirms cell membrane localization by similarity to human HSPA8. Human ortholog interacts with cell surface receptors and is involved in antigen presentation. Reason: Plasma membrane localization is supported by IBA and by similarity to the well-characterized human ortholog. Supporting Evidence: GO_REF:0000033 IBA from multiple orthologs
GO:0016887 ATP hydrolysis activity	IBA GO_REF:0000033	ACCEPT	Summary: ATP hydrolysis is the core enzymatic activity of Hspa8 (EC 3.6.4.10), driving the chaperone cycle through conformational changes that regulate substrate binding and release. Also confirmed by IDA from PMID:12588994. Reason: ATP hydrolysis activity is the central enzymatic function of Hspa8/Hsc70, confirmed by its EC classification and extensive biochemical characterization. Supporting Evidence: PMID:12588994 Hsc70 associates with newly synthesized cyclin D1 and is a component of a mature, catalytically active cyclin D1/CDK4 holoenzyme complex
GO:0031072 heat shock protein binding	IBA GO_REF:0000033	ACCEPT	Summary: Hspa8 binds multiple heat shock proteins including HSPH1/Hsp105 and various J-domain co-chaperones (DNAJ family members) as part of its chaperone machine. Direct interaction with HSPH1 confirmed in mouse (PMID:9675148). Hsp105 family members function alongside Hsc70/Hsp40 in suppressing aggregation of denatured proteins (PMID:14644449). Reason: Heat shock protein binding is a core functional property of Hspa8, which operates in complexes with HSP90, small HSPs, and J-domain proteins. Directly demonstrated in mouse. Supporting Evidence: PMID:14644449 Hsc70/Hsp40 suppressed the aggregation of heat-denatured protein in the presence of ATP rather than ADP
GO:0044183 protein folding chaperone	IBA GO_REF:0000033	ACCEPT	Summary: Protein folding chaperone activity is the primary molecular function of Hspa8/Hsc70. It binds client polypeptides through its substrate-binding domain and assists their folding through ATP-driven conformational cycles. This is the recommended replacement for GO:0051082 for HSP70 family members per UPB project guidelines. Reason: This is the core molecular function of Hspa8 as a constitutive HSP70 family chaperone, extensively documented. The IBA annotation correctly captures the foldase function at the appropriate level of specificity. Supporting Evidence: PMID:21151134 the CSPalpha-Hsc70-SGT complex binds directly to monomeric SNAP-25 to prevent its aggregation, enabling SNARE-complex formation
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: Hspa8 is primarily a cytosolic protein, supported by IBA across many HSP70 orthologs and confirmed by IDA in mouse (PMID:16906134). Reason: Cytosol is the primary subcellular location where Hspa8 performs its housekeeping chaperone functions.
GO:0072318 clathrin coat disassembly	IBA GO_REF:0000033	ACCEPT	Summary: Hspa8/Hsc70 is essential for clathrin coat disassembly, working with auxilin (DNAJC6) to uncoat clathrin-coated vesicles via ATP-dependent disassembly (PMID:8524399). Also confirmed by IDA in mouse (PMID:8524399) and IGI from auxilin knockout studies (PMID:20160091). Reason: Clathrin coat disassembly is a well-established core function of Hspa8. 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:20160091 Neuronally expressed auxilin and ubiquitously expressed cyclin-G-dependent kinase (GAK) are homologous proteins that act as cochaperones to support the Hsc70-dependent clathrin uncoating
GO:0042026 protein refolding	IBA GO_REF:0000033	ACCEPT	Summary: Hspa8 participates in protein refolding, including refolding of heat-denatured substrates. Demonstrated in mouse by interaction with Hsp105 in refolding assays (PMID:14644449). Reason: Protein refolding is a well-documented core activity of the HSP70 chaperone machine. Supporting Evidence: PMID:14644449 Hsc70/Hsp40 suppressed the aggregation of heat-denatured protein in the presence of ATP rather than ADP
GO:0007165 signal transduction	IEA GO_REF:0000108	MARK AS OVER ANNOTATED	Summary: Signal transduction is overly broad for Hspa8. While Hspa8 modulates some signaling pathways indirectly through its chaperone activity, its primary role is as a molecular chaperone, not a signaling molecule. Reason: Hspa8 is a molecular chaperone, not a signaling protein. The IEA annotation to signal transduction is too broad and does not capture the specific mechanistic role of Hspa8. Consistent with the human HSPA8 review.
GO:0000166 nucleotide binding	IEA GO_REF:0000043	ACCEPT	Summary: Hspa8 binds ATP and ADP through its nucleotide-binding domain (NBD), which drives the chaperone conformational cycle. This is a parent term of the more specific GO:0005524 (ATP binding). Reason: Nucleotide binding is a core biochemical property of Hspa8, required for its chaperone function. While more general than ATP binding, it is accurate as an IEA annotation.
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: ATP binding is a core biochemical activity of Hspa8, required for its chaperone cycle. The NBD (residues 2-386) contains well-characterized ATP-binding sites confirmed by crystallography (PDB:3CQX). Reason: ATP binding is essential for Hspa8 function, confirmed by crystal structure and biochemical assays.
GO:0005681 spliceosomal complex	IEA GO_REF:0000043	ACCEPT	Summary: Hspa8 is a component of the PRP19-CDC5L spliceosomal complex, as stated in UniProt and confirmed for the human ortholog. The NAS annotation to GO:0000398 (mRNA splicing, via spliceosome) from PMID:23742842 also supports this. Reason: Spliceosomal complex membership is supported by the established role of Hspa8/HSC70 in the PRP19-CDC5L complex.
GO:0005730 nucleolus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Nucleolar localization of Hspa8 from IEA mapping of UniProt subcellular location. UniProt states Hspa8 translocates to nucleoli upon heat shock. Reason: Hspa8 is found in the nucleolus upon stress, but this is not a primary site of function under normal conditions.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Cytoplasmic localization of Hspa8 is well-established and consistent with the IBA annotation. Reason: Correct IEA annotation, consistent with IBA and experimental evidence.
GO:0005765 lysosomal membrane	IEA GO_REF:0000120	ACCEPT	Summary: Hspa8 associates with the lysosomal membrane during CMA, where it delivers KFERQ-motif substrates to LAMP2A for translocation. UniProt confirms lysosome membrane localization as a peripheral membrane protein on the cytoplasmic side. Reason: Lysosomal membrane localization is a core feature of Hspa8's role in CMA.
GO:0005886 plasma membrane	IEA GO_REF:0000044	ACCEPT	Summary: Plasma membrane localization of Hspa8 is consistent with the IBA annotation and UniProt subcellular location. Reason: Consistent with IBA annotation and UniProt data.
GO:0006397 mRNA processing	IEA GO_REF:0000043	ACCEPT	Summary: Hspa8 participates in mRNA processing as a component of the PRP19-CDC5L spliceosomal complex. Also supported by NAS annotation to GO:0000398 from PMID:23742842. Reason: Supported by Hspa8's established role in the PRP19-CDC5L complex involved in splicing.
GO:0006457 protein folding	IEA GO_REF:0000117	ACCEPT	Summary: Protein folding is a core biological process for Hspa8. This is confirmed by multiple IDA annotations from PMID:12588994 and PMID:21151134. Reason: Protein folding is the primary biological process in which Hspa8 participates. Consistent with extensive experimental evidence.
GO:0006914 autophagy	IEA GO_REF:0000120	ACCEPT	Summary: Hspa8 is central to chaperone-mediated autophagy (CMA), recognizing KFERQ-motif substrates and delivering them to LAMP2A at the lysosomal membrane (PMID:30718432). Also involved in late endosomal microautophagy (PMID:21238931). Reason: Autophagy involvement is a core function of Hspa8 through its essential role in CMA and endosomal microautophagy.
GO:0008289 lipid binding	IEA GO_REF:0000117	ACCEPT	Summary: Hspa8 binds lipids including phosphatidylserine (confirmed by IDA from PMID:21238931 for the endosomal microautophagy role) and is found associated with lipid droplets via Plin2/Plin3 interactions (PMID:25961502). Reason: Lipid binding is documented for Hspa8. The IDA annotation for phosphatidylserine binding (PMID:21238931) and interactions with perilipin proteins at lipid droplets support this.
GO:0008380 RNA splicing	IEA GO_REF:0000043	ACCEPT	Summary: Hspa8 is involved in RNA splicing as part of the PRP19-CDC5L spliceosomal complex. Also supported by the IMP annotation for positive regulation of mRNA splicing from PMID:23636947. Reason: Supported by Hspa8's established role in the spliceosome.
GO:0016787 hydrolase activity	IEA GO_REF:0000043	ACCEPT	Summary: Hspa8 has hydrolase activity (ATP hydrolysis, EC 3.6.4.10). This is a parent term of the more specific GO:0016887 (ATP hydrolysis activity). Reason: Accurate but general; more specific ATP hydrolysis activity terms also annotated. Acceptable as a broader IEA annotation.
GO:0016887 ATP hydrolysis activity	IEA GO_REF:0000120	ACCEPT	Summary: ATP hydrolysis activity is a core enzymatic function of Hspa8, redundant with the IBA annotation but correct. Reason: Correct IEA annotation consistent with the IBA annotation for this core function.
GO:0042470 melanosome	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Hspa8 was identified in melanosomes. UniProt confirms melanosome localization by similarity. This likely reflects its role as an abundant chaperone found in many compartments. Reason: IEA-based from subcellular location mapping. Hspa8 is an abundant protein found in many subcellular fractions; melanosome localization is not a core function.
GO:0043168 anion binding	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Anion binding for Hspa8 likely reflects ATP/ADP binding (these are anions). This is an overly broad IEA annotation. Reason: Too generic. The specific activity is ATP binding (GO:0005524), which is already annotated. Anion binding does not provide additional functional information.
GO:0005515 protein binding	IPI PMID:20111006 Kinesin-1/Hsc70-dependent mechanism of slow axonal transport...	REMOVE	Summary: Protein binding annotation from IntAct based on interaction with Klc1 (kinesin light chain 1). The interaction is relevant to slow axonal transport function of Hsc70. Reason: GO:0005515 (protein binding) is uninformative for a molecular chaperone that by definition interacts with many substrate proteins and co-chaperones. More specific MF terms are preferable.
GO:0005515 protein binding	IPI PMID:25961502 Degradation of lipid droplet-associated proteins by chaperon...	REMOVE	Summary: Protein binding annotation from IntAct based on interaction with Plin2 and Plin3 (perilipins). Relevant to CMA-mediated degradation of lipid droplet-associated proteins. Reason: GO:0005515 (protein binding) is uninformative for a molecular chaperone. The CMA substrate recognition function is better captured by GO:0030674 (protein-macromolecule adaptor activity) and GO:0061684 (chaperone-mediated autophagy).
GO:0005515 protein binding	IPI PMID:26581985 Identification of Viral and Host Proteins That Interact with...	REMOVE	Summary: Protein binding annotation from IntAct based on interaction with murine gammaherpesvirus 68 LANA. Relevant to the viral replication role of Hsc70. Reason: GO:0005515 (protein binding) is uninformative for a molecular chaperone. The virus-related function is better captured by the host-virus interaction annotations from this same paper.
GO:0032991 protein-containing complex	ISO GO_REF:0000096	ACCEPT	Summary: Hspa8 is found in multiple protein-containing complexes including the PRP19-CDC5L spliceosomal complex, the CASA complex (BAG3-HSC70-HSPB8-STUB1), and chaperone-substrate complexes. Reason: Generic but accurate. Hspa8 participates in multiple defined protein complexes.
GO:0000082 G1/S transition of mitotic cell cycle	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Hspa8 is involved in G1/S transition through its role in stabilizing cyclin D1 and the cyclin D1/CDK4 complex (PMID:12588994). Reason: While supported by evidence in mouse (PMID:12588994), cell cycle regulation is a downstream consequence of Hspa8 chaperone activity, not a core function.
GO:0001822 kidney development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Kidney development is a tissue-specific phenotypic association, not a core molecular function. Reason: A pleiotropic consequence of Hspa8's ubiquitous chaperone functions. Not a core function.
GO:0001916 positive regulation of T cell mediated cytotoxicity	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. HSP70 family members are known to present antigens and modulate immune responses. This is a downstream consequence of chaperone activity. Reason: Immune function modulation is a non-core downstream consequence of Hspa8's chaperone and antigen presentation roles.
GO:0001917 photoreceptor inner segment	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. As a ubiquitous protein, Hspa8 is expected to be found in many cell types including photoreceptors. Reason: Reflects ubiquitous expression. Not a core localization.
GO:0003723 RNA binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Hspa8 has been found in mRNP granules and the PRP19-CDC5L spliceosomal complex, both of which involve RNA. UniProt notes it is part of an IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Reason: While Hspa8 is found in RNA-containing complexes, RNA binding is not its primary molecular function.
GO:0005102 signaling receptor binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Hspa8 can bind cell surface receptors but this is not a core chaperone function. Reason: A non-core interaction. Hspa8 is primarily a chaperone, not a signaling ligand.
GO:0005776 autophagosome	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Hspa8 is involved in autophagy pathways (CMA) and may be present in autophagosomes. Reason: Hspa8's primary autophagy role is in CMA at the lysosomal membrane, not within autophagosomes per se.
GO:0005874 microtubule	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Hspa8 may associate with microtubules as part of its role in axonal transport and cytoskeletal quality control. Reason: Microtubule association is not a core localization for Hspa8.
GO:0005882 intermediate filament	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Hspa8 may associate with intermediate filaments as part of its chaperone quality control role. Reason: Not a core localization. Likely reflects proteomic detection in cytoskeletal fractions.
GO:0006606 protein import into nucleus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. HSP70 family chaperones are known to assist in nuclear import of certain protein substrates. Reason: A non-core downstream consequence of Hspa8's chaperone activity.
GO:0007519 skeletal muscle tissue development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Hspa8 is involved in muscle maintenance through the CASA complex (BAG3-HSC70-HSPB8-STUB1) as shown by PMID:20060297. Reason: Muscle maintenance via CASA is a documented but non-core developmental role.
GO:0008021 synaptic vesicle	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Hspa8 is associated with synaptic vesicles through its role in clathrin uncoating and SNARE complex assembly with CSPalpha (PMID:21151134). Reason: Consistent with well-documented synaptic roles of Hspa8 in clathrin uncoating and SNARE chaperoning.
GO:0008088 axo-dendritic transport	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Hspa8 is involved in slow axonal transport through interaction with kinesin light chain (Klc1) (PMID:20111006). Reason: A documented but non-core neuronal function of Hspa8.
GO:0009410 response to xenobiotic stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. HSP70 chaperones can be upregulated in response to xenobiotics as part of the general stress response. Reason: A non-core stress response annotation. Hspa8 is constitutively expressed and less stress-inducible than HSPA1A.
GO:0009986 cell surface	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Consistent with plasma membrane IBA annotation. Hspa8 is found at the cell surface. Reason: Consistent with the well-documented cell surface localization of Hspa8.
GO:0010045 response to nickel cation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Likely reflects general stress response to heavy metals. Reason: A non-core stress response annotation reflecting general chaperone upregulation.
GO:0010628 positive regulation of gene expression	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Hspa8 can influence gene expression through regulation of transcription factors and HSF1 signaling. Reason: An indirect downstream consequence of Hspa8's chaperone activity, not a core function.
GO:0010667 negative regulation of cardiac muscle cell apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. HSP70 family members have anti-apoptotic properties. Hspa8 interacts with BAG5 and JPH2 in cardiac tissue. Reason: A tissue-specific non-core downstream consequence of Hspa8's chaperone and protein quality control activities.
GO:0014069 postsynaptic density	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Hspa8 is found in the postsynaptic density. Mouse-specific evidence shows Hspa8 at the postsynaptic specialization membrane (PMID:21209184) and glutamatergic synapses (PMID:28234934). Reason: Consistent with direct experimental evidence from SynGO showing Hspa8 in postsynaptic compartments.
GO:0014823 response to activity	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Hspa8 levels and function respond to neuronal activity, consistent with its role in synaptic vesicle cycling and SNAP-25 chaperoning (PMID:21151134). Reason: A non-core response annotation reflecting Hspa8's role in activity-dependent synaptic maintenance.
GO:0019899 enzyme binding	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Hspa8 binds multiple enzymes including CDK4 (PMID:12588994) and various kinases. Reason: While generic, enzyme binding is accurate given Hspa8's documented interactions with kinases and other enzymatic partners.
GO:0021549 cerebellum development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Hspa8 is ubiquitously expressed and pleiotropic. Cerebellum development is a tissue-specific phenotypic association. Reason: A pleiotropic consequence of Hspa8's ubiquitous chaperone functions, not a core function.
GO:0030424 axon	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Hspa8 is found in axons, consistent with its role in slow axonal transport (PMID:20111006) and synaptic function. Reason: Consistent with documented axonal transport and presynaptic functions of Hspa8.
GO:0030425 dendrite	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Hspa8 is found in dendrites, consistent with its role in postsynaptic organization (PMID:28234934, PMID:21209184). Reason: Consistent with documented dendritic and postsynaptic functions of Hspa8.
GO:0030900 forebrain development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. A tissue-specific developmental annotation. Reason: A pleiotropic consequence of Hspa8's ubiquitous chaperone functions, not a core function.
GO:0031686 A1 adenosine receptor binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. A specific receptor interaction transferred from rat evidence. Reason: A non-core interaction. This specific binding is not well-characterized as a core function of Hspa8.
GO:0032279 asymmetric synapse	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Consistent with Hspa8's role at glutamatergic synapses (PMID:21209184, PMID:28234934). Reason: Consistent with SynGO experimental evidence for Hspa8 at glutamatergic (asymmetric) synapses.
GO:0032355 response to estradiol	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Likely reflects HSP70 involvement in steroid hormone receptor chaperoning. Reason: A non-core response annotation related to Hspa8's role in hormone receptor chaperoning.
GO:0032570 response to progesterone	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Likely reflects HSP70 involvement in steroid hormone receptor chaperoning. Reason: A non-core response annotation related to Hspa8's role in hormone receptor chaperoning.
GO:0032991 protein-containing complex	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Redundant with ISO annotation for same term. Reason: Correct and consistent with ISO annotation.
GO:0034605 cellular response to heat	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. While Hspa8 is constitutively expressed (unlike HSPA1A), it participates in the heat shock response by assisting with protein refolding and by regulating HSF1. Reason: As a constitutive chaperone, Hspa8 is a first responder to heat stress, assisting with protein refolding.
