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).
| 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. Falcon deep research confirms ATP hydrolysis as the core biochemical engine driving client binding/release cycles. 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 file:mouse/Hspa8/Hspa8-deep-research-falcon.md HSC70βs core biochemical activity is **ATP hydrolysis coupled to cycles of client binding and release**, which enables folding/holding/refolding and quality control routing. |
| 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. Falcon deep research emphasizes that J-domain proteins (DNAJ/HSP40) stimulate HSC70 ATP hydrolysis and promote client handoff. Supporting Evidence: PMID:14644449 Hsc70/Hsp40 suppressed the aggregation of heat-denatured protein in the presence of ATP rather than ADP file:mouse/Hspa8/Hspa8-deep-research-falcon.md **J-domain proteins/HSP40s** stimulate ATP hydrolysis and client handoff. |
| 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. Falcon deep research independently identifies this housekeeping foldase/proteostasis activity as the primary, mechanistically coherent function from which Hspa8's pleiotropy derives. Supporting Evidence: PMID:21151134 the CSPalpha-Hsc70-SGT complex binds directly to monomeric SNAP-25 to prevent its aggregation, enabling SNARE-complex formation file:mouse/Hspa8/Hspa8-deep-research-falcon.md HSC70/HSPA8 is a core proteostasis factor that (i) assists folding of nascent and stress-denatured proteins, (ii) prevents aggregation, and (iii) helps route damaged clients toward degradation pathways (proteasome/autophagy) |
| 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). Falcon deep research confirms HSC70/HSPA8 is primarily a cytosolic chaperone supporting basal proteostasis. Reason: Cytosol is the primary subcellular location where Hspa8 performs its housekeeping chaperone functions. Supporting Evidence: file:mouse/Hspa8/Hspa8-deep-research-falcon.md HSC70/HSPA8 is primarily a **cytosolic** chaperone supporting basal proteostasis, with cofactor engagement through its EEVD tail |
| 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. Falcon deep research independently corroborates that Hsc70/HSPA8 is the key ATPase that uncoats clathrin lattices and that this requires the J-domain cochaperones GAK or auxilin. 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 file:mouse/Hspa8/Hspa8-deep-research-falcon.md Park et al. (J Cell Sci, 2015) provide direct evidence that Hsc70 (HSPA8) drives clathrin uncoating/chaperoning and that this activity requires J-domain cochaperones **GAK** (ubiquitous) or **auxilin** (neuronal). |
| 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. Falcon deep research reinforces that Hspa8's breadth of phenotypes is best understood as the downstream consequence of a single conserved biochemical engine (ATP-driven binding/release cycles) deployed in diverse cellular contexts, rather than a distinct signaling function. |
| 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. Falcon deep research confirms HSC70 operates at the cytosolic face of lysosomes to recognize substrates and deliver them to LAMP-2A. Reason: Lysosomal membrane localization is a core feature of Hspa8's role in CMA. Supporting Evidence: file:mouse/Hspa8/Hspa8-deep-research-falcon.md In CMA, HSC70 operates at the **cytosolic face of lysosomes** to recognize substrates and deliver them to LAMP-2A |
| 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). Falcon deep research confirms HSC70/HSPA8 as the central recognition chaperone of CMA, recognizing KFERQ-like motifs and delivering substrates to the lysosomal surface. Reason: Autophagy involvement is a core function of Hspa8 through its essential role in CMA and endosomal microautophagy. Supporting Evidence: file:mouse/Hspa8/Hspa8-deep-research-falcon.md **CMA substrates** bearing a **KFERQ-like pentapeptide motif**, which is necessary and sufficient to target proteins to CMA when appended to a reporter (huang2024selectiveproteindegradation pages 4-5). In CMA, the substrate motif is first recognized by HSC70 and delivered to the lysosomal surface |
| 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). Falcon deep research notes that in mouse neurons Hspa8 mRNA is the most abundant dendritic chaperone mRNA, with stress-induced dendritic localization and local translation. Reason: Consistent with documented dendritic and postsynaptic functions of Hspa8. Supporting Evidence: file:mouse/Hspa8/Hspa8-deep-research-falcon.md A 2024 preprint reports that **Hspa8 mRNA is the most abundant dendritic chaperone mRNA** in mouse neurons, and that proteotoxic stress increases dendritic localization via microtubule-based transport and enhances local translation |
| 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). Falcon deep research confirms Hsc70/HSPA8 is a key ATPase that remodels and uncoats clathrin lattices after vesicle budding. Reason: Clathrin-uncoating ATPase activity is a specific and well-documented molecular function of Hspa8. Supporting Evidence: file:mouse/Hspa8/Hspa8-deep-research-falcon.md HSC70/HSPA8 is a key ATPase that remodels and **uncoats clathrin lattices** after vesicle budding. |
| 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. Falcon deep research confirms the substrate complex docks at the cytosolic tail of LAMP-2A, whose multimerization forms the translocation complex. 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 file:mouse/Hspa8/Hspa8-deep-research-falcon.md The complex is delivered to lysosomal membranes, where it binds the cytosolic tail of **LAMP-2A**; LAMP-2A multimerizes to form the translocation complex |
| 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 CSPΞ± 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 CSPΞ±-Hsc70-SGT complex binds directly to monomeric SNAP-25 to prevent its aggregation, enabling SNARE-complex formation |
| GO:0006457 protein folding | IDA PMID:21151134 CSPΞ± 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 CSPΞ±-Hsc70-SGT complex binds directly to monomeric SNAP-25 to prevent its aggregation, enabling SNARE-complex formation |
| GO:0006457 protein folding | IMP PMID:21151134 CSPΞ± 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 CSPΞ± 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 CSPΞ± 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 CSPΞ± resides in presynaptic terminals, where it forms a chaperone complex with Hsc70 and SGT |
| GO:0098793 presynapse | IDA PMID:21151134 CSPΞ± 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 CSPΞ± resides in presynaptic terminals, where it forms a chaperone complex with Hsc70 and SGT |
| GO:0098793 presynapse | IMP PMID:21151134 CSPΞ± 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. |
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