GO:0042277 peptide binding	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Hspa8 binds peptide substrates through its substrate-binding domain (SBD), which is central to its chaperone function. Reason: Peptide binding is a core property of the substrate-binding domain of Hspa8.
GO:0042594 response to starvation	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. CMA is upregulated during starvation, and Hspa8 is the substrate recognition component of CMA. Reason: CMA is activated by starvation, making this a functionally relevant annotation for Hspa8.
GO:0043025 neuronal cell body	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. As a ubiquitous cytosolic protein, Hspa8 is present in neuronal cell bodies. Reason: Consistent with ubiquitous expression and neuronal localization studies.
GO:0043195 terminal bouton	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Consistent with Hspa8's well-documented presynaptic functions. Reason: Consistent with presynaptic roles in clathrin uncoating and SNARE chaperoning (PMID:21151134).
GO:0043197 dendritic spine	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Hspa8 regulates spine morphology via FILIP and myosin IIb (PMID:28234934). Reason: Consistent with direct experimental evidence showing Hspa8's role in dendritic spine morphology regulation.
GO:0043198 dendritic shaft	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Consistent with dendritic localization. Reason: Consistent with dendritic localization of Hspa8.
GO:0043204 perikaryon	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. As a ubiquitous cytosolic protein, Hspa8 is present in the perikaryon. Reason: Consistent with ubiquitous expression.
GO:0044309 neuron spine	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Consistent with dendritic spine annotation and PMID:28234934. Reason: Consistent with experimental evidence for Hspa8 in spine morphology regulation.
GO:0044743 protein transmembrane import into intracellular organelle	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Hspa8 is involved in protein import into mitochondria (delivering preproteins to TOMM70) and in CMA (delivering substrates to the lysosomal membrane for translocation). Reason: Supported by documented roles in mitochondrial import and CMA translocation.
GO:0044849 estrous cycle	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Likely reflects expression changes during the estrous cycle. Reason: A non-core developmental/reproductive annotation.
GO:0045471 response to ethanol	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Likely reflects general stress response to ethanol. Reason: A non-core stress response annotation.
GO:0045862 positive regulation of proteolysis	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Hspa8 promotes proteolysis through CMA (targeting substrates for lysosomal degradation) and through CHIP/STUB1-mediated ubiquitination. Reason: Consistent with Hspa8's established roles in CMA and CHIP-mediated proteasomal targeting.
GO:0048471 perinuclear region of cytoplasm	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Also supported by IDA from PMID:14627652 in mouse, where detection was in context of aggresome association. Reason: Supported by direct experimental evidence in mouse.
GO:0050766 positive regulation of phagocytosis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. HSP70 family members promote phagocytosis through their cell surface roles. Reason: A non-core immunological function downstream of Hspa8's cell surface and antigen presentation roles.
GO:0051082 unfolded protein binding	IEA GO_REF:0000120	MODIFY	Summary: Per the UPB project decision rules for HSP70 family, GO:0051082 (unfolded protein binding) should be modified to GO:0044183 (protein folding chaperone). Hspa8/HSC70 is a context-dependent foldase/holdase chaperone that actively assists folding through ATP-driven conformational cycles. Reason: GO:0051082 does not capture the active chaperone mechanism of Hspa8. Per UPB project guidelines for HSP70 family members, the correct term is GO:0044183 (protein folding chaperone), which is already annotated via IBA. Proposed replacements: protein folding chaperone
GO:0061635 regulation of protein complex stability	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Hspa8 regulates protein complex stability, e.g. SNARE complex stability at synapses (PMID:21151134) and clathrin coat stability. Reason: Consistent with Hspa8's roles in SNARE chaperoning and clathrin uncoating.
GO:0061684 chaperone-mediated autophagy	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. CMA is a core function of Hspa8 (PMID:30718432). Redundant with IDA and ISO annotations. Reason: CMA is a core function of Hspa8. Consistent with multiple other annotations.
GO:0070301 cellular response to hydrogen peroxide	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Hspa8 may be involved in cellular response to oxidative stress. Reason: A non-core stress response annotation.
GO:0071276 cellular response to cadmium ion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Likely reflects general stress response to heavy metals. Reason: A non-core stress response annotation.
GO:0072318 clathrin coat disassembly	IEA GO_REF:0000120	ACCEPT	Summary: Clathrin coat disassembly is a core function of Hspa8, redundant with IBA and IDA annotations. Confirmed by PMID:8524399. Reason: Correct IEA annotation, consistent with IBA and IDA evidence.
GO:0097214 positive regulation of lysosomal membrane permeability	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Related to Hspa8's role at the lysosomal membrane in CMA. Reason: A downstream consequence of Hspa8's CMA activity, not a core function per se.
GO:0098690 glycinergic synapse	IEA GO_REF:0000120	ACCEPT	Summary: Hspa8 is found at glycinergic synapses. Confirmed by IDA from PMID:21209184 showing Hsc70 binds gephyrin at inhibitory synapses. Reason: Consistent with direct experimental evidence (PMID:21209184).
GO:0098793 presynapse	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Hspa8 is found at the presynapse, confirmed by multiple IDA annotations (PMID:21151134, PMID:24616664). Reason: Consistent with extensive experimental evidence for presynaptic localization.
GO:0098794 postsynapse	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Hspa8 is found at the postsynapse, consistent with PMID:21209184 and PMID:28234934. Reason: Consistent with experimental evidence for postsynaptic localization.
GO:0098880 maintenance of postsynaptic specialization structure	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Hspa8 regulates gephyrin clustering at inhibitory synapses (PMID:21209184) and postsynapse organization via FILIP/myosin IIb (PMID:28234934). Reason: Consistent with direct experimental evidence for Hspa8's role in postsynaptic organization.
GO:0098978 glutamatergic synapse	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Confirmed by IDA from PMID:21209184 and PMID:28234934 showing Hspa8 at glutamatergic synapses. Reason: Consistent with SynGO experimental evidence.
GO:1904592 positive regulation of protein refolding	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Hspa8 promotes protein refolding, consistent with its core chaperone function. Reason: Consistent with Hspa8's core protein refolding activity.
GO:1904593 prostaglandin binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. VGF-derived peptide TLQP-21 interacts with Hspa8 (by similarity per UniProt). Reason: A non-core binding activity. Not well-characterized as a core function.
GO:1904764 chaperone-mediated autophagy translocation complex disassembly	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Hspa8 is involved in disassembly of the CMA translocation complex at the lysosomal membrane. Consistent with its core CMA role. Reason: CMA translocation complex disassembly is part of the core CMA function of Hspa8.
GO:1990832 slow axonal transport	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Hspa8 interacts with kinesin light chain 1 (Klc1) for slow axonal transport (PMID:20111006). Reason: A documented but non-core neuronal transport function.
GO:1990833 clathrin-uncoating ATPase activity	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Hspa8 uses its ATPase activity specifically for clathrin uncoating, working with auxilin/DNAJC6 (PMID:8524399). Reason: Clathrin-uncoating ATPase activity is a specific and well-documented molecular function of Hspa8.
GO:1990834 response to odorant	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl IEA from rat ortholog. Likely reflects expression in olfactory neurons. Reason: A non-core annotation likely reflecting ubiquitous expression.
GO:1990836 lysosomal matrix	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl IEA from rat ortholog. Hspa8 may be found in the lysosomal matrix as part of CMA substrate delivery. Also present in late endosome lumen (Reactome TAS). Reason: Consistent with Hspa8's role in CMA, where it delivers substrates to the lysosomal lumen.
GO:0005737 cytoplasm	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Consistent with IBA and IEA annotations. Reason: Correct and redundant with other evidence.
GO:0043085 positive regulation of catalytic activity	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat. Hspa8 can activate catalytic activity, e.g. CDK4 kinase maturation (PMID:12588994). Reason: A non-core downstream consequence of Hspa8's chaperone activity on kinase maturation.
GO:0046777 protein autophosphorylation	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat. Hspa8 involvement in protein autophosphorylation is an indirect consequence of its chaperone activity. Reason: Indirect consequence of chaperone activity on kinase substrates.
GO:0061684 chaperone-mediated autophagy	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. CMA is a core function. Redundant with IDA and IEA annotations. Reason: Core function, consistent with multiple annotations.
GO:0160020 positive regulation of ferroptosis	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: ISO from human HSPA8. CMA-mediated degradation of GPX4 promotes ferroptosis (PMID:30718432). This is a downstream consequence of CMA activity rather than a core function. Reason: Directly demonstrated in mouse (PMID:30718432).
GO:0000974 Prp19 complex	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Hspa8 is a component of the PRP19-CDC5L spliceosomal complex. Reason: Well-established component of the PRP19-CDC5L complex per UniProt.
GO:0001664 G protein-coupled receptor binding	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: ISO from human HSPA8. GPCR binding is a non-core interaction. Reason: A non-core interaction. Not a primary function of Hspa8.
GO:0001916 positive regulation of T cell mediated cytotoxicity	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat. Non-core immune function. Redundant with IEA annotation. Reason: Non-core immune function downstream of chaperone/antigen presentation roles.
GO:0001917 photoreceptor inner segment	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat. Redundant with IEA annotation. Reflects ubiquitous expression. Reason: Not a core localization. Reflects ubiquitous expression.
GO:0003723 RNA binding	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat. Redundant with IEA annotation. Hspa8 binds RNA in mRNP granules. Reason: Not a core molecular function. Hspa8 is primarily a protein chaperone.
GO:0005102 signaling receptor binding	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat. Redundant with IEA annotation. Reason: Non-core interaction.
GO:0005524 ATP binding	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Core function. Redundant with IEA annotation. Reason: Core biochemical function.
GO:0005615 extracellular space	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: ISO from human HSPA8. Hspa8 can be released extracellularly and found in exosomes. Reason: Non-core localization. Hspa8 is primarily intracellular.
GO:0005634 nucleus	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Consistent with IBA annotation. Nuclear localization upon stress. Reason: Consistent with IBA annotation.
GO:0005765 lysosomal membrane	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Core CMA-related localization. Redundant with IEA annotation. Reason: Core localization for CMA function.
GO:0005765 lysosomal membrane	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Core CMA-related localization. Redundant with other annotations. Reason: Core localization for CMA function.
GO:0005776 autophagosome	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat. Redundant with IEA annotation. Reason: Not the primary autophagy compartment for Hspa8; CMA occurs at the lysosome.
GO:0005829 cytosol	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Core localization. Redundant with IBA annotation. Reason: Core localization.
GO:0005874 microtubule	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat. Redundant with IEA annotation. Reason: Not a core localization.
GO:0005882 intermediate filament	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat. Redundant with IEA annotation. Reason: Not a core localization.
GO:0006606 protein import into nucleus	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat. Redundant with IEA annotation. Reason: Non-core downstream consequence of chaperone activity.
GO:0008021 synaptic vesicle	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IEA annotation. Consistent with synaptic roles. Reason: Consistent with well-documented synaptic roles.
GO:0009986 cell surface	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IEA annotation. Reason: Consistent with cell surface localization.
GO:0010628 positive regulation of gene expression	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat. Redundant with IEA annotation. Reason: Non-core downstream consequence.
GO:0010667 negative regulation of cardiac muscle cell apoptotic process	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat. Redundant with IEA annotation. Reason: Non-core tissue-specific consequence.
GO:0014069 postsynaptic density	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IEA annotation. Supported by SynGO data. Reason: Consistent with experimental evidence for postsynaptic localization.
GO:0016887 ATP hydrolysis activity	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Core enzymatic function. Redundant with IBA and IEA annotations. Reason: Core enzymatic function.
GO:0019899 enzyme binding	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IEA annotation. Reason: Consistent with documented enzyme interactions.
GO:0019899 enzyme binding	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Redundant with IEA and ISO from rat. Reason: Consistent with documented enzyme interactions.
GO:0030163 protein catabolic process	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Hspa8 promotes protein catabolism through CMA and CHIP-mediated ubiquitination. Reason: Consistent with Hspa8's roles in CMA and ERAD.
GO:0030335 positive regulation of cell migration	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: ISO from human HSPA8. Cell migration regulation is a non-core downstream consequence. Reason: Non-core downstream consequence of Hspa8's chaperone activity.
GO:0030424 axon	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IEA annotation. Consistent with axonal roles. Reason: Consistent with documented axonal transport functions.
GO:0030425 dendrite	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IEA annotation. Reason: Consistent with dendritic localization.
GO:0030674 protein-macromolecule adaptor activity	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Hspa8 acts as an adaptor in CMA, bridging substrates to LAMP2A. Also supported by IDA in mouse (PMID:30718432). Reason: Core molecular function in CMA substrate recognition and delivery.
GO:0031072 heat shock protein binding	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Redundant with IBA annotation. Reason: Core function.
GO:0031625 ubiquitin protein ligase binding	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Hspa8 binds CHIP/STUB1 E3 ligase for ubiquitination of misfolded substrates. Reason: Well-established interaction with CHIP/STUB1 central to protein quality control.
GO:0031647 regulation of protein stability	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Core consequence of chaperone function in protein quality control. Reason: Core consequence of Hspa8's chaperone function.
GO:0031686 A1 adenosine receptor binding	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat. Redundant with IEA annotation. Reason: Non-core specific binding interaction.
GO:0032279 asymmetric synapse	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IEA annotation. Reason: Consistent with SynGO evidence.
GO:0042026 protein refolding	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Core function. Redundant with IBA annotation. Reason: Core function.
GO:0042277 peptide binding	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IEA annotation. Reason: Core property of the substrate-binding domain.
GO:0043025 neuronal cell body	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IEA annotation. Reason: Consistent with ubiquitous expression.
GO:0043195 terminal bouton	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IEA annotation. Reason: Consistent with presynaptic roles.
GO:0043197 dendritic spine	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IEA annotation. Reason: Consistent with spine morphology role (PMID:28234934).
GO:0043198 dendritic shaft	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IEA annotation. Reason: Consistent with dendritic localization.
GO:0043204 perikaryon	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IEA annotation. Reason: Consistent with ubiquitous expression.
GO:0044309 neuron spine	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IEA annotation. Reason: Consistent with spine morphology role.
GO:0045862 positive regulation of proteolysis	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IEA annotation. Reason: Consistent with CMA and CHIP-mediated proteolysis roles.
GO:0045892 negative regulation of DNA-templated transcription	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: ISO from human HSPA8. Hspa8 acts as a repressor of transcriptional activation, inhibiting CITED1 coactivator activity on Smad-mediated transcription. Reason: A documented but non-core transcriptional regulatory function.
GO:0046034 ATP metabolic process	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Hspa8 is involved in ATP metabolism through its ATPase cycle. Reason: Consistent with Hspa8's ATP-dependent chaperone mechanism.
GO:0048018 receptor ligand activity	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: ISO from human HSPA8. Hspa8 can act as a receptor ligand at the cell surface, e.g. binding LPS receptors. Reason: Non-core function related to extracellular/cell surface roles.
GO:0048471 perinuclear region of cytoplasm	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat. Redundant with IEA and IDA (PMID:14627652) annotations. Perinuclear localization is context-dependent. Reason: Supported by direct experimental evidence in mouse.
GO:0050766 positive regulation of phagocytosis	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat. Redundant with IEA annotation. Reason: Non-core immune function.
GO:0051082 unfolded protein binding	ISO GO_REF:0000096	MODIFY	Summary: ISO from rat. Per UPB project guidelines for HSP70 family, should be modified to GO:0044183 (protein folding chaperone). Reason: GO:0051082 does not capture the active chaperone mechanism of Hspa8. The correct replacement is GO:0044183 (protein folding chaperone). Proposed replacements: protein folding chaperone
GO:0051082 unfolded protein binding	ISO GO_REF:0000119	MODIFY	Summary: ISO from human HSPA8. Per UPB project guidelines for HSP70 family, should be modified to GO:0044183 (protein folding chaperone). Reason: GO:0051082 does not capture the active chaperone mechanism of Hspa8. The correct replacement is GO:0044183 (protein folding chaperone). Proposed replacements: protein folding chaperone
GO:0051087 protein-folding chaperone binding	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Hspa8 binds multiple co-chaperones including J-domain proteins, NEFs, and TPR proteins. Reason: Well-established interaction with co-chaperones is central to Hspa8 function.
GO:0055131 C3HC4-type RING finger domain binding	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Reflects interaction with CHIP/STUB1 and RNF207 RING-type E3 ligases. Reason: Reflects the functional interaction between Hspa8 and RING-type E3 ligases.
GO:0061635 regulation of protein complex stability	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IEA annotation. Consistent with SNARE chaperoning and clathrin uncoating roles. Reason: Consistent with documented roles.
GO:0061684 chaperone-mediated autophagy	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IDA, IEA, and other ISO annotations. Reason: Core function.
GO:0061740 protein targeting to lysosome involved in chaperone-mediated autophagy	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Hspa8 specifically recognizes KFERQ motifs and targets substrates to the lysosomal membrane for CMA degradation (PMID:30718432). Reason: Core CMA function. Directly demonstrated in mouse (PMID:30718432).
GO:0070062 extracellular exosome	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: ISO from human HSPA8. Also supported by IDA in mouse (PMID:19724054). Reason: Non-core localization. Hspa8 is found in exosomes but this is not a primary function.
GO:0072318 clathrin coat disassembly	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Core function. Redundant with IBA and IDA annotations. Reason: Core function.
GO:0072318 clathrin coat disassembly	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Core function. Redundant with other annotations. Reason: Core function.
GO:0097214 positive regulation of lysosomal membrane permeability	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat. Redundant with IEA annotation. Reason: Non-core downstream consequence of CMA activity.
GO:0098690 glycinergic synapse	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IEA and IDA (PMID:21209184) annotations. Reason: Consistent with direct experimental evidence.
GO:0098793 presynapse	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IEA and IDA annotations. Reason: Consistent with extensive experimental evidence.
GO:0098794 postsynapse	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Supported by IDA evidence for Hsc70 at postsynaptic sites where it regulates gephyrin clustering (PMID:21209184) and dendritic spine organization via FILIP/myosin IIb (PMID:28234934). Reason: Consistent with direct experimental evidence in mouse.
GO:0098880 maintenance of postsynaptic specialization structure	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Hspa8 regulates gephyrin clustering at inhibitory synapses (PMID:21209184) and dendritic spine morphology via FILIP/myosin IIb (PMID:28234934), both contributing to postsynaptic specialization maintenance. Reason: Supported by direct experimental evidence in mouse for postsynaptic structural roles.
GO:0098978 glutamatergic synapse	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Redundant with IDA (PMID:21209184, PMID:28234934) and EXP (PMID:28234934) annotations. Reason: Consistent with direct experimental evidence.
GO:0101031 protein folding chaperone complex	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Hspa8 forms functional chaperone complexes including the CSPalpha-Hsc70-SGT complex (PMID:21151134) and the BAG3-Hsc70-HSPB8 CASA complex (PMID:20060297). Reason: Core function. Hspa8 is a central component of multiple chaperone complexes.
GO:0140545 ATP-dependent protein disaggregase activity	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. HSP70 family members, in conjunction with HSPH1 (Hsp105/Hsp110 family), form a bi-chaperone disaggregase system. The Hsp70-Hsp110-Hsp40 complex can solubilize aggregated proteins in an ATP-dependent manner (PMID:14644449). Reason: Supported by evidence that Hsc70 cooperates with Hsp105 in suppressing aggregation and promoting disaggregation.
GO:1900226 negative regulation of NLRP3 inflammasome complex assembly	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: ISO from human HSPA8. Reported role for HSP70 family in NLRP3 inflammasome regulation, but primary evidence is for HSPA8/Hsc70 in human cells. Reason: Non-core downstream consequence of chaperone activity. Not a primary function of Hspa8.
GO:1902904 negative regulation of supramolecular fiber organization	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: ISO from human HSPA8. May relate to roles in preventing protein aggregation into fibers, consistent with general chaperone activity. Reason: Non-core downstream consequence of chaperone activity.
GO:1904592 positive regulation of protein refolding	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Consistent with core chaperone function of Hspa8 in promoting protein refolding through ATP-dependent cycles. Reason: Core chaperone function. Hspa8 promotes refolding of denatured substrates.
GO:1904593 prostaglandin binding	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat. Prostaglandin binding has been reported for HSP70 family members but is not a core function. Reason: Peripheral binding activity; not a core chaperone function.
GO:1904764 chaperone-mediated autophagy translocation complex disassembly	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. After CMA substrate translocation into the lysosome, Hspa8 mediates the disassembly of the LAMP2A translocation complex, an essential step in the CMA cycle. Reason: Core CMA function. Hspa8 acts on both cytosolic and lumenal sides of the lysosomal membrane.
GO:1990833 clathrin-uncoating ATPase activity	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. Core function. Hspa8 uses ATP hydrolysis to drive clathrin triskelion release from coated vesicles, working with auxilin/GAK co-chaperones (PMID:8524399, PMID:20160091). Reason: Core enzymatic activity directly demonstrated in mouse.
GO:1990836 lysosomal matrix	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat. A fraction of Hspa8 resides in the lysosomal lumen where it participates in CMA translocation complex disassembly. Reason: Consistent with CMA function requiring lumenal Hsc70.
GO:1990904 ribonucleoprotein complex	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human HSPA8. Hspa8 is a component of the Prp19/CDC5L spliceosome complex (PMID:23742842), consistent with roles in mRNA splicing. Reason: Documented component of the Prp19 spliceosome complex.
GO:0030674 protein-macromolecule adaptor activity	IDA PMID:30718432 Chaperone-mediated autophagy is involved in the execution of...	ACCEPT	Summary: IDA from PMID:30718432. In the context of ferroptosis, Hspa8 recognizes KFERQ motifs on GPX4 and delivers it to the lysosomal membrane for CMA-mediated degradation, acting as an adaptor between substrate and LAMP2A receptor. Reason: Core CMA function. Hspa8 serves as a substrate adaptor in CMA by recognizing KFERQ-like motifs and targeting substrates to LAMP2A. Supporting Evidence: 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:0061684 chaperone-mediated autophagy	IDA PMID:30718432 Chaperone-mediated autophagy is involved in the execution of...	ACCEPT	Summary: IDA from PMID:30718432. Directly demonstrated that Hspa8/Hsc70-mediated CMA promotes GPX4 degradation during ferroptosis. Reason: Core function. CMA is one of the best-established roles of Hspa8. Supporting Evidence: PMID:30718432 inhibition of CMA stabilized GPX4 and reduced ferroptosis
GO:0160020 positive regulation of ferroptosis	IDA PMID:30718432 Chaperone-mediated autophagy is involved in the execution of...	KEEP AS NON CORE	Summary: IDA from PMID:30718432. Hspa8 promotes ferroptosis through CMA-mediated degradation of GPX4, a key anti-ferroptotic enzyme. Inhibition of HSP90/CMA stabilized GPX4 and reduced ferroptosis. Reason: This is a downstream consequence of CMA activity rather than a core function. Ferroptosis promotion is context-dependent (requires CMA activation by erastin). Supporting Evidence: PMID:30718432 activation of CMA is involved in the execution of ferroptosis
GO:0000398 mRNA splicing, via spliceosome	NAS PMID:23742842 Splicing and beyond: the many faces of the Prp19 complex.	KEEP AS NON CORE	Summary: NAS from PMID:23742842 review article. Hspa8 is a component of the Prp19/CDC5L spliceosome complex. The Prp19 complex functions in splicing catalytic activation. Reason: Documented role as component of Prp19 complex, but this is a secondary/moonlighting function rather than core chaperone activity.
GO:0006457 protein folding	IEP PMID:21151134 CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 ...	ACCEPT	Summary: IEP from PMID:21151134. Expression pattern evidence for protein folding activity at presynaptic terminals where the CSPalpha-Hsc70-SGT complex chaperones SNAP-25. Reason: Core function. The CSPalpha-Hsc70-SGT complex directly chaperones SNAP-25 to maintain SNARE-complex assembly. Supporting Evidence: PMID:21151134 the CSPα-Hsc70-SGT complex binds directly to monomeric SNAP-25 to prevent its aggregation, enabling SNARE-complex formation
GO:0006457 protein folding	IDA PMID:21151134 CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 ...	ACCEPT	Summary: IDA from PMID:21151134. Direct assay showing Hsc70 as part of the CSPalpha-Hsc70-SGT chaperone complex that maintains SNAP-25 in a folding-competent state for SNARE complex formation. Reason: Core function. Directly demonstrated. Supporting Evidence: PMID:21151134 the CSPα-Hsc70-SGT complex binds directly to monomeric SNAP-25 to prevent its aggregation, enabling SNARE-complex formation
GO:0006457 protein folding	IMP PMID:21151134 CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 ...	ACCEPT	Summary: IMP from PMID:21151134. Mutant phenotype evidence. Deletion of CSPalpha produces abnormal SNAP-25 conformer that inhibits SNARE-complex formation, indicating the CSPalpha-Hsc70-SGT complex is required for proper SNAP-25 folding. Reason: Core function. Mutant phenotype supports chaperone-dependent protein folding at presynaptic terminals. Supporting Evidence: PMID:21151134 Deletion of CSPα produces an abnormal SNAP-25 conformer that inhibits SNARE-complex formation, and is subject to ubiquitylation and proteasomal degradation
GO:0098684 photoreceptor ribbon synapse	IDA PMID:24616664 Evidence for a Clathrin-independent mode of endocytosis at a...	ACCEPT	Summary: IDA from PMID:24616664. Immunocytochemistry detected Hsc70 (anti-uncoating ATPase antibody) at photoreceptor ribbon synapses in mouse retina. Hsc70 was absent from Clathrin-independent endocytic clusters, supporting its specific role in CME at these synapses. Reason: Direct immunolocalization in mouse retina photoreceptor terminals. Supporting Evidence: PMID:24616664 clusters labeled for Dynamin3, Endophilin1, and Synaptojanin1, but not for AP180, Clathrin LC, and hsc70
GO:0098690 glycinergic synapse	IDA PMID:21209184 Heat shock cognate protein 70 regulates gephyrin clustering.	ACCEPT	Summary: IDA from PMID:21209184. Hsc70 localizes to glycinergic synapses where it regulates gephyrin clustering. Hsc70 inhibition altered gephyrin cluster density at inhibitory synapses. Reason: Directly demonstrated in mouse neurons.
GO:0098793 presynapse	IEP PMID:21151134 CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 ...	ACCEPT	Summary: IEP from PMID:21151134. Hsc70 is expressed at presynaptic terminals where it forms the CSPalpha-Hsc70-SGT chaperone complex. Reason: Expression pattern consistent with presynaptic localization. Supporting Evidence: PMID:21151134 The protein CSPα resides in presynaptic terminals, where it forms a chaperone complex with Hsc70 and SGT
GO:0098793 presynapse	IDA PMID:21151134 CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 ...	ACCEPT	Summary: IDA from PMID:21151134. Hsc70 directly localized to presynaptic terminals as part of the CSPalpha-Hsc70-SGT complex. Reason: Directly demonstrated. Supporting Evidence: PMID:21151134 The protein CSPα resides in presynaptic terminals, where it forms a chaperone complex with Hsc70 and SGT
GO:0098793 presynapse	IMP PMID:21151134 CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 ...	ACCEPT	Summary: IMP from PMID:21151134. CSPalpha-knockout mice show presynaptic defects indicating functional requirement for the Hsc70-containing chaperone complex at presynaptic terminals. Reason: Mutant phenotype supports presynaptic localization and function.
GO:0098793 presynapse	IDA PMID:24616664 Evidence for a Clathrin-independent mode of endocytosis at a...	ACCEPT	Summary: IDA from PMID:24616664. Hsc70 detected at presynaptic terminals of mouse photoreceptor ribbon synapses and bipolar cell terminals by immunocytochemistry. Reason: Direct immunolocalization in mouse retinal synapses. Supporting Evidence: PMID:24616664 In mouse ON bipolar cell terminals, Clathrin-mediated endocytosis seemed to be the dominant mode of endocytosis at all adaptation states analyzed
GO:0098978 glutamatergic synapse	IDA PMID:21209184 Heat shock cognate protein 70 regulates gephyrin clustering.	ACCEPT	Summary: IDA from PMID:21209184. Hsc70 localizes to glutamatergic synapses. The study examined Hsc70 distribution at both excitatory and inhibitory synapses. Reason: Directly demonstrated in mouse neurons.
GO:0098978 glutamatergic synapse	IDA PMID:28234934 Subcellular distribution of non-muscle myosin IIb is control...	ACCEPT	Summary: IDA from PMID:28234934. Hsc70 localizes to glutamatergic synapses where it controls subcellular distribution of non-muscle myosin IIb via FILIP interaction in dendritic spines. Reason: Directly demonstrated in mouse neurons. Supporting Evidence: PMID:28234934 Hsc70 interacts with FILIP to mediate its effects on non-muscle myosin IIb and to regulate spine morphology
GO:0098978 glutamatergic synapse	EXP PMID:28234934 Subcellular distribution of non-muscle myosin IIb is control...	ACCEPT	Summary: EXP from PMID:28234934. Experimental evidence for Hsc70 at glutamatergic synapses from the FILIP/myosin IIb study. Reason: Redundant with IDA from same study, but valid experimental evidence. Supporting Evidence: PMID:28234934 in primary cultured neurons, an inhibitor of Hsc70 impeded the morphological change in spines induced by FILIP
GO:0099175 regulation of postsynapse organization	IDA PMID:28234934 Subcellular distribution of non-muscle myosin IIb is control...	ACCEPT	Summary: IDA from PMID:28234934. Hsc70 regulates dendritic spine morphology through FILIP-mediated control of myosin IIb subcellular distribution, thereby regulating postsynaptic organization. Reason: Directly demonstrated in mouse neurons. Supporting Evidence: PMID:28234934 Inhibition of ATPase activity of Hsc70 impaired the effect of FILIP on the subcellular distribution of non-muscle myosin IIb
GO:0099175 regulation of postsynapse organization	EXP PMID:28234934 Subcellular distribution of non-muscle myosin IIb is control...	ACCEPT	Summary: EXP from PMID:28234934. Experimental evidence for regulation of postsynapse organization. Redundant with IDA from same study. Reason: Valid experimental evidence. Supporting Evidence: PMID:28234934 in primary cultured neurons, an inhibitor of Hsc70 impeded the morphological change in spines induced by FILIP
GO:0099634 postsynaptic specialization membrane	IDA PMID:21209184 Heat shock cognate protein 70 regulates gephyrin clustering.	ACCEPT	Summary: IDA from PMID:21209184. Hsc70 detected at the postsynaptic specialization membrane where it regulates gephyrin clustering at inhibitory synapses. Reason: Directly demonstrated in mouse neurons.
GO:0072318 clathrin coat disassembly	IDA PMID:8524399 Role of auxilin in uncoating clathrin-coated vesicles.	ACCEPT	Summary: IDA from PMID:8524399. Directly demonstrated that Hsc70 drives clathrin coat disassembly from coated vesicles in conjunction with the co-chaperone auxilin, using ATP hydrolysis. Reason: Core function. Landmark study establishing Hsc70 role in clathrin uncoating. Supporting Evidence: PMID:8524399 Role of auxilin in uncoating clathrin-coated vesicles
GO:0005765 lysosomal membrane	ISS GO_REF:0000024	ACCEPT	Summary: ISS by curator judgment. Hspa8 associates with the lysosomal membrane via LAMP2A during CMA, both on the cytosolic and lumenal sides. Reason: Core CMA localization. Hspa8 binds LAMP2A on the lysosomal membrane.
GO:0030674 protein-macromolecule adaptor activity	ISS GO_REF:0000024	ACCEPT	Summary: ISS by curator judgment. Redundant with IDA from PMID:30718432. Reason: Core CMA function. Hspa8 serves as an adaptor between KFERQ-motif substrates and LAMP2A.
GO:0061740 protein targeting to lysosome involved in chaperone-mediated autophagy	ISS GO_REF:0000024	ACCEPT	Summary: ISS by curator judgment. Redundant with ISO from GO_REF:0000119. Core CMA function. Reason: Core CMA function.
GO:0001786 phosphatidylserine binding	IDA PMID:21238931 Microautophagy of cytosolic proteins by late endosomes.	ACCEPT	Summary: IDA from PMID:21238931. During endosomal microautophagy, Hsc70 binds to the endosomal membrane through electrostatic interactions via its cationic domain. The study identified phosphatidylserine as a binding partner, though the interaction is mediated via electrostatic rather than specific lipid-binding mechanisms. Reason: Directly demonstrated. Important for Hsc70 targeting to endosomal membranes during 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:0061635 regulation of protein complex stability	ISS GO_REF:0000024	ACCEPT	Summary: ISS by curator judgment. Redundant with ISO annotations. Consistent with SNARE chaperoning and clathrin uncoating roles. Reason: Consistent with documented roles in maintaining protein complex stability.
GO:0005515 protein binding	IPI PMID:35044787 Loss-of-function mutations in the co-chaperone protein BAG5 ...	REMOVE	Summary: IPI from PMID:35044787. BAG5 loss-of-function study showing Hsc70 interacts with BAG5 co-chaperone. Protein binding is uninformative. Reason: GO:0005515 protein binding is uninformative. The interaction with BAG5 co-chaperone is better captured by heat shock protein binding or co-chaperone binding annotations.
GO:0035651 AP-3 adaptor complex binding	IDA PMID:19010779 Hermansky-Pudlak syndrome protein complexes associate with p...	KEEP AS NON CORE	Summary: IDA from PMID:19010779. Hsc70 was identified as an AP-3 interacting protein by mass spectrometry in a cross-linking/purification study of Hermansky-Pudlak syndrome protein complexes. Reason: Valid interaction but represents a peripheral function of Hspa8 rather than a core chaperone activity. Supporting Evidence: PMID:19010779 AP-3 was co-isolated with BLOC-1, BLOC-2, and homotypic fusion and vacuole protein sorting complex subunits
GO:0061684 chaperone-mediated autophagy	ISO GO_REF:0000008	ACCEPT	Summary: ISO from MGI curated orthology. Redundant with IDA (PMID:30718432), IEA, and other ISO annotations. Reason: Core function.
GO:0005515 protein binding	IPI PMID:18346207 A novel calcium-binding protein is associated with tau prote...	REMOVE	Summary: IPI from PMID:18346207. Hsc70 co-immunoprecipitated with tau and a novel calcium-binding protein in tauopathy mouse model. Protein binding is uninformative. Reason: GO:0005515 protein binding is uninformative. The interaction in tauopathy context does not describe a specific molecular function.
GO:0031906 late endosome lumen	TAS Reactome:R-MMU-9631080	ACCEPT	Summary: TAS from Reactome pathway for substrate translocation into late endosomal lumen. Consistent with Hsc70 role in endosomal microautophagy (PMID:21238931). Reason: Consistent with documented role in endosomal microautophagy where Hsc70 delivers substrates to late endosomes.
GO:0048471 perinuclear region of cytoplasm	IDA PMID:14627652 Emerging role for autophagy in the removal of aggresomes in ...	KEEP AS NON CORE	Summary: IDA from PMID:14627652. Hsc70 was detected at the perinuclear region associated with aggresomes in Schwann cells with misfolded PMP22 protein. This is a stress-induced localization rather than constitutive. Reason: Valid localization but context-dependent (aggresome association), not a primary constitutive localization.
GO:0005829 cytosol	TAS Reactome:R-MMU-9613507	ACCEPT	Summary: TAS from Reactome pathway for Plins/Hspa8 binding Prkaa2. Cytosolic localization is well established. Reason: Cytosol is a primary localization for Hspa8.
GO:0005829 cytosol	TAS Reactome:R-MMU-9613545	ACCEPT	Summary: TAS from Reactome pathway for Prkaa2 phosphorylation of Plins. Redundant cytosol annotation. Reason: Cytosol is a primary localization.
GO:0005829 cytosol	TAS Reactome:R-MMU-9613562	ACCEPT	Summary: TAS from Reactome pathway for Prkaa2 dissociation from p-Plins/Hspa8. Redundant cytosol annotation. Reason: Cytosol is a primary localization.
GO:0005829 cytosol	TAS Reactome:R-MMU-9613670	ACCEPT	Summary: TAS from Reactome pathway for p-Plins translocation from lipid droplet to cytosol. Redundant cytosol annotation. Reason: Cytosol is a primary localization.
GO:0005829 cytosol	TAS Reactome:R-MMU-9631076	ACCEPT	Summary: TAS from Reactome pathway for Hspa8/substrate binding to late endosomal phospholipids. Redundant cytosol annotation. Reason: Cytosol is a primary localization.
GO:0005829 cytosol	TAS Reactome:R-MMU-9631080	ACCEPT	Summary: TAS from Reactome pathway for substrate translocation into late endosomal lumen. Redundant cytosol annotation. Reason: Cytosol is a primary localization.
GO:0005737 cytoplasm	IDA PMID:26581985 Identification of Viral and Host Proteins That Interact with...	ACCEPT	Summary: IDA from PMID:26581985. Hsc70 detected in the cytoplasm in studies of MHV68 viral replication. Hspa8 was recruited to nuclei in an mLANA-dependent process during viral infection. Reason: Cytoplasm is a primary localization for Hspa8. Supporting Evidence: PMID:26581985 mLANA-dependent recruitment of Hsc70 to nuclei of productively infected cells
GO:0044788 host-mediated perturbation of viral process	IMP PMID:26581985 Identification of Viral and Host Proteins That Interact with...	KEEP AS NON CORE	Summary: IMP from PMID:26581985. Pharmacologic inhibition and shRNA-mediated knockdown of Hsc70 impaired MHV68 lytic replication, correlating with impaired viral protein expression and reduced viral DNA replication. Reason: Valid but context-dependent interaction with a specific virus. Not a core chaperone function. 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	IMP PMID:26581985 Identification of Viral and Host Proteins That Interact with...	KEEP AS NON CORE	Summary: IMP from PMID:26581985. Hsc70 facilitates MHV68 lytic replication through interaction with mLANA. This is a host factor co-opted by the virus rather than a host defense mechanism. Reason: Valid but represents viral exploitation of chaperone function rather than core host function. Supporting Evidence: PMID:26581985 Hsc70 facilitates MHV68 protein expression and DNA replication, thus contributing to efficient MHV68 lytic replication
GO:0005765 lysosomal membrane	ISO GO_REF:0000008	ACCEPT	Summary: ISO from MGI curated orthology. Redundant with ISS (GO_REF:0000024) and ISO (GO_REF:0000096/0000119) annotations. Reason: Core CMA localization.
GO:0032984 protein-containing complex disassembly	ISO GO_REF:0000008	ACCEPT	Summary: ISO from MGI curated orthology. Consistent with clathrin coat disassembly and CMA translocation complex disassembly roles. Reason: Consistent with multiple documented roles in complex disassembly.
GO:1990836 lysosomal matrix	ISO GO_REF:0000008	ACCEPT	Summary: ISO from MGI curated orthology. Redundant with ISO from GO_REF:0000096. Reason: Consistent with lumenal Hsc70 role in CMA.
GO:0005770 late endosome	IDA PMID:21238931 Microautophagy of cytosolic proteins by late endosomes.	ACCEPT	Summary: IDA from PMID:21238931. Hsc70 localizes to late endosomes where it mediates endosomal microautophagy by delivering cytosolic proteins for internalization into MVB vesicles. Reason: Directly demonstrated. Important localization for endosomal microautophagy function. Supporting Evidence: PMID:21238931 distinct autophagic mechanisms control cytosolic protein delivery to late endosomes and identify a microautophagy-like process that delivers soluble cytosolic proteins to the vesicles of late endosomes/multivesicular bodies
GO:0061738 late endosomal microautophagy	IMP PMID:21238931 Microautophagy of cytosolic proteins by late endosomes.	ACCEPT	Summary: IMP from PMID:21238931. Hsc70 mediates a microautophagy-like process that delivers soluble cytosolic proteins to late endosome/MVB vesicles, distinct from CMA. Requires the cationic domain of Hsc70 for membrane interactions. Reason: Well-established secondary autophagy function of Hsc70. Supporting Evidence: PMID:21238931 Endosomal microautophagy occurs during MVB formation, relying on the ESCRT I and III systems for formation of the vesicles in which the cytosolic cargo is internalized
GO:0061684 chaperone-mediated autophagy	ISS GO_REF:0000024	ACCEPT	Summary: ISS by curator judgment. Redundant with IDA, IEA, ISO, and other annotations for CMA. Reason: Core function.
GO:1904764 chaperone-mediated autophagy translocation complex disassembly	ISS GO_REF:0000024	ACCEPT	Summary: ISS by curator judgment. Redundant with ISO annotations. Core CMA function. Reason: Core CMA function.
GO:0005515 protein binding	IPI PMID:20060297 Chaperone-assisted selective autophagy is essential for musc...	REMOVE	Summary: IPI from PMID:20060297 (CASA pathway). Hsc70 interacts with BAG3 and HSPB8 in the chaperone-assisted selective autophagy complex. Protein binding is uninformative. Reason: GO:0005515 protein binding is uninformative. The CASA complex interactions are better captured by specific chaperone complex annotations.
GO:0016887 ATP hydrolysis activity	ISO GO_REF:0000008	ACCEPT	Summary: ISO from MGI curated orthology. Core enzymatic activity of Hspa8 as an ATPase. Reason: Core enzymatic activity.
GO:0042026 protein refolding	ISS GO_REF:0000024	ACCEPT	Summary: ISS by curator judgment. Core chaperone function of Hspa8 in promoting refolding of denatured proteins through ATP-dependent cycles. Reason: Core chaperone function.
GO:0043209 myelin sheath	HDA PMID:17634366 Proteolipid protein is required for transport of sirtuin 2 i...	KEEP AS NON CORE	Summary: HDA from PMID:17634366. Hsc70 detected in CNS myelin proteome by mass spectrometry. The study focused on proteolipid protein-dependent transport of sirtuin 2 into myelin. Reason: Valid proteomic detection but represents a secondary localization rather than a core function.
GO:0048026 positive regulation of mRNA splicing, via spliceosome	IMP PMID:23636947 A broadly applicable high-throughput screening strategy iden...	KEEP AS NON CORE	Summary: IMP from PMID:23636947. High-throughput screening study identified factors affecting Dlg4 (Psd-95) exon 18 alternative splicing. Hsc70 was likely identified as part of the Prp19 complex contribution to splicing regulation. Reason: Valid but represents a secondary/moonlighting function of Hspa8 through its role in the Prp19 spliceosome complex.
GO:0072318 clathrin coat disassembly	IGI PMID:20160091 Endocytosis and clathrin-uncoating defects at synapses of au...	ACCEPT	Summary: IGI from PMID:20160091. Auxilin knockout mouse study demonstrating that the auxilin-Hsc70 system is required for efficient clathrin uncoating at synapses. Genetic interaction evidence. Reason: Core function. Genetic evidence supporting Hsc70 role in clathrin uncoating. Supporting Evidence: PMID:20160091 Endocytosis and clathrin-uncoating defects at synapses of auxilin knockout mice
GO:0005515 protein binding	IPI PMID:23055941 RAB-like 2 has an essential role in male fertility, sperm in...	REMOVE	Summary: IPI from PMID:23055941. RABL2 co-immunoprecipitation study in sperm. Protein binding is uninformative. Reason: GO:0005515 protein binding is uninformative.
GO:0000974 Prp19 complex	ISS GO_REF:0000024	ACCEPT	Summary: ISS by curator judgment. Hspa8 is a documented component of the Prp19/CDC5L spliceosome complex (PMID:23742842). UniProt confirms Hspa8 as a Prp19-CDC5L complex component. Reason: Well-documented complex membership, consistent with mRNA splicing role.
GO:0005634 nucleus	ISS GO_REF:0000024	ACCEPT	Summary: ISS by curator judgment. Hspa8 localizes to the nucleus as part of the Prp19 complex and in viral infection contexts (PMID:26581985). UniProt lists nucleolus as a subcellular localization. Reason: Consistent with Prp19 complex membership and nuclear roles documented in UniProt.
GO:0005515 protein binding	IPI PMID:12588994 Hsc70 regulates accumulation of cyclin D1 and cyclin D1-depe...	REMOVE	Summary: IPI from PMID:12588994. Hsc70 interacts with cyclin D1 and CDK4 to regulate cell cycle. Protein binding is uninformative. Reason: GO:0005515 protein binding is uninformative. The cyclin D1/CDK4 interaction is better represented by the regulation of cell cycle annotation.
GO:0045892 negative regulation of DNA-templated transcription	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS by curator judgment. HSP70 family members have been reported to influence transcription, possibly through effects on transcription factor stability/folding. Reason: Plausible but indirect consequence of chaperone activity rather than a core function.
GO:0005515 protein binding	IPI PMID:14644449 Hsp105 but not Hsp70 family proteins suppress the aggregatio...	REMOVE	Summary: IPI from PMID:14644449. Hsc70 interacts with Hsp105 and Hsp40 in aggregation suppression assays. Protein binding is uninformative. Reason: GO:0005515 protein binding is uninformative. These co-chaperone interactions are better captured by heat shock protein binding and protein folding annotations.
GO:0070062 extracellular exosome	IDA PMID:19724054 The water channel aquaporin-1 partitions into exosomes durin...	KEEP AS NON CORE	Summary: IDA from PMID:19724054. Hsc70 detected in exosomes during reticulocyte maturation. Also supported by ISO from human HSPA8. Reason: Valid localization but non-core. Hspa8 is found in exosomes but this is not a primary function.
GO:1990904 ribonucleoprotein complex	ISS GO_REF:0000024	ACCEPT	Summary: ISS by curator judgment. Redundant with ISO from GO_REF:0000119. Consistent with Prp19 complex membership. Reason: Consistent with Prp19 spliceosome complex membership.
GO:0005829 cytosol	IDA PMID:16906134 Editing-defective tRNA synthetase causes protein misfolding ...	ACCEPT	Summary: IDA from PMID:16906134. Hsc70 detected in the cytosol. Study of editing-defective tRNA synthetase; Hsc70 identified as a cytosolic protein in the context of protein misfolding. Reason: Cytosol is a primary localization for Hspa8.
GO:0051082 unfolded protein binding	IPI PMID:12588994 Hsc70 regulates accumulation of cyclin D1 and cyclin D1-depe...	MODIFY	Summary: IPI from PMID:12588994. Hsc70 binds unfolded/denatured substrates including cyclin D1. Per UPB project decision rules for HSP70 family, this should be modified to GO:0044183 (protein folding chaperone). Reason: Per UPB project decision rules, GO:0051082 for HSP70-family foldases should be modified to GO:0044183 (protein folding chaperone). Hspa8 is a bona fide ATP-dependent foldase, not merely a passive binder of unfolded proteins. Proposed replacements: protein folding chaperone
GO:0006457 protein folding	IGI PMID:14644449 Hsp105 but not Hsp70 family proteins suppress the aggregatio...	ACCEPT	Summary: IGI from PMID:14644449. Genetic interaction with Hsp105 showing cooperative suppression of heat-denatured protein aggregation. Hsp70 family members contribute to protein folding in conjunction with co-chaperones. Reason: Core function. Genetic interaction evidence for cooperative protein folding. Supporting Evidence: PMID:14644449 Hsp105 but not Hsp70 family proteins suppress the aggregation of heat-denatured protein in the presence of ADP
GO:0016887 ATP hydrolysis activity	IDA PMID:12588994 Hsc70 regulates accumulation of cyclin D1 and cyclin D1-depe...	ACCEPT	Summary: IDA from PMID:12588994. Hsc70 ATPase activity demonstrated in the context of cyclin D1/CDK4 regulation. Core enzymatic activity of all HSP70 family members. Reason: Core enzymatic activity.
GO:0006457 protein folding	IDA PMID:12588994 Hsc70 regulates accumulation of cyclin D1 and cyclin D1-depe...	ACCEPT	Summary: IDA from PMID:12588994. Hsc70 functions in protein folding, specifically demonstrated in the context of maintaining cyclin D1 stability through its chaperone activity. Reason: Core function.
GO:0051726 regulation of cell cycle	IDA PMID:12588994 Hsc70 regulates accumulation of cyclin D1 and cyclin D1-depe...	KEEP AS NON CORE	Summary: IDA from PMID:12588994. Hsc70 regulates accumulation of cyclin D1 and cyclin D1-dependent protein kinase CDK4, thereby influencing G1/S transition. Reason: Valid downstream consequence of chaperone activity on cell cycle proteins, but cell cycle regulation is not a core molecular function of Hspa8.

📄 View Raw YAML

id: P63017
gene_symbol: Hspa8
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:10090
  label: Mus musculus
description: Hspa8 (also known as Hsc70 or Hsc73) is the constitutively expressed member of the HSP70 family
  of molecular chaperones in mouse. It functions as an ATP-dependent foldase chaperone that uses
  nucleotide-driven conformational changes to bind and release unfolded or misfolded substrate proteins,
  promoting their correct folding. Hspa8 plays central roles in protein quality control, chaperone-mediated
  autophagy (CMA) where it recognizes KFERQ motifs on substrate proteins for lysosomal degradation,
  clathrin coat disassembly via its interaction with auxilin (DNAJC6), protein disaggregation (with HSPH1),
  and as a component of the spliceosomal PRP19-CDC5L complex. It is also involved in SNARE complex
  assembly at presynaptic terminals through the CSPalpha-Hsc70-SGT chaperone complex, and in late
  endosomal microautophagy. Mouse Hspa8 protein sequence is nearly identical to human HSPA8 (P11142).
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Hspa8 is found in the nucleus, consistent with its role as a component of the PRP19-CDC5L spliceosomal complex and its stress-induced nuclear/nucleolar translocation (UniProt CC).
    action: ACCEPT
    reason: Nuclear localization is well-supported by IBA across HSP70 orthologs and consistent with Hspa8's role in splicing and stress response. UniProt notes it translocates to nuclei upon heat shock.
    supported_by:
      - reference_id: GO_REF:0000033
        supporting_text: "IBA from multiple orthologs including human P11142, yeast SSA1/SSA2, S. pombe"
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Hspa8 is primarily cytoplasmic as the constitutive HSP70 chaperone. This is its main subcellular compartment.
    action: ACCEPT
    reason: Cytoplasmic localization is a core feature of Hspa8/Hsc70, the constitutive cytosolic HSP70 family member. Supported by IBA across many orthologs.
    supported_by:
      - reference_id: GO_REF:0000033
        supporting_text: "IBA from diverse orthologs including yeast, fly, worm, human"
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Hspa8 localizes to the plasma membrane. UniProt confirms cell membrane localization by similarity to human HSPA8. Human ortholog interacts with cell surface receptors and is involved in antigen presentation.
    action: ACCEPT
    reason: Plasma membrane localization is supported by IBA and by similarity to the well-characterized human ortholog.
    supported_by:
      - reference_id: GO_REF:0000033
        supporting_text: "IBA from multiple orthologs"
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ATP hydrolysis is the core enzymatic activity of Hspa8 (EC 3.6.4.10), driving the chaperone cycle through conformational changes that regulate substrate binding and release. Also confirmed by IDA from PMID:12588994.
    action: ACCEPT
    reason: ATP hydrolysis activity is the central enzymatic function of Hspa8/Hsc70, confirmed by its EC classification and extensive biochemical characterization.
    supported_by:
      - reference_id: PMID:12588994
        supporting_text: "Hsc70 associates with newly synthesized cyclin D1 and is a component of a mature, catalytically active cyclin D1/CDK4 holoenzyme complex"
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Hspa8 binds multiple heat shock proteins including HSPH1/Hsp105 and various J-domain co-chaperones (DNAJ family members) as part of its chaperone machine. Direct interaction with HSPH1 confirmed in mouse (PMID:9675148). Hsp105 family members function alongside Hsc70/Hsp40 in suppressing aggregation of denatured proteins (PMID:14644449).
    action: ACCEPT
    reason: Heat shock protein binding is a core functional property of Hspa8, which operates in complexes with HSP90, small HSPs, and J-domain proteins. Directly demonstrated in mouse.
    supported_by:
      - reference_id: PMID:14644449
        supporting_text: "Hsc70/Hsp40 suppressed the aggregation of heat-denatured protein in the presence of ATP rather than ADP"
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Protein folding chaperone activity is the primary molecular function of Hspa8/Hsc70. It binds client polypeptides through its substrate-binding domain and assists their folding through ATP-driven conformational cycles. This is the recommended replacement for GO:0051082 for HSP70 family members per UPB project guidelines.
    action: ACCEPT
    reason: This is the core molecular function of Hspa8 as a constitutive HSP70 family chaperone, extensively documented. The IBA annotation correctly captures the foldase function at the appropriate level of specificity.
    supported_by:
      - reference_id: PMID:21151134
        supporting_text: "the CSPalpha-Hsc70-SGT complex binds directly to monomeric SNAP-25 to prevent its aggregation, enabling SNARE-complex formation"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Hspa8 is primarily a cytosolic protein, supported by IBA across many HSP70 orthologs and confirmed by IDA in mouse (PMID:16906134).
    action: ACCEPT
    reason: Cytosol is the primary subcellular location where Hspa8 performs its housekeeping chaperone functions.
- term:
    id: GO:0072318
    label: clathrin coat disassembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Hspa8/Hsc70 is essential for clathrin coat disassembly, working with auxilin (DNAJC6) to uncoat clathrin-coated vesicles via ATP-dependent disassembly (PMID:8524399). Also confirmed by IDA in mouse (PMID:8524399) and IGI from auxilin knockout studies (PMID:20160091).
    action: ACCEPT
    reason: Clathrin coat disassembly is a well-established core function of Hspa8.
    supported_by:
      - reference_id: PMID:8524399
        supporting_text: "This process is effected by the chaperone protein hsp70c together with a 100K cofactor which we here identify as the coat protein auxilin"
      - reference_id: PMID:20160091
        supporting_text: "Neuronally expressed auxilin and ubiquitously expressed cyclin-G-dependent kinase (GAK) are homologous proteins that act as cochaperones to support the Hsc70-dependent clathrin uncoating"
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Hspa8 participates in protein refolding, including refolding of heat-denatured substrates. Demonstrated in mouse by interaction with Hsp105 in refolding assays (PMID:14644449).
    action: ACCEPT
    reason: Protein refolding is a well-documented core activity of the HSP70 chaperone machine.
    supported_by:
      - reference_id: PMID:14644449
        supporting_text: "Hsc70/Hsp40 suppressed the aggregation of heat-denatured protein in the presence of ATP rather than ADP"
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: Signal transduction is overly broad for Hspa8. While Hspa8 modulates some signaling pathways indirectly through its chaperone activity, its primary role is as a molecular chaperone, not a signaling molecule.
    action: MARK_AS_OVER_ANNOTATED
    reason: Hspa8 is a molecular chaperone, not a signaling protein. The IEA annotation to signal transduction is too broad and does not capture the specific mechanistic role of Hspa8. Consistent with the human HSPA8 review.
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Hspa8 binds ATP and ADP through its nucleotide-binding domain (NBD), which drives the chaperone conformational cycle. This is a parent term of the more specific GO:0005524 (ATP binding).
    action: ACCEPT
    reason: Nucleotide binding is a core biochemical property of Hspa8, required for its chaperone function. While more general than ATP binding, it is accurate as an IEA annotation.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: ATP binding is a core biochemical activity of Hspa8, required for its chaperone cycle. The NBD (residues 2-386) contains well-characterized ATP-binding sites confirmed by crystallography (PDB:3CQX).
    action: ACCEPT
    reason: ATP binding is essential for Hspa8 function, confirmed by crystal structure and biochemical assays.
- term:
    id: GO:0005681
    label: spliceosomal complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Hspa8 is a component of the PRP19-CDC5L spliceosomal complex, as stated in UniProt and confirmed for the human ortholog. The NAS annotation to GO:0000398 (mRNA splicing, via spliceosome) from PMID:23742842 also supports this.
    action: ACCEPT
    reason: Spliceosomal complex membership is supported by the established role of Hspa8/HSC70 in the PRP19-CDC5L complex.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Nucleolar localization of Hspa8 from IEA mapping of UniProt subcellular location. UniProt states Hspa8 translocates to nucleoli upon heat shock.
    action: KEEP_AS_NON_CORE
    reason: Hspa8 is found in the nucleolus upon stress, but this is not a primary site of function under normal conditions.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Cytoplasmic localization of Hspa8 is well-established and consistent with the IBA annotation.
    action: ACCEPT
    reason: Correct IEA annotation, consistent with IBA and experimental evidence.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Hspa8 associates with the lysosomal membrane during CMA, where it delivers KFERQ-motif substrates to LAMP2A for translocation. UniProt confirms lysosome membrane localization as a peripheral membrane protein on the cytoplasmic side.
    action: ACCEPT
    reason: Lysosomal membrane localization is a core feature of Hspa8's role in CMA.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Plasma membrane localization of Hspa8 is consistent with the IBA annotation and UniProt subcellular location.
    action: ACCEPT
    reason: Consistent with IBA annotation and UniProt data.
- term:
    id: GO:0006397
    label: mRNA processing
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Hspa8 participates in mRNA processing as a component of the PRP19-CDC5L spliceosomal complex. Also supported by NAS annotation to GO:0000398 from PMID:23742842.
    action: ACCEPT
    reason: Supported by Hspa8's established role in the PRP19-CDC5L complex involved in splicing.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Protein folding is a core biological process for Hspa8. This is confirmed by multiple IDA annotations from PMID:12588994 and PMID:21151134.
    action: ACCEPT
    reason: Protein folding is the primary biological process in which Hspa8 participates. Consistent with extensive experimental evidence.
- term:
    id: GO:0006914
    label: autophagy
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Hspa8 is central to chaperone-mediated autophagy (CMA), recognizing KFERQ-motif substrates and delivering them to LAMP2A at the lysosomal membrane (PMID:30718432). Also involved in late endosomal microautophagy (PMID:21238931).
    action: ACCEPT
    reason: Autophagy involvement is a core function of Hspa8 through its essential role in CMA and endosomal microautophagy.
- term:
    id: GO:0008289
    label: lipid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Hspa8 binds lipids including phosphatidylserine (confirmed by IDA from PMID:21238931 for the endosomal microautophagy role) and is found associated with lipid droplets via Plin2/Plin3 interactions (PMID:25961502).
    action: ACCEPT
    reason: Lipid binding is documented for Hspa8. The IDA annotation for phosphatidylserine binding (PMID:21238931) and interactions with perilipin proteins at lipid droplets support this.
- term:
    id: GO:0008380
    label: RNA splicing
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Hspa8 is involved in RNA splicing as part of the PRP19-CDC5L spliceosomal complex. Also supported by the IMP annotation for positive regulation of mRNA splicing from PMID:23636947.
    action: ACCEPT
    reason: Supported by Hspa8's established role in the spliceosome.
- term:
    id: GO:0016787
    label: hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Hspa8 has hydrolase activity (ATP hydrolysis, EC 3.6.4.10). This is a parent term of the more specific GO:0016887 (ATP hydrolysis activity).
    action: ACCEPT
    reason: Accurate but general; more specific ATP hydrolysis activity terms also annotated. Acceptable as a broader IEA annotation.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: ATP hydrolysis activity is a core enzymatic function of Hspa8, redundant with the IBA annotation but correct.
    action: ACCEPT
    reason: Correct IEA annotation consistent with the IBA annotation for this core function.
- term:
    id: GO:0042470
    label: melanosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Hspa8 was identified in melanosomes. UniProt confirms melanosome localization by similarity. This likely reflects its role as an abundant chaperone found in many compartments.
    action: KEEP_AS_NON_CORE
    reason: IEA-based from subcellular location mapping. Hspa8 is an abundant protein found in many subcellular fractions; melanosome localization is not a core function.
- term:
    id: GO:0043168
    label: anion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Anion binding for Hspa8 likely reflects ATP/ADP binding (these are anions). This is an overly broad IEA annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Too generic. The specific activity is ATP binding (GO:0005524), which is already annotated. Anion binding does not provide additional functional information.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20111006
  review:
    summary: Protein binding annotation from IntAct based on interaction with Klc1 (kinesin light chain 1). The interaction is relevant to slow axonal transport function of Hsc70.
    action: REMOVE
    reason: GO:0005515 (protein binding) is uninformative for a molecular chaperone that by definition interacts with many substrate proteins and co-chaperones. More specific MF terms are preferable.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25961502
  review:
    summary: Protein binding annotation from IntAct based on interaction with Plin2 and Plin3 (perilipins). Relevant to CMA-mediated degradation of lipid droplet-associated proteins.
    action: REMOVE
    reason: GO:0005515 (protein binding) is uninformative for a molecular chaperone. The CMA substrate recognition function is better captured by GO:0030674 (protein-macromolecule adaptor activity) and GO:0061684 (chaperone-mediated autophagy).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26581985
  review:
    summary: Protein binding annotation from IntAct based on interaction with murine gammaherpesvirus 68 LANA. Relevant to the viral replication role of Hsc70.
    action: REMOVE
    reason: GO:0005515 (protein binding) is uninformative for a molecular chaperone. The virus-related function is better captured by the host-virus interaction annotations from this same paper.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Hspa8 is found in multiple protein-containing complexes including the PRP19-CDC5L spliceosomal complex, the CASA complex (BAG3-HSC70-HSPB8-STUB1), and chaperone-substrate complexes.
    action: ACCEPT
    reason: Generic but accurate. Hspa8 participates in multiple defined protein complexes.
- term:
    id: GO:0000082
    label: G1/S transition of mitotic cell cycle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 is involved in G1/S transition through its role in stabilizing cyclin D1 and the cyclin D1/CDK4 complex (PMID:12588994).
    action: KEEP_AS_NON_CORE
    reason: While supported by evidence in mouse (PMID:12588994), cell cycle regulation is a downstream consequence of Hspa8 chaperone activity, not a core function.
- term:
    id: GO:0001822
    label: kidney development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Kidney development is a tissue-specific phenotypic association, not a core molecular function.
    action: KEEP_AS_NON_CORE
    reason: A pleiotropic consequence of Hspa8's ubiquitous chaperone functions. Not a core function.
- term:
    id: GO:0001916
    label: positive regulation of T cell mediated cytotoxicity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. HSP70 family members are known to present antigens and modulate immune responses. This is a downstream consequence of chaperone activity.
    action: KEEP_AS_NON_CORE
    reason: Immune function modulation is a non-core downstream consequence of Hspa8's chaperone and antigen presentation roles.
- term:
    id: GO:0001917
    label: photoreceptor inner segment
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. As a ubiquitous protein, Hspa8 is expected to be found in many cell types including photoreceptors.
    action: KEEP_AS_NON_CORE
    reason: Reflects ubiquitous expression. Not a core localization.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 has been found in mRNP granules and the PRP19-CDC5L spliceosomal complex, both of which involve RNA. UniProt notes it is part of an IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs.
    action: KEEP_AS_NON_CORE
    reason: While Hspa8 is found in RNA-containing complexes, RNA binding is not its primary molecular function.
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 can bind cell surface receptors but this is not a core chaperone function.
    action: KEEP_AS_NON_CORE
    reason: A non-core interaction. Hspa8 is primarily a chaperone, not a signaling ligand.
- term:
    id: GO:0005776
    label: autophagosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 is involved in autophagy pathways (CMA) and may be present in autophagosomes.
    action: KEEP_AS_NON_CORE
    reason: Hspa8's primary autophagy role is in CMA at the lysosomal membrane, not within autophagosomes per se.
- term:
    id: GO:0005874
    label: microtubule
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 may associate with microtubules as part of its role in axonal transport and cytoskeletal quality control.
    action: KEEP_AS_NON_CORE
    reason: Microtubule association is not a core localization for Hspa8.
- term:
    id: GO:0005882
    label: intermediate filament
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 may associate with intermediate filaments as part of its chaperone quality control role.
    action: KEEP_AS_NON_CORE
    reason: Not a core localization. Likely reflects proteomic detection in cytoskeletal fractions.
- term:
    id: GO:0006606
    label: protein import into nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. HSP70 family chaperones are known to assist in nuclear import of certain protein substrates.
    action: KEEP_AS_NON_CORE
    reason: A non-core downstream consequence of Hspa8's chaperone activity.
- term:
    id: GO:0007519
    label: skeletal muscle tissue development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 is involved in muscle maintenance through the CASA complex (BAG3-HSC70-HSPB8-STUB1) as shown by PMID:20060297.
    action: KEEP_AS_NON_CORE
    reason: Muscle maintenance via CASA is a documented but non-core developmental role.
- term:
    id: GO:0008021
    label: synaptic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 is associated with synaptic vesicles through its role in clathrin uncoating and SNARE complex assembly with CSPalpha (PMID:21151134).
    action: ACCEPT
    reason: Consistent with well-documented synaptic roles of Hspa8 in clathrin uncoating and SNARE chaperoning.
- term:
    id: GO:0008088
    label: axo-dendritic transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 is involved in slow axonal transport through interaction with kinesin light chain (Klc1) (PMID:20111006).
    action: KEEP_AS_NON_CORE
    reason: A documented but non-core neuronal function of Hspa8.
- term:
    id: GO:0009410
    label: response to xenobiotic stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. HSP70 chaperones can be upregulated in response to xenobiotics as part of the general stress response.
    action: KEEP_AS_NON_CORE
    reason: A non-core stress response annotation. Hspa8 is constitutively expressed and less stress-inducible than HSPA1A.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Consistent with plasma membrane IBA annotation. Hspa8 is found at the cell surface.
    action: ACCEPT
    reason: Consistent with the well-documented cell surface localization of Hspa8.
- term:
    id: GO:0010045
    label: response to nickel cation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Likely reflects general stress response to heavy metals.
    action: KEEP_AS_NON_CORE
    reason: A non-core stress response annotation reflecting general chaperone upregulation.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 can influence gene expression through regulation of transcription factors and HSF1 signaling.
    action: KEEP_AS_NON_CORE
    reason: An indirect downstream consequence of Hspa8's chaperone activity, not a core function.
- term:
    id: GO:0010667
    label: negative regulation of cardiac muscle cell apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. HSP70 family members have anti-apoptotic properties. Hspa8 interacts with BAG5 and JPH2 in cardiac tissue.
    action: KEEP_AS_NON_CORE
    reason: A tissue-specific non-core downstream consequence of Hspa8's chaperone and protein quality control activities.
- term:
    id: GO:0014069
    label: postsynaptic density
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 is found in the postsynaptic density. Mouse-specific evidence shows Hspa8 at the postsynaptic specialization membrane (PMID:21209184) and glutamatergic synapses (PMID:28234934).
    action: ACCEPT
    reason: Consistent with direct experimental evidence from SynGO showing Hspa8 in postsynaptic compartments.
- term:
    id: GO:0014823
    label: response to activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 levels and function respond to neuronal activity, consistent with its role in synaptic vesicle cycling and SNAP-25 chaperoning (PMID:21151134).
    action: KEEP_AS_NON_CORE
    reason: A non-core response annotation reflecting Hspa8's role in activity-dependent synaptic maintenance.
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 binds multiple enzymes including CDK4 (PMID:12588994) and various kinases.
    action: ACCEPT
    reason: While generic, enzyme binding is accurate given Hspa8's documented interactions with kinases and other enzymatic partners.
- term:
    id: GO:0021549
    label: cerebellum development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 is ubiquitously expressed and pleiotropic. Cerebellum development is a tissue-specific phenotypic association.
    action: KEEP_AS_NON_CORE
    reason: A pleiotropic consequence of Hspa8's ubiquitous chaperone functions, not a core function.
- term:
    id: GO:0030424
    label: axon
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 is found in axons, consistent with its role in slow axonal transport (PMID:20111006) and synaptic function.
    action: ACCEPT
    reason: Consistent with documented axonal transport and presynaptic functions of Hspa8.
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 is found in dendrites, consistent with its role in postsynaptic organization (PMID:28234934, PMID:21209184).
    action: ACCEPT
    reason: Consistent with documented dendritic and postsynaptic functions of Hspa8.
- term:
    id: GO:0030900
    label: forebrain development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. A tissue-specific developmental annotation.
    action: KEEP_AS_NON_CORE
    reason: A pleiotropic consequence of Hspa8's ubiquitous chaperone functions, not a core function.
- term:
    id: GO:0031686
    label: A1 adenosine receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. A specific receptor interaction transferred from rat evidence.
    action: KEEP_AS_NON_CORE
    reason: A non-core interaction. This specific binding is not well-characterized as a core function of Hspa8.
- term:
    id: GO:0032279
    label: asymmetric synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Consistent with Hspa8's role at glutamatergic synapses (PMID:21209184, PMID:28234934).
    action: ACCEPT
    reason: Consistent with SynGO experimental evidence for Hspa8 at glutamatergic (asymmetric) synapses.
- term:
    id: GO:0032355
    label: response to estradiol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Likely reflects HSP70 involvement in steroid hormone receptor chaperoning.
    action: KEEP_AS_NON_CORE
    reason: A non-core response annotation related to Hspa8's role in hormone receptor chaperoning.
- term:
    id: GO:0032570
    label: response to progesterone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Likely reflects HSP70 involvement in steroid hormone receptor chaperoning.
    action: KEEP_AS_NON_CORE
    reason: A non-core response annotation related to Hspa8's role in hormone receptor chaperoning.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Redundant with ISO annotation for same term.
    action: ACCEPT
    reason: Correct and consistent with ISO annotation.
- term:
    id: GO:0034605
    label: cellular response to heat
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. While Hspa8 is constitutively expressed (unlike HSPA1A), it participates in the heat shock response by assisting with protein refolding and by regulating HSF1.
    action: ACCEPT
    reason: As a constitutive chaperone, Hspa8 is a first responder to heat stress, assisting with protein refolding.
- term:
    id: GO:0042277
    label: peptide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 binds peptide substrates through its substrate-binding domain (SBD), which is central to its chaperone function.
    action: ACCEPT
    reason: Peptide binding is a core property of the substrate-binding domain of Hspa8.
- term:
    id: GO:0042594
    label: response to starvation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. CMA is upregulated during starvation, and Hspa8 is the substrate recognition component of CMA.
    action: ACCEPT
    reason: CMA is activated by starvation, making this a functionally relevant annotation for Hspa8.
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. As a ubiquitous cytosolic protein, Hspa8 is present in neuronal cell bodies.
    action: ACCEPT
    reason: Consistent with ubiquitous expression and neuronal localization studies.
- term:
    id: GO:0043195
    label: terminal bouton
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Consistent with Hspa8's well-documented presynaptic functions.
    action: ACCEPT
    reason: Consistent with presynaptic roles in clathrin uncoating and SNARE chaperoning (PMID:21151134).
- term:
    id: GO:0043197
    label: dendritic spine
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 regulates spine morphology via FILIP and myosin IIb (PMID:28234934).
    action: ACCEPT
    reason: Consistent with direct experimental evidence showing Hspa8's role in dendritic spine morphology regulation.
- term:
    id: GO:0043198
    label: dendritic shaft
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Consistent with dendritic localization.
    action: ACCEPT
    reason: Consistent with dendritic localization of Hspa8.
- term:
    id: GO:0043204
    label: perikaryon
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. As a ubiquitous cytosolic protein, Hspa8 is present in the perikaryon.
    action: ACCEPT
    reason: Consistent with ubiquitous expression.
- term:
    id: GO:0044309
    label: neuron spine
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Consistent with dendritic spine annotation and PMID:28234934.
    action: ACCEPT
    reason: Consistent with experimental evidence for Hspa8 in spine morphology regulation.
- term:
    id: GO:0044743
    label: protein transmembrane import into intracellular organelle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 is involved in protein import into mitochondria (delivering preproteins to TOMM70) and in CMA (delivering substrates to the lysosomal membrane for translocation).
    action: ACCEPT
    reason: Supported by documented roles in mitochondrial import and CMA translocation.
- term:
    id: GO:0044849
    label: estrous cycle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Likely reflects expression changes during the estrous cycle.
    action: KEEP_AS_NON_CORE
    reason: A non-core developmental/reproductive annotation.
- term:
    id: GO:0045471
    label: response to ethanol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Likely reflects general stress response to ethanol.
    action: KEEP_AS_NON_CORE
    reason: A non-core stress response annotation.
- term:
    id: GO:0045862
    label: positive regulation of proteolysis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 promotes proteolysis through CMA (targeting substrates for lysosomal degradation) and through CHIP/STUB1-mediated ubiquitination.
    action: ACCEPT
    reason: Consistent with Hspa8's established roles in CMA and CHIP-mediated proteasomal targeting.
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Also supported by IDA from PMID:14627652 in mouse, where detection was in context of aggresome association.
    action: KEEP_AS_NON_CORE
    reason: Supported by direct experimental evidence in mouse.
- term:
    id: GO:0050766
    label: positive regulation of phagocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. HSP70 family members promote phagocytosis through their cell surface roles.
    action: KEEP_AS_NON_CORE
    reason: A non-core immunological function downstream of Hspa8's cell surface and antigen presentation roles.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Per the UPB project decision rules for HSP70 family, GO:0051082 (unfolded protein binding) should be modified to GO:0044183 (protein folding chaperone). Hspa8/HSC70 is a context-dependent foldase/holdase chaperone that actively assists folding through ATP-driven conformational cycles.
    action: MODIFY
    reason: GO:0051082 does not capture the active chaperone mechanism of Hspa8. Per UPB project guidelines for HSP70 family members, the correct term is GO:0044183 (protein folding chaperone), which is already annotated via IBA.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
- term:
    id: GO:0061635
    label: regulation of protein complex stability
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 regulates protein complex stability, e.g. SNARE complex stability at synapses (PMID:21151134) and clathrin coat stability.
    action: ACCEPT
    reason: Consistent with Hspa8's roles in SNARE chaperoning and clathrin uncoating.
- term:
    id: GO:0061684
    label: chaperone-mediated autophagy
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. CMA is a core function of Hspa8 (PMID:30718432). Redundant with IDA and ISO annotations.
    action: ACCEPT
    reason: CMA is a core function of Hspa8. Consistent with multiple other annotations.
- term:
    id: GO:0070301
    label: cellular response to hydrogen peroxide
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 may be involved in cellular response to oxidative stress.
    action: KEEP_AS_NON_CORE
    reason: A non-core stress response annotation.
- term:
    id: GO:0071276
    label: cellular response to cadmium ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Likely reflects general stress response to heavy metals.
    action: KEEP_AS_NON_CORE
    reason: A non-core stress response annotation.
- term:
    id: GO:0072318
    label: clathrin coat disassembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Clathrin coat disassembly is a core function of Hspa8, redundant with IBA and IDA annotations. Confirmed by PMID:8524399.
    action: ACCEPT
    reason: Correct IEA annotation, consistent with IBA and IDA evidence.
- term:
    id: GO:0097214
    label: positive regulation of lysosomal membrane permeability
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Related to Hspa8's role at the lysosomal membrane in CMA.
    action: KEEP_AS_NON_CORE
    reason: A downstream consequence of Hspa8's CMA activity, not a core function per se.
- term:
    id: GO:0098690
    label: glycinergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Hspa8 is found at glycinergic synapses. Confirmed by IDA from PMID:21209184 showing Hsc70 binds gephyrin at inhibitory synapses.
    action: ACCEPT
    reason: Consistent with direct experimental evidence (PMID:21209184).
- term:
    id: GO:0098793
    label: presynapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 is found at the presynapse, confirmed by multiple IDA annotations (PMID:21151134, PMID:24616664).
    action: ACCEPT
    reason: Consistent with extensive experimental evidence for presynaptic localization.
- term:
    id: GO:0098794
    label: postsynapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 is found at the postsynapse, consistent with PMID:21209184 and PMID:28234934.
    action: ACCEPT
    reason: Consistent with experimental evidence for postsynaptic localization.
- term:
    id: GO:0098880
    label: maintenance of postsynaptic specialization structure
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 regulates gephyrin clustering at inhibitory synapses (PMID:21209184) and postsynapse organization via FILIP/myosin IIb (PMID:28234934).
    action: ACCEPT
    reason: Consistent with direct experimental evidence for Hspa8's role in postsynaptic organization.
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Confirmed by IDA from PMID:21209184 and PMID:28234934 showing Hspa8 at glutamatergic synapses.
    action: ACCEPT
    reason: Consistent with SynGO experimental evidence.
- term:
    id: GO:1904592
    label: positive regulation of protein refolding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 promotes protein refolding, consistent with its core chaperone function.
    action: ACCEPT
    reason: Consistent with Hspa8's core protein refolding activity.
- term:
    id: GO:1904593
    label: prostaglandin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. VGF-derived peptide TLQP-21 interacts with Hspa8 (by similarity per UniProt).
    action: KEEP_AS_NON_CORE
    reason: A non-core binding activity. Not well-characterized as a core function.
- term:
    id: GO:1904764
    label: chaperone-mediated autophagy translocation complex disassembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 is involved in disassembly of the CMA translocation complex at the lysosomal membrane. Consistent with its core CMA role.
    action: ACCEPT
    reason: CMA translocation complex disassembly is part of the core CMA function of Hspa8.
- term:
    id: GO:1990832
    label: slow axonal transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 interacts with kinesin light chain 1 (Klc1) for slow axonal transport (PMID:20111006).
    action: KEEP_AS_NON_CORE
    reason: A documented but non-core neuronal transport function.
- term:
    id: GO:1990833
    label: clathrin-uncoating ATPase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 uses its ATPase activity specifically for clathrin uncoating, working with auxilin/DNAJC6 (PMID:8524399).
    action: ACCEPT
    reason: Clathrin-uncoating ATPase activity is a specific and well-documented molecular function of Hspa8.
- term:
    id: GO:1990834
    label: response to odorant
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Likely reflects expression in olfactory neurons.
    action: KEEP_AS_NON_CORE
    reason: A non-core annotation likely reflecting ubiquitous expression.
- term:
    id: GO:1990836
    label: lysosomal matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl IEA from rat ortholog. Hspa8 may be found in the lysosomal matrix as part of CMA substrate delivery. Also present in late endosome lumen (Reactome TAS).
    action: ACCEPT
    reason: Consistent with Hspa8's role in CMA, where it delivers substrates to the lysosomal lumen.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Consistent with IBA and IEA annotations.
    action: ACCEPT
    reason: Correct and redundant with other evidence.
- term:
    id: GO:0043085
    label: positive regulation of catalytic activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Hspa8 can activate catalytic activity, e.g. CDK4 kinase maturation (PMID:12588994).
    action: KEEP_AS_NON_CORE
    reason: A non-core downstream consequence of Hspa8's chaperone activity on kinase maturation.
- term:
    id: GO:0046777
    label: protein autophosphorylation
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Hspa8 involvement in protein autophosphorylation is an indirect consequence of its chaperone activity.
    action: KEEP_AS_NON_CORE
    reason: Indirect consequence of chaperone activity on kinase substrates.
- term:
    id: GO:0061684
    label: chaperone-mediated autophagy
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. CMA is a core function. Redundant with IDA and IEA annotations.
    action: ACCEPT
    reason: Core function, consistent with multiple annotations.
- term:
    id: GO:0160020
    label: positive regulation of ferroptosis
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. CMA-mediated degradation of GPX4 promotes ferroptosis (PMID:30718432). This is a downstream consequence of CMA activity rather than a core function.
    action: KEEP_AS_NON_CORE
    reason: Directly demonstrated in mouse (PMID:30718432).
- term:
    id: GO:0000974
    label: Prp19 complex
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Hspa8 is a component of the PRP19-CDC5L spliceosomal complex.
    action: ACCEPT
    reason: Well-established component of the PRP19-CDC5L complex per UniProt.
- term:
    id: GO:0001664
    label: G protein-coupled receptor binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. GPCR binding is a non-core interaction.
    action: KEEP_AS_NON_CORE
    reason: A non-core interaction. Not a primary function of Hspa8.
- term:
    id: GO:0001916
    label: positive regulation of T cell mediated cytotoxicity
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Non-core immune function. Redundant with IEA annotation.
    action: KEEP_AS_NON_CORE
    reason: Non-core immune function downstream of chaperone/antigen presentation roles.
- term:
    id: GO:0001917
    label: photoreceptor inner segment
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation. Reflects ubiquitous expression.
    action: KEEP_AS_NON_CORE
    reason: Not a core localization. Reflects ubiquitous expression.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation. Hspa8 binds RNA in mRNP granules.
    action: KEEP_AS_NON_CORE
    reason: Not a core molecular function. Hspa8 is primarily a protein chaperone.
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: KEEP_AS_NON_CORE
    reason: Non-core interaction.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Core function. Redundant with IEA annotation.
    action: ACCEPT
    reason: Core biochemical function.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Hspa8 can be released extracellularly and found in exosomes.
    action: KEEP_AS_NON_CORE
    reason: Non-core localization. Hspa8 is primarily intracellular.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Consistent with IBA annotation. Nuclear localization upon stress.
    action: ACCEPT
    reason: Consistent with IBA annotation.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Core CMA-related localization. Redundant with IEA annotation.
    action: ACCEPT
    reason: Core localization for CMA function.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Core CMA-related localization. Redundant with other annotations.
    action: ACCEPT
    reason: Core localization for CMA function.
- term:
    id: GO:0005776
    label: autophagosome
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: KEEP_AS_NON_CORE
    reason: Not the primary autophagy compartment for Hspa8; CMA occurs at the lysosome.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Core localization. Redundant with IBA annotation.
    action: ACCEPT
    reason: Core localization.
- term:
    id: GO:0005874
    label: microtubule
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: KEEP_AS_NON_CORE
    reason: Not a core localization.
- term:
    id: GO:0005882
    label: intermediate filament
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: KEEP_AS_NON_CORE
    reason: Not a core localization.
- term:
    id: GO:0006606
    label: protein import into nucleus
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: KEEP_AS_NON_CORE
    reason: Non-core downstream consequence of chaperone activity.
- term:
    id: GO:0008021
    label: synaptic vesicle
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation. Consistent with synaptic roles.
    action: ACCEPT
    reason: Consistent with well-documented synaptic roles.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: ACCEPT
    reason: Consistent with cell surface localization.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: KEEP_AS_NON_CORE
    reason: Non-core downstream consequence.
- term:
    id: GO:0010667
    label: negative regulation of cardiac muscle cell apoptotic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: KEEP_AS_NON_CORE
    reason: Non-core tissue-specific consequence.
- term:
    id: GO:0014069
    label: postsynaptic density
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation. Supported by SynGO data.
    action: ACCEPT
    reason: Consistent with experimental evidence for postsynaptic localization.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Core enzymatic function. Redundant with IBA and IEA annotations.
    action: ACCEPT
    reason: Core enzymatic function.
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: ACCEPT
    reason: Consistent with documented enzyme interactions.
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Redundant with IEA and ISO from rat.
    action: ACCEPT
    reason: Consistent with documented enzyme interactions.
- term:
    id: GO:0030163
    label: protein catabolic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Hspa8 promotes protein catabolism through CMA and CHIP-mediated ubiquitination.
    action: ACCEPT
    reason: Consistent with Hspa8's roles in CMA and ERAD.
- term:
    id: GO:0030335
    label: positive regulation of cell migration
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Cell migration regulation is a non-core downstream consequence.
    action: KEEP_AS_NON_CORE
    reason: Non-core downstream consequence of Hspa8's chaperone activity.
- term:
    id: GO:0030424
    label: axon
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation. Consistent with axonal roles.
    action: ACCEPT
    reason: Consistent with documented axonal transport functions.
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: ACCEPT
    reason: Consistent with dendritic localization.
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Hspa8 acts as an adaptor in CMA, bridging substrates to LAMP2A. Also supported by IDA in mouse (PMID:30718432).
    action: ACCEPT
    reason: Core molecular function in CMA substrate recognition and delivery.
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Redundant with IBA annotation.
    action: ACCEPT
    reason: Core function.
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Hspa8 binds CHIP/STUB1 E3 ligase for ubiquitination of misfolded substrates.
    action: ACCEPT
    reason: Well-established interaction with CHIP/STUB1 central to protein quality control.
- term:
    id: GO:0031647
    label: regulation of protein stability
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Core consequence of chaperone function in protein quality control.
    action: ACCEPT
    reason: Core consequence of Hspa8's chaperone function.
- term:
    id: GO:0031686
    label: A1 adenosine receptor binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: KEEP_AS_NON_CORE
    reason: Non-core specific binding interaction.
- term:
    id: GO:0032279
    label: asymmetric synapse
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: ACCEPT
    reason: Consistent with SynGO evidence.
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Core function. Redundant with IBA annotation.
    action: ACCEPT
    reason: Core function.
- term:
    id: GO:0042277
    label: peptide binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: ACCEPT
    reason: Core property of the substrate-binding domain.
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: ACCEPT
    reason: Consistent with ubiquitous expression.
- term:
    id: GO:0043195
    label: terminal bouton
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: ACCEPT
    reason: Consistent with presynaptic roles.
- term:
    id: GO:0043197
    label: dendritic spine
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: ACCEPT
    reason: Consistent with spine morphology role (PMID:28234934).
- term:
    id: GO:0043198
    label: dendritic shaft
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: ACCEPT
    reason: Consistent with dendritic localization.
- term:
    id: GO:0043204
    label: perikaryon
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: ACCEPT
    reason: Consistent with ubiquitous expression.
- term:
    id: GO:0044309
    label: neuron spine
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: ACCEPT
    reason: Consistent with spine morphology role.
- term:
    id: GO:0045862
    label: positive regulation of proteolysis
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: ACCEPT
    reason: Consistent with CMA and CHIP-mediated proteolysis roles.
- term:
    id: GO:0045892
    label: negative regulation of DNA-templated transcription
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Hspa8 acts as a repressor of transcriptional activation, inhibiting CITED1 coactivator activity on Smad-mediated transcription.
    action: KEEP_AS_NON_CORE
    reason: A documented but non-core transcriptional regulatory function.
- term:
    id: GO:0046034
    label: ATP metabolic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Hspa8 is involved in ATP metabolism through its ATPase cycle.
    action: ACCEPT
    reason: Consistent with Hspa8's ATP-dependent chaperone mechanism.
- term:
    id: GO:0048018
    label: receptor ligand activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Hspa8 can act as a receptor ligand at the cell surface, e.g. binding LPS receptors.
    action: KEEP_AS_NON_CORE
    reason: Non-core function related to extracellular/cell surface roles.
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA and IDA (PMID:14627652) annotations. Perinuclear localization is context-dependent.
    action: KEEP_AS_NON_CORE
    reason: Supported by direct experimental evidence in mouse.
- term:
    id: GO:0050766
    label: positive regulation of phagocytosis
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: KEEP_AS_NON_CORE
    reason: Non-core immune function.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Per UPB project guidelines for HSP70 family, should be modified to GO:0044183 (protein folding chaperone).
    action: MODIFY
    reason: GO:0051082 does not capture the active chaperone mechanism of Hspa8. The correct replacement is GO:0044183 (protein folding chaperone).
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Per UPB project guidelines for HSP70 family, should be modified to GO:0044183 (protein folding chaperone).
    action: MODIFY
    reason: GO:0051082 does not capture the active chaperone mechanism of Hspa8. The correct replacement is GO:0044183 (protein folding chaperone).
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Hspa8 binds multiple co-chaperones including J-domain proteins, NEFs, and TPR proteins.
    action: ACCEPT
    reason: Well-established interaction with co-chaperones is central to Hspa8 function.
- term:
    id: GO:0055131
    label: C3HC4-type RING finger domain binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Reflects interaction with CHIP/STUB1 and RNF207 RING-type E3 ligases.
    action: ACCEPT
    reason: Reflects the functional interaction between Hspa8 and RING-type E3 ligases.
- term:
    id: GO:0061635
    label: regulation of protein complex stability
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation. Consistent with SNARE chaperoning and clathrin uncoating roles.
    action: ACCEPT
    reason: Consistent with documented roles.
- term:
    id: GO:0061684
    label: chaperone-mediated autophagy
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IDA, IEA, and other ISO annotations.
    action: ACCEPT
    reason: Core function.
- term:
    id: GO:0061740
    label: protein targeting to lysosome involved in chaperone-mediated autophagy
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Hspa8 specifically recognizes KFERQ motifs and targets substrates to the lysosomal membrane for CMA degradation (PMID:30718432).
    action: ACCEPT
    reason: Core CMA function. Directly demonstrated in mouse (PMID:30718432).
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Also supported by IDA in mouse (PMID:19724054).
    action: KEEP_AS_NON_CORE
    reason: Non-core localization. Hspa8 is found in exosomes but this is not a primary function.
- term:
    id: GO:0072318
    label: clathrin coat disassembly
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Core function. Redundant with IBA and IDA annotations.
    action: ACCEPT
    reason: Core function.
- term:
    id: GO:0072318
    label: clathrin coat disassembly
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Core function. Redundant with other annotations.
    action: ACCEPT
    reason: Core function.
- term:
    id: GO:0097214
    label: positive regulation of lysosomal membrane permeability
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA annotation.
    action: KEEP_AS_NON_CORE
    reason: Non-core downstream consequence of CMA activity.
- term:
    id: GO:0098690
    label: glycinergic synapse
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA and IDA (PMID:21209184) annotations.
    action: ACCEPT
    reason: Consistent with direct experimental evidence.
- term:
    id: GO:0098793
    label: presynapse
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IEA and IDA annotations.
    action: ACCEPT
    reason: Consistent with extensive experimental evidence.
- term:
    id: GO:0098794
    label: postsynapse
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Supported by IDA evidence for Hsc70 at postsynaptic sites where it regulates gephyrin clustering (PMID:21209184) and dendritic spine organization via FILIP/myosin IIb (PMID:28234934).
    action: ACCEPT
    reason: Consistent with direct experimental evidence in mouse.
- term:
    id: GO:0098880
    label: maintenance of postsynaptic specialization structure
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Hspa8 regulates gephyrin clustering at inhibitory synapses (PMID:21209184) and dendritic spine morphology via FILIP/myosin IIb (PMID:28234934), both contributing to postsynaptic specialization maintenance.
    action: ACCEPT
    reason: Supported by direct experimental evidence in mouse for postsynaptic structural roles.
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Redundant with IDA (PMID:21209184, PMID:28234934) and EXP (PMID:28234934) annotations.
    action: ACCEPT
    reason: Consistent with direct experimental evidence.
- term:
    id: GO:0101031
    label: protein folding chaperone complex
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Hspa8 forms functional chaperone complexes including the CSPalpha-Hsc70-SGT complex (PMID:21151134) and the BAG3-Hsc70-HSPB8 CASA complex (PMID:20060297).
    action: ACCEPT
    reason: Core function. Hspa8 is a central component of multiple chaperone complexes.
- term:
    id: GO:0140545
    label: ATP-dependent protein disaggregase activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. HSP70 family members, in conjunction with HSPH1 (Hsp105/Hsp110 family), form a bi-chaperone disaggregase system. The Hsp70-Hsp110-Hsp40 complex can solubilize aggregated proteins in an ATP-dependent manner (PMID:14644449).
    action: ACCEPT
    reason: Supported by evidence that Hsc70 cooperates with Hsp105 in suppressing aggregation and promoting disaggregation.
- term:
    id: GO:1900226
    label: negative regulation of NLRP3 inflammasome complex assembly
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Reported role for HSP70 family in NLRP3 inflammasome regulation, but primary evidence is for HSPA8/Hsc70 in human cells.
    action: KEEP_AS_NON_CORE
    reason: Non-core downstream consequence of chaperone activity. Not a primary function of Hspa8.
- term:
    id: GO:1902904
    label: negative regulation of supramolecular fiber organization
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. May relate to roles in preventing protein aggregation into fibers, consistent with general chaperone activity.
    action: KEEP_AS_NON_CORE
    reason: Non-core downstream consequence of chaperone activity.
- term:
    id: GO:1904592
    label: positive regulation of protein refolding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Consistent with core chaperone function of Hspa8 in promoting protein refolding through ATP-dependent cycles.
    action: ACCEPT
    reason: Core chaperone function. Hspa8 promotes refolding of denatured substrates.
- term:
    id: GO:1904593
    label: prostaglandin binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Prostaglandin binding has been reported for HSP70 family members but is not a core function.
    action: KEEP_AS_NON_CORE
    reason: Peripheral binding activity; not a core chaperone function.
- term:
    id: GO:1904764
    label: chaperone-mediated autophagy translocation complex disassembly
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. After CMA substrate translocation into the lysosome, Hspa8 mediates the disassembly of the LAMP2A translocation complex, an essential step in the CMA cycle.
    action: ACCEPT
    reason: Core CMA function. Hspa8 acts on both cytosolic and lumenal sides of the lysosomal membrane.
- term:
    id: GO:1990833
    label: clathrin-uncoating ATPase activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. Core function. Hspa8 uses ATP hydrolysis to drive clathrin triskelion release from coated vesicles, working with auxilin/GAK co-chaperones (PMID:8524399, PMID:20160091).
    action: ACCEPT
    reason: Core enzymatic activity directly demonstrated in mouse.
- term:
    id: GO:1990836
    label: lysosomal matrix
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO from rat. A fraction of Hspa8 resides in the lysosomal lumen where it participates in CMA translocation complex disassembly.
    action: ACCEPT
    reason: Consistent with CMA function requiring lumenal Hsc70.
- term:
    id: GO:1990904
    label: ribonucleoprotein complex
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO from human HSPA8. Hspa8 is a component of the Prp19/CDC5L spliceosome complex (PMID:23742842), consistent with roles in mRNA splicing.
    action: ACCEPT
    reason: Documented component of the Prp19 spliceosome complex.
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:30718432
  review:
    summary: IDA from PMID:30718432. In the context of ferroptosis, Hspa8 recognizes KFERQ motifs on GPX4 and delivers it to the lysosomal membrane for CMA-mediated degradation, acting as an adaptor between substrate and LAMP2A receptor.
    action: ACCEPT
    reason: Core CMA function. Hspa8 serves as a substrate adaptor in CMA by recognizing KFERQ-like motifs and targeting substrates to LAMP2A.
    supported_by:
      - reference_id: PMID:30718432
        supporting_text: 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
- term:
    id: GO:0061684
    label: chaperone-mediated autophagy
  evidence_type: IDA
  original_reference_id: PMID:30718432
  review:
    summary: IDA from PMID:30718432. Directly demonstrated that Hspa8/Hsc70-mediated CMA promotes GPX4 degradation during ferroptosis.
    action: ACCEPT
    reason: Core function. CMA is one of the best-established roles of Hspa8.
    supported_by:
      - reference_id: PMID:30718432
        supporting_text: inhibition of CMA stabilized GPX4 and reduced ferroptosis
- term:
    id: GO:0160020
    label: positive regulation of ferroptosis
  evidence_type: IDA
  original_reference_id: PMID:30718432
  review:
    summary: IDA from PMID:30718432. Hspa8 promotes ferroptosis through CMA-mediated degradation of GPX4, a key anti-ferroptotic enzyme. Inhibition of HSP90/CMA stabilized GPX4 and reduced ferroptosis.
    action: KEEP_AS_NON_CORE
    reason: This is a downstream consequence of CMA activity rather than a core function. Ferroptosis promotion is context-dependent (requires CMA activation by erastin).
    supported_by:
      - reference_id: PMID:30718432
        supporting_text: activation of CMA is involved in the execution of ferroptosis
- term:
    id: GO:0000398
    label: mRNA splicing, via spliceosome
  evidence_type: NAS
  original_reference_id: PMID:23742842
  review:
    summary: NAS from PMID:23742842 review article. Hspa8 is a component of the Prp19/CDC5L spliceosome complex. The Prp19 complex functions in splicing catalytic activation.
    action: KEEP_AS_NON_CORE
    reason: Documented role as component of Prp19 complex, but this is a secondary/moonlighting function rather than core chaperone activity.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEP
  original_reference_id: PMID:21151134
  review:
    summary: IEP from PMID:21151134. Expression pattern evidence for protein folding activity at presynaptic terminals where the CSPalpha-Hsc70-SGT complex chaperones SNAP-25.
    action: ACCEPT
    reason: Core function. The CSPalpha-Hsc70-SGT complex directly chaperones SNAP-25 to maintain SNARE-complex assembly.
    supported_by:
      - reference_id: PMID:21151134
        supporting_text: the CSPα-Hsc70-SGT complex binds directly to monomeric SNAP-25 to prevent its aggregation, enabling SNARE-complex formation
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IDA
  original_reference_id: PMID:21151134
  review:
    summary: IDA from PMID:21151134. Direct assay showing Hsc70 as part of the CSPalpha-Hsc70-SGT chaperone complex that maintains SNAP-25 in a folding-competent state for SNARE complex formation.
    action: ACCEPT
    reason: Core function. Directly demonstrated.
    supported_by:
      - reference_id: PMID:21151134
        supporting_text: the CSPα-Hsc70-SGT complex binds directly to monomeric SNAP-25 to prevent its aggregation, enabling SNARE-complex formation
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IMP
  original_reference_id: PMID:21151134
  review:
    summary: IMP from PMID:21151134. Mutant phenotype evidence. Deletion of CSPalpha produces abnormal SNAP-25 conformer that inhibits SNARE-complex formation, indicating the CSPalpha-Hsc70-SGT complex is required for proper SNAP-25 folding.
    action: ACCEPT
    reason: Core function. Mutant phenotype supports chaperone-dependent protein folding at presynaptic terminals.
    supported_by:
      - reference_id: PMID:21151134
        supporting_text: Deletion of CSPα produces an abnormal SNAP-25 conformer that inhibits SNARE-complex formation, and is subject to ubiquitylation and proteasomal degradation
- term:
    id: GO:0098684
    label: photoreceptor ribbon synapse
  evidence_type: IDA
  original_reference_id: PMID:24616664
  review:
    summary: IDA from PMID:24616664. Immunocytochemistry detected Hsc70 (anti-uncoating ATPase antibody) at photoreceptor ribbon synapses in mouse retina. Hsc70 was absent from Clathrin-independent endocytic clusters, supporting its specific role in CME at these synapses.
    action: ACCEPT
    reason: Direct immunolocalization in mouse retina photoreceptor terminals.
    supported_by:
      - reference_id: PMID:24616664
        supporting_text: clusters labeled for Dynamin3, Endophilin1, and Synaptojanin1, but not for AP180, Clathrin LC, and hsc70
- term:
    id: GO:0098690
    label: glycinergic synapse
  evidence_type: IDA
  original_reference_id: PMID:21209184
  review:
    summary: IDA from PMID:21209184. Hsc70 localizes to glycinergic synapses where it regulates gephyrin clustering. Hsc70 inhibition altered gephyrin cluster density at inhibitory synapses.
    action: ACCEPT
    reason: Directly demonstrated in mouse neurons.
- term:
    id: GO:0098793
    label: presynapse
  evidence_type: IEP
  original_reference_id: PMID:21151134
  review:
    summary: IEP from PMID:21151134. Hsc70 is expressed at presynaptic terminals where it forms the CSPalpha-Hsc70-SGT chaperone complex.
    action: ACCEPT
    reason: Expression pattern consistent with presynaptic localization.
    supported_by:
      - reference_id: PMID:21151134
        supporting_text: The protein CSPα resides in presynaptic terminals, where it forms a chaperone complex with Hsc70 and SGT
- term:
    id: GO:0098793
    label: presynapse
  evidence_type: IDA
  original_reference_id: PMID:21151134
  review:
    summary: IDA from PMID:21151134. Hsc70 directly localized to presynaptic terminals as part of the CSPalpha-Hsc70-SGT complex.
    action: ACCEPT
    reason: Directly demonstrated.
    supported_by:
      - reference_id: PMID:21151134
        supporting_text: The protein CSPα resides in presynaptic terminals, where it forms a chaperone complex with Hsc70 and SGT
- term:
    id: GO:0098793
    label: presynapse
  evidence_type: IMP
  original_reference_id: PMID:21151134
  review:
    summary: IMP from PMID:21151134. CSPalpha-knockout mice show presynaptic defects indicating functional requirement for the Hsc70-containing chaperone complex at presynaptic terminals.
    action: ACCEPT
    reason: Mutant phenotype supports presynaptic localization and function.
- term:
    id: GO:0098793
    label: presynapse
  evidence_type: IDA
  original_reference_id: PMID:24616664
  review:
    summary: IDA from PMID:24616664. Hsc70 detected at presynaptic terminals of mouse photoreceptor ribbon synapses and bipolar cell terminals by immunocytochemistry.
    action: ACCEPT
    reason: Direct immunolocalization in mouse retinal synapses.
    supported_by:
      - reference_id: PMID:24616664
        supporting_text: In mouse ON bipolar cell terminals, Clathrin-mediated endocytosis seemed to be the dominant mode of endocytosis at all adaptation states analyzed
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IDA
  original_reference_id: PMID:21209184
  review:
    summary: IDA from PMID:21209184. Hsc70 localizes to glutamatergic synapses. The study examined Hsc70 distribution at both excitatory and inhibitory synapses.
    action: ACCEPT
    reason: Directly demonstrated in mouse neurons.
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IDA
  original_reference_id: PMID:28234934
  review:
    summary: IDA from PMID:28234934. Hsc70 localizes to glutamatergic synapses where it controls subcellular distribution of non-muscle myosin IIb via FILIP interaction in dendritic spines.
    action: ACCEPT
    reason: Directly demonstrated in mouse neurons.
    supported_by:
      - reference_id: PMID:28234934
        supporting_text: Hsc70 interacts with FILIP to mediate its effects on non-muscle myosin IIb and to regulate spine morphology
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: EXP
  original_reference_id: PMID:28234934
  review:
    summary: EXP from PMID:28234934. Experimental evidence for Hsc70 at glutamatergic synapses from the FILIP/myosin IIb study.
    action: ACCEPT
    reason: Redundant with IDA from same study, but valid experimental evidence.
    supported_by:
      - reference_id: PMID:28234934
        supporting_text: in primary cultured neurons, an inhibitor of Hsc70 impeded the morphological change in spines induced by FILIP
- term:
    id: GO:0099175
    label: regulation of postsynapse organization
  evidence_type: IDA
  original_reference_id: PMID:28234934
  review:
    summary: IDA from PMID:28234934. Hsc70 regulates dendritic spine morphology through FILIP-mediated control of myosin IIb subcellular distribution, thereby regulating postsynaptic organization.
    action: ACCEPT
    reason: Directly demonstrated in mouse neurons.
    supported_by:
      - reference_id: PMID:28234934
        supporting_text: Inhibition of ATPase activity of Hsc70 impaired the effect of FILIP on the subcellular distribution of non-muscle myosin IIb
- term:
    id: GO:0099175
    label: regulation of postsynapse organization
  evidence_type: EXP
  original_reference_id: PMID:28234934
  review:
    summary: EXP from PMID:28234934. Experimental evidence for regulation of postsynapse organization. Redundant with IDA from same study.
    action: ACCEPT
    reason: Valid experimental evidence.
    supported_by:
      - reference_id: PMID:28234934
        supporting_text: in primary cultured neurons, an inhibitor of Hsc70 impeded the morphological change in spines induced by FILIP
- term:
    id: GO:0099634
    label: postsynaptic specialization membrane
  evidence_type: IDA
  original_reference_id: PMID:21209184
  review:
    summary: IDA from PMID:21209184. Hsc70 detected at the postsynaptic specialization membrane where it regulates gephyrin clustering at inhibitory synapses.
    action: ACCEPT
    reason: Directly demonstrated in mouse neurons.
- term:
    id: GO:0072318
    label: clathrin coat disassembly
  evidence_type: IDA
  original_reference_id: PMID:8524399
  review:
    summary: IDA from PMID:8524399. Directly demonstrated that Hsc70 drives clathrin coat disassembly from coated vesicles in conjunction with the co-chaperone auxilin, using ATP hydrolysis.
    action: ACCEPT
    reason: Core function. Landmark study establishing Hsc70 role in clathrin uncoating.
    supported_by:
      - reference_id: PMID:8524399
        supporting_text: Role of auxilin in uncoating clathrin-coated vesicles
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS by curator judgment. Hspa8 associates with the lysosomal membrane via LAMP2A during CMA, both on the cytosolic and lumenal sides.
    action: ACCEPT
    reason: Core CMA localization. Hspa8 binds LAMP2A on the lysosomal membrane.
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS by curator judgment. Redundant with IDA from PMID:30718432.
    action: ACCEPT
    reason: Core CMA function. Hspa8 serves as an adaptor between KFERQ-motif substrates and LAMP2A.
- term:
    id: GO:0061740
    label: protein targeting to lysosome involved in chaperone-mediated autophagy
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS by curator judgment. Redundant with ISO from GO_REF:0000119. Core CMA function.
    action: ACCEPT
    reason: Core CMA function.
- term:
    id: GO:0001786
    label: phosphatidylserine binding
  evidence_type: IDA
  original_reference_id: PMID:21238931
  review:
    summary: IDA from PMID:21238931. During endosomal microautophagy, Hsc70 binds to the endosomal membrane through electrostatic interactions via its cationic domain. The study identified phosphatidylserine as a binding partner, though the interaction is mediated via electrostatic rather than specific lipid-binding mechanisms.
    action: ACCEPT
    reason: Directly demonstrated. Important for Hsc70 targeting to endosomal membranes during microautophagy.
    supported_by:
      - reference_id: PMID:21238931
        supporting_text: Protein cargo selection is mediated by the chaperone hsc70 and requires the cationic domain of hsc70 for electrostatic interactions with the endosomal membrane
- term:
    id: GO:0061635
    label: regulation of protein complex stability
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS by curator judgment. Redundant with ISO annotations. Consistent with SNARE chaperoning and clathrin uncoating roles.
    action: ACCEPT
    reason: Consistent with documented roles in maintaining protein complex stability.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35044787
  review:
    summary: IPI from PMID:35044787. BAG5 loss-of-function study showing Hsc70 interacts with BAG5 co-chaperone. Protein binding is uninformative.
    action: REMOVE
    reason: GO:0005515 protein binding is uninformative. The interaction with BAG5 co-chaperone is better captured by heat shock protein binding or co-chaperone binding annotations.
- term:
    id: GO:0035651
    label: AP-3 adaptor complex binding
  evidence_type: IDA
  original_reference_id: PMID:19010779
  review:
    summary: IDA from PMID:19010779. Hsc70 was identified as an AP-3 interacting protein by mass spectrometry in a cross-linking/purification study of Hermansky-Pudlak syndrome protein complexes.
    action: KEEP_AS_NON_CORE
    reason: Valid interaction but represents a peripheral function of Hspa8 rather than a core chaperone activity.
    supported_by:
      - reference_id: PMID:19010779
        supporting_text: AP-3 was co-isolated with BLOC-1, BLOC-2, and homotypic fusion and vacuole protein sorting complex subunits
- term:
    id: GO:0061684
    label: chaperone-mediated autophagy
  evidence_type: ISO
  original_reference_id: GO_REF:0000008
  review:
    summary: ISO from MGI curated orthology. Redundant with IDA (PMID:30718432), IEA, and other ISO annotations.
    action: ACCEPT
    reason: Core function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18346207
  review:
    summary: IPI from PMID:18346207. Hsc70 co-immunoprecipitated with tau and a novel calcium-binding protein in tauopathy mouse model. Protein binding is uninformative.
    action: REMOVE
    reason: GO:0005515 protein binding is uninformative. The interaction in tauopathy context does not describe a specific molecular function.
- term:
    id: GO:0031906
    label: late endosome lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9631080
  review:
    summary: TAS from Reactome pathway for substrate translocation into late endosomal lumen. Consistent with Hsc70 role in endosomal microautophagy (PMID:21238931).
    action: ACCEPT
    reason: Consistent with documented role in endosomal microautophagy where Hsc70 delivers substrates to late endosomes.
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:14627652
  review:
    summary: IDA from PMID:14627652. Hsc70 was detected at the perinuclear region associated with aggresomes in Schwann cells with misfolded PMP22 protein. This is a stress-induced localization rather than constitutive.
    action: KEEP_AS_NON_CORE
    reason: Valid localization but context-dependent (aggresome association), not a primary constitutive localization.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9613507
  review:
    summary: TAS from Reactome pathway for Plins/Hspa8 binding Prkaa2. Cytosolic localization is well established.
    action: ACCEPT
    reason: Cytosol is a primary localization for Hspa8.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9613545
  review:
    summary: TAS from Reactome pathway for Prkaa2 phosphorylation of Plins. Redundant cytosol annotation.
    action: ACCEPT
    reason: Cytosol is a primary localization.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9613562
  review:
    summary: TAS from Reactome pathway for Prkaa2 dissociation from p-Plins/Hspa8. Redundant cytosol annotation.
    action: ACCEPT
    reason: Cytosol is a primary localization.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9613670
  review:
    summary: TAS from Reactome pathway for p-Plins translocation from lipid droplet to cytosol. Redundant cytosol annotation.
    action: ACCEPT
    reason: Cytosol is a primary localization.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9631076
  review:
    summary: TAS from Reactome pathway for Hspa8/substrate binding to late endosomal phospholipids. Redundant cytosol annotation.
    action: ACCEPT
    reason: Cytosol is a primary localization.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9631080
  review:
    summary: TAS from Reactome pathway for substrate translocation into late endosomal lumen. Redundant cytosol annotation.
    action: ACCEPT
    reason: Cytosol is a primary localization.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:26581985
  review:
    summary: IDA from PMID:26581985. Hsc70 detected in the cytoplasm in studies of MHV68 viral replication. Hspa8 was recruited to nuclei in an mLANA-dependent process during viral infection.
    action: ACCEPT
    reason: Cytoplasm is a primary localization for Hspa8.
    supported_by:
      - reference_id: PMID:26581985
        supporting_text: mLANA-dependent recruitment of Hsc70 to nuclei of productively infected cells
- term:
    id: GO:0044788
    label: host-mediated perturbation of viral process
  evidence_type: IMP
  original_reference_id: PMID:26581985
  review:
    summary: IMP from PMID:26581985. Pharmacologic inhibition and shRNA-mediated knockdown of Hsc70 impaired MHV68 lytic replication, correlating with impaired viral protein expression and reduced viral DNA replication.
    action: KEEP_AS_NON_CORE
    reason: Valid but context-dependent interaction with a specific virus. Not a core chaperone function.
    supported_by:
      - reference_id: PMID:26581985
        supporting_text: Pharmacologic inhibition and small hairpin RNA (shRNA)-mediated knockdown of Hsc70 impaired MHV68 lytic replication
- term:
    id: GO:0044829
    label: host-mediated activation of viral genome replication
  evidence_type: IMP
  original_reference_id: PMID:26581985
  review:
    summary: IMP from PMID:26581985. Hsc70 facilitates MHV68 lytic replication through interaction with mLANA. This is a host factor co-opted by the virus rather than a host defense mechanism.
    action: KEEP_AS_NON_CORE
    reason: Valid but represents viral exploitation of chaperone function rather than core host function.
    supported_by:
      - reference_id: PMID:26581985
        supporting_text: Hsc70 facilitates MHV68 protein expression and DNA replication, thus contributing to efficient MHV68 lytic replication
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: ISO
  original_reference_id: GO_REF:0000008
  review:
    summary: ISO from MGI curated orthology. Redundant with ISS (GO_REF:0000024) and ISO (GO_REF:0000096/0000119) annotations.
    action: ACCEPT
    reason: Core CMA localization.
- term:
    id: GO:0032984
    label: protein-containing complex disassembly
  evidence_type: ISO
  original_reference_id: GO_REF:0000008
  review:
    summary: ISO from MGI curated orthology. Consistent with clathrin coat disassembly and CMA translocation complex disassembly roles.
    action: ACCEPT
    reason: Consistent with multiple documented roles in complex disassembly.
- term:
    id: GO:1990836
    label: lysosomal matrix
  evidence_type: ISO
  original_reference_id: GO_REF:0000008
  review:
    summary: ISO from MGI curated orthology. Redundant with ISO from GO_REF:0000096.
    action: ACCEPT
    reason: Consistent with lumenal Hsc70 role in CMA.
- term:
    id: GO:0005770
    label: late endosome
  evidence_type: IDA
  original_reference_id: PMID:21238931
  review:
    summary: IDA from PMID:21238931. Hsc70 localizes to late endosomes where it mediates endosomal microautophagy by delivering cytosolic proteins for internalization into MVB vesicles.
    action: ACCEPT
    reason: Directly demonstrated. Important localization for endosomal microautophagy function.
    supported_by:
      - reference_id: PMID:21238931
        supporting_text: distinct autophagic mechanisms control cytosolic protein delivery to late endosomes and identify a microautophagy-like process that delivers soluble cytosolic proteins to the vesicles of late endosomes/multivesicular bodies
- term:
    id: GO:0061738
    label: late endosomal microautophagy
  evidence_type: IMP
  original_reference_id: PMID:21238931
  review:
    summary: IMP from PMID:21238931. Hsc70 mediates a microautophagy-like process that delivers soluble cytosolic proteins to late endosome/MVB vesicles, distinct from CMA. Requires the cationic domain of Hsc70 for membrane interactions.
    action: ACCEPT
    reason: Well-established secondary autophagy function of Hsc70.
    supported_by:
      - reference_id: PMID:21238931
        supporting_text: Endosomal microautophagy occurs during MVB formation, relying on the ESCRT I and III systems for formation of the vesicles in which the cytosolic cargo is internalized
- term:
    id: GO:0061684
    label: chaperone-mediated autophagy
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS by curator judgment. Redundant with IDA, IEA, ISO, and other annotations for CMA.
    action: ACCEPT
    reason: Core function.
- term:
    id: GO:1904764
    label: chaperone-mediated autophagy translocation complex disassembly
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS by curator judgment. Redundant with ISO annotations. Core CMA function.
    action: ACCEPT
    reason: Core CMA function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20060297
  review:
    summary: IPI from PMID:20060297 (CASA pathway). Hsc70 interacts with BAG3 and HSPB8 in the chaperone-assisted selective autophagy complex. Protein binding is uninformative.
    action: REMOVE
    reason: GO:0005515 protein binding is uninformative. The CASA complex interactions are better captured by specific chaperone complex annotations.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000008
  review:
    summary: ISO from MGI curated orthology. Core enzymatic activity of Hspa8 as an ATPase.
    action: ACCEPT
    reason: Core enzymatic activity.
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS by curator judgment. Core chaperone function of Hspa8 in promoting refolding of denatured proteins through ATP-dependent cycles.
    action: ACCEPT
    reason: Core chaperone function.
- term:
    id: GO:0043209
    label: myelin sheath
  evidence_type: HDA
  original_reference_id: PMID:17634366
  review:
    summary: HDA from PMID:17634366. Hsc70 detected in CNS myelin proteome by mass spectrometry. The study focused on proteolipid protein-dependent transport of sirtuin 2 into myelin.
    action: KEEP_AS_NON_CORE
    reason: Valid proteomic detection but represents a secondary localization rather than a core function.
- term:
    id: GO:0048026
    label: positive regulation of mRNA splicing, via spliceosome
  evidence_type: IMP
  original_reference_id: PMID:23636947
  review:
    summary: IMP from PMID:23636947. High-throughput screening study identified factors affecting Dlg4 (Psd-95) exon 18 alternative splicing. Hsc70 was likely identified as part of the Prp19 complex contribution to splicing regulation.
    action: KEEP_AS_NON_CORE
    reason: Valid but represents a secondary/moonlighting function of Hspa8 through its role in the Prp19 spliceosome complex.
- term:
    id: GO:0072318
    label: clathrin coat disassembly
  evidence_type: IGI
  original_reference_id: PMID:20160091
  review:
    summary: IGI from PMID:20160091. Auxilin knockout mouse study demonstrating that the auxilin-Hsc70 system is required for efficient clathrin uncoating at synapses. Genetic interaction evidence.
    action: ACCEPT
    reason: Core function. Genetic evidence supporting Hsc70 role in clathrin uncoating.
    supported_by:
      - reference_id: PMID:20160091
        supporting_text: Endocytosis and clathrin-uncoating defects at synapses of auxilin knockout mice
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23055941
  review:
    summary: IPI from PMID:23055941. RABL2 co-immunoprecipitation study in sperm. Protein binding is uninformative.
    action: REMOVE
    reason: GO:0005515 protein binding is uninformative.
- term:
    id: GO:0000974
    label: Prp19 complex
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS by curator judgment. Hspa8 is a documented component of the Prp19/CDC5L spliceosome complex (PMID:23742842). UniProt confirms Hspa8 as a Prp19-CDC5L complex component.
    action: ACCEPT
    reason: Well-documented complex membership, consistent with mRNA splicing role.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS by curator judgment. Hspa8 localizes to the nucleus as part of the Prp19 complex and in viral infection contexts (PMID:26581985). UniProt lists nucleolus as a subcellular localization.
    action: ACCEPT
    reason: Consistent with Prp19 complex membership and nuclear roles documented in UniProt.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12588994
  review:
    summary: IPI from PMID:12588994. Hsc70 interacts with cyclin D1 and CDK4 to regulate cell cycle. Protein binding is uninformative.
    action: REMOVE
    reason: GO:0005515 protein binding is uninformative. The cyclin D1/CDK4 interaction is better represented by the regulation of cell cycle annotation.
- term:
    id: GO:0045892
    label: negative regulation of DNA-templated transcription
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS by curator judgment. HSP70 family members have been reported to influence transcription, possibly through effects on transcription factor stability/folding.
    action: KEEP_AS_NON_CORE
    reason: Plausible but indirect consequence of chaperone activity rather than a core function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14644449
  review:
    summary: IPI from PMID:14644449. Hsc70 interacts with Hsp105 and Hsp40 in aggregation suppression assays. Protein binding is uninformative.
    action: REMOVE
    reason: GO:0005515 protein binding is uninformative. These co-chaperone interactions are better captured by heat shock protein binding and protein folding annotations.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: IDA
  original_reference_id: PMID:19724054
  review:
    summary: IDA from PMID:19724054. Hsc70 detected in exosomes during reticulocyte maturation. Also supported by ISO from human HSPA8.
    action: KEEP_AS_NON_CORE
    reason: Valid localization but non-core. Hspa8 is found in exosomes but this is not a primary function.
- term:
    id: GO:1990904
    label: ribonucleoprotein complex
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS by curator judgment. Redundant with ISO from GO_REF:0000119. Consistent with Prp19 complex membership.
    action: ACCEPT
    reason: Consistent with Prp19 spliceosome complex membership.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:16906134
  review:
    summary: IDA from PMID:16906134. Hsc70 detected in the cytosol. Study of editing-defective tRNA synthetase; Hsc70 identified as a cytosolic protein in the context of protein misfolding.
    action: ACCEPT
    reason: Cytosol is a primary localization for Hspa8.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IPI
  original_reference_id: PMID:12588994
  review:
    summary: IPI from PMID:12588994. Hsc70 binds unfolded/denatured substrates including cyclin D1. Per UPB project decision rules for HSP70 family, this should be modified to GO:0044183 (protein folding chaperone).
    action: MODIFY
    reason: Per UPB project decision rules, GO:0051082 for HSP70-family foldases should be modified to GO:0044183 (protein folding chaperone). Hspa8 is a bona fide ATP-dependent foldase, not merely a passive binder of unfolded proteins.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IGI
  original_reference_id: PMID:14644449
  review:
    summary: IGI from PMID:14644449. Genetic interaction with Hsp105 showing cooperative suppression of heat-denatured protein aggregation. Hsp70 family members contribute to protein folding in conjunction with co-chaperones.
    action: ACCEPT
    reason: Core function. Genetic interaction evidence for cooperative protein folding.
    supported_by:
      - reference_id: PMID:14644449
        supporting_text: Hsp105 but not Hsp70 family proteins suppress the aggregation of heat-denatured protein in the presence of ADP
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IDA
  original_reference_id: PMID:12588994
  review:
    summary: IDA from PMID:12588994. Hsc70 ATPase activity demonstrated in the context of cyclin D1/CDK4 regulation. Core enzymatic activity of all HSP70 family members.
    action: ACCEPT
    reason: Core enzymatic activity.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IDA
  original_reference_id: PMID:12588994
  review:
    summary: IDA from PMID:12588994. Hsc70 functions in protein folding, specifically demonstrated in the context of maintaining cyclin D1 stability through its chaperone activity.
    action: ACCEPT
    reason: Core function.
- term:
    id: GO:0051726
    label: regulation of cell cycle
  evidence_type: IDA
  original_reference_id: PMID:12588994
  review:
    summary: IDA from PMID:12588994. Hsc70 regulates accumulation of cyclin D1 and cyclin D1-dependent protein kinase CDK4, thereby influencing G1/S transition.
    action: KEEP_AS_NON_CORE
    reason: Valid downstream consequence of chaperone activity on cell cycle proteins, but cell cycle regulation is not a core molecular function of Hspa8.
references:
- id: GO_REF:0000008
  title: Gene Ontology annotation by the MGI curatorial staff, curated orthology
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000096
  title: Automated transfer of experimentally-verified manual GO annotation data to
    mouse-rat orthologs
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000119
  title: Automated transfer of experimentally-verified manual GO annotation data to
    mouse-human orthologs
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12588994
  title: Hsc70 regulates accumulation of cyclin D1 and cyclin D1-dependent protein
    kinase.
  findings: []
- id: PMID:14627652
  title: Emerging role for autophagy in the removal of aggresomes in Schwann cells.
  findings: []
- id: PMID:14644449
  title: Hsp105 but not Hsp70 family proteins suppress the aggregation of heat-denatured
    protein in the presence of ADP.
  findings: []
- id: PMID:16906134
  title: Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration.
  findings: []
- id: PMID:17634366
  title: Proteolipid protein is required for transport of sirtuin 2 into CNS myelin.
  findings: []
- id: PMID:18346207
  title: A novel calcium-binding protein is associated with tau proteins in tauopathy.
  findings: []
- id: PMID:19010779
  title: Hermansky-Pudlak syndrome protein complexes associate with phosphatidylinositol
    4-kinase type II alpha in neuronal and non-neuronal cells.
  findings: []
- id: PMID:19724054
  title: 'The water channel aquaporin-1 partitions into exosomes during reticulocyte
    maturation: implication for the regulation of cell volume.'
  findings: []
- id: PMID:20060297
  title: Chaperone-assisted selective autophagy is essential for muscle maintenance.
  findings: []
- id: PMID:20111006
  title: Kinesin-1/Hsc70-dependent mechanism of slow axonal transport and its relation
    to fast axonal transport.
  findings: []
- id: PMID:20160091
  title: Endocytosis and clathrin-uncoating defects at synapses of auxilin knockout
    mice.
  findings: []
- id: PMID:21151134
  title: CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic
    activity.
  findings: []
- id: PMID:21209184
  title: Heat shock cognate protein 70 regulates gephyrin clustering.
  findings: []
- id: PMID:21238931
  title: Microautophagy of cytosolic proteins by late endosomes.
  findings: []
- id: PMID:23055941
  title: RAB-like 2 has an essential role in male fertility, sperm intra-flagellar
    transport, and tail assembly.
  findings: []
- id: PMID:23636947
  title: A broadly applicable high-throughput screening strategy identifies new regulators
    of Dlg4 (Psd-95) alternative splicing.
  findings: []
- id: PMID:23742842
  title: 'Splicing and beyond: the many faces of the Prp19 complex.'
  findings: []
- id: PMID:24616664
  title: Evidence for a Clathrin-independent mode of endocytosis at a continuously
    active sensory synapse.
  findings: []
- id: PMID:25961502
  title: Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy
    facilitates lipolysis.
  findings: []
- id: PMID:26581985
  title: 'Identification of Viral and Host Proteins That Interact with Murine Gammaherpesvirus
    68 Latency-Associated Nuclear Antigen during Lytic Replication: a Role for Hsc70
    in Viral Replication.'
  findings: []
- id: PMID:28234934
  title: Subcellular distribution of non-muscle myosin IIb is controlled by FILIP
    through Hsc70.
  findings: []
- id: PMID:30718432
  title: Chaperone-mediated autophagy is involved in the execution of ferroptosis.
  findings: []
- id: PMID:35044787
  title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated
    cardiomyopathy requiring heart transplantation.
  findings: []
- id: PMID:8524399
  title: Role of auxilin in uncoating clathrin-coated vesicles.
  findings: []
- id: Reactome:R-MMU-9613507
  title: Plins:Hspa8 binds Prkaa2
  findings: []
- id: Reactome:R-MMU-9613545
  title: Prkaa2 phosphorylates Plins
  findings: []
- id: Reactome:R-MMU-9613562
  title: Prkaa2 dissociate from p-Plins:Hspa8
  findings: []
- id: Reactome:R-MMU-9613670
  title: p-Plins translocate from lipid droplet surface to cytosol
  findings: []
- id: Reactome:R-MMU-9631076
  title: Hspa8:substrate binds late endosomal phospholipids
  findings: []
- id: Reactome:R-MMU-9631080
  title: Substrate translocates into late endosomal lumen
  findings: []
core_functions:
- molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  description: Hspa8/Hsc70 is a constitutive ATP-dependent molecular chaperone that binds unfolded or
    misfolded client polypeptides through its substrate-binding domain and assists their folding through
    iterative cycles of ATP binding, hydrolysis, and ADP release. This is the primary molecular function.
    At presynaptic terminals, the CSPalpha-Hsc70-SGT complex chaperones SNAP-25 for SNARE complex
    assembly (PMID:21151134).
  directly_involved_in:
  - id: GO:0006457
    label: protein folding
  - id: GO:0042026
    label: protein refolding
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0098793
    label: presynapse
- molecular_function:
    id: GO:0016887
    label: ATP hydrolysis activity
  description: ATP hydrolysis (EC 3.6.4.10) is the core enzymatic activity driving the Hspa8 chaperone
    cycle. J-domain co-chaperones (DNAJ family) stimulate ATPase activity, coupling substrate recognition
    to high-affinity client binding. Also essential for clathrin-uncoating ATPase activity.
  locations:
  - id: GO:0005829
    label: cytosol
- molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  description: Hspa8 is the essential substrate-recognition chaperone in CMA, recognizing KFERQ-like
    pentapeptide motifs on cytosolic proteins (including GPX4 during ferroptosis; PMID:30718432) and
    delivering them to LAMP2A at the lysosomal membrane for translocation and degradation.
  directly_involved_in:
  - id: GO:0061684
    label: chaperone-mediated autophagy
  - id: GO:0061740
    label: protein targeting to lysosome involved in chaperone-mediated autophagy
  locations:
  - id: GO:0005765
    label: lysosomal membrane
- molecular_function:
    id: GO:1990833
    label: clathrin-uncoating ATPase activity
  description: Hspa8 mediates ATP-dependent disassembly of clathrin lattices on coated vesicles, working
    with auxilin (DNAJC6) or GAK as J-domain co-chaperones (PMID:8524399, PMID:20160091).
  directly_involved_in:
  - id: GO:0072318
    label: clathrin coat disassembly
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0098793
    label: presynapse
- molecular_function:
    id: GO:0140545
    label: ATP-dependent protein disaggregase activity
  description: Hspa8 collaborates with Hsp105/HSPH1 and DNAJ co-chaperones to form a mammalian disaggregase
    complex that solubilizes protein aggregates (PMID:14644449).
  locations:
  - id: GO:0005829
    label: cytosol

Gene Description

Existing Annotations Review

Core Functions

ATP hydrolysis (EC 3.6.4.10) is the core enzymatic activity driving the Hspa8 chaperone cycle. J-domain co-chaperones (DNAJ family) stimulate ATPase activity, coupling substrate recognition to high-affinity client binding. Also essential for clathrin-uncoating ATPase activity.

Hspa8 is the essential substrate-recognition chaperone in CMA, recognizing KFERQ-like pentapeptide motifs on cytosolic proteins (including GPX4 during ferroptosis; PMID:30718432) and delivering them to LAMP2A at the lysosomal membrane for translocation and degradation.

Hspa8 mediates ATP-dependent disassembly of clathrin lattices on coated vesicles, working with auxilin (DNAJC6) or GAK as J-domain co-chaperones (PMID:8524399, PMID:20160091).

Hspa8 collaborates with Hsp105/HSPH1 and DNAJ co-chaperones to form a mammalian disaggregase complex that solubilizes protein aggregates (PMID:14644449).

References

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