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).
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
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
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.
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.
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
HSC70’s core biochemical activity is **ATP hydrolysis coupled to cycles of client binding and release**, which enables folding/holding/refolding and quality control routing.
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.
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.
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)
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
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.
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).
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.
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.
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.
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.
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.
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.
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
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.
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
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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).
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.
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.
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.
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.
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.
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
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).
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.
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.
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.
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.
Deletion of CSPα produces an abnormal SNAP-25 conformer that inhibits SNARE-complex formation, and is subject to ubiquitylation and proteasomal degradation
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Core Functions
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).
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).
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
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.
Role of auxilin in uncoating clathrin-coated vesicles.
Reactome:R-MMU-9613507
Plins:Hspa8 binds Prkaa2
Reactome:R-MMU-9613545
Prkaa2 phosphorylates Plins
Reactome:R-MMU-9613562
Prkaa2 dissociate from p-Plins:Hspa8
Reactome:R-MMU-9613670
p-Plins translocate from lipid droplet surface to cytosol
Reactome:R-MMU-9631076
Hspa8:substrate binds late endosomal phospholipids
Reactome:R-MMU-9631080
Substrate translocates into late endosomal lumen
file:mouse/Hspa8/Hspa8-deep-research-falcon.md
Falcon deep research report on mouse Hspa8 (HSC70/HSC73, UniProt P63017)
Mouse Hspa8 (HSC70/HSC73) is the constitutively expressed cytosolic HSP70-family
chaperone whose core biochemical activity is ATP hydrolysis (EC 3.6.4.10) coupled to
cycles of client binding and release, with an N-terminal nucleotide-binding domain
(NBD) and a C-terminal substrate-binding domain (SBD).
"HSC70’s core biochemical activity is **ATP hydrolysis coupled to cycles of client binding and release**, which enables folding/holding/refolding and quality control routing."
HSC70/HSPA8 contains an N-terminal nucleotide-binding domain (NBD) that binds and
hydrolyzes ATP and a C-terminal substrate-binding domain (SBD) that binds client
peptides; the ADP-bound state has highest substrate affinity.
"Structurally, HSP70s (including HSC70/HSPA8) contain an **N-terminal nucleotide-binding domain (NBD)** that binds/hydrolyzes ATP and a **C-terminal substrate-binding domain (SBD)** that binds client peptides; a C-terminal tail containing **EEVD** mediates cofactor interactions"
In chaperone-mediated autophagy (CMA), HSC70 recognizes substrates bearing a
KFERQ-like pentapeptide motif and delivers them to the lysosomal surface, where the
complex binds the cytosolic tail of LAMP-2A.
"**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"
HSC70/HSPA8 is the central substrate-recognition chaperone of CMA, recognizing the
KFERQ-like motif and docking substrates at LAMP-2A, whose multimerization forms the
translocation complex.
"The complex is delivered to lysosomal membranes, where it binds the cytosolic tail of **LAMP-2A**; LAMP-2A multimerizes to form the translocation complex"
HSC70/HSPA8 is a key ATPase that uncoats clathrin lattices after vesicle budding,
an activity that requires the J-domain cochaperones GAK (ubiquitous) or auxilin
(neuronal).
"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)."
J-domain proteins (DNAJ/HSP40) stimulate HSC70 ATP hydrolysis and promote client
handoff, while nucleotide exchange factors (NEFs, e.g. BAG family, Hsp110-like)
accelerate ADP-to-ATP exchange.
"**J-domain proteins (DNAJ/HSP40)** stimulate HSC70 ATP hydrolysis and promote client handoff"
As a core proteostasis factor, HSC70/HSPA8 assists folding of nascent and
stress-denatured proteins, prevents aggregation, and helps route damaged clients
toward proteasome/autophagy degradation pathways.
"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)"
HSC70/HSPA8 acts predominantly in the cytosol as the constitutive housekeeping
chaperone, also operating at the cytosolic face of lysosomes during CMA.
"HSC70/HSPA8 is primarily a **cytosolic** chaperone supporting basal proteostasis, with cofactor engagement through its EEVD tail"
A 2024 study reports a noncanonical 'amyloidase' function of HSPA8 that suppresses
necroptosis by dismantling RHIM-containing fibrils; pharmacologic HSPA8 inhibition
can potentiate necroptosis.
"A 2024 Molecular Biology of the Cell study reports a noncanonical function of HSPA8 as an “amyloidase” that suppresses necroptosis by dismantling RHIM-containing fibrils, and shows that **pharmacologic inhibition** of HSPA8 can potentiate necroptosis and improve responses to microtubule-targeting chemotherapy"
In mouse neurons, Hspa8 mRNA is the most abundant dendritic chaperone mRNA, and
proteotoxic stress increases its dendritic localization and local translation.
"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"
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Research Report: Mouse Hspa8 (HSC70/HSC73) Functional Annotation (UniProt: P63017)
0. Scope and identity verification
Target verified: The user-specified UniProt entry P63017 corresponds to mouse Hspa8, encoding the constitutively expressed cytosolic HSP70-family chaperone commonly called HSC70/HSC73 (heat shock cognate 70/73). Across multiple sources, “Hsc70” is explicitly equated with HSPA8 and described with the canonical HSP70 domain architecture and ATP-driven chaperone cycle expected for Hspa8/P63017 (melikov2024heatshockprotein pages 5-6, park2015theclathrinbindingand pages 1-2).
Ambiguity note: The retrieved full-text corpus did not contain an explicit “UniProt P63017” string match; therefore, UniProt accession mapping is taken from the user-provided UniProt record and cross-validated by concordant naming (Hsc70 ≡ HSPA8) and functional/structural features in the literature (melikov2024heatshockprotein pages 5-6, park2015theclathrinbindingand pages 1-2).
1. Key concepts and definitions (current understanding)
1.1 What Hspa8/HSC70 is
Hspa8 encodes a molecular chaperone in the HSP70 family that supports proteostasis under basal (“housekeeping”) conditions, distinct from stress-inducible HSP70 paralogs. Structurally, HSP70s (including HSC70/HSPA8) contain an N-terminal nucleotide-binding domain (NBD) that binds/hydrolyzes ATP and a C-terminal substrate-binding domain (SBD) that binds client peptides; a C-terminal tail containing EEVD mediates cofactor interactions (melikov2024heatshockprotein pages 5-6).
1.2 Enzymatic activity and reaction cycle (EC 3.6.4.10)
HSC70’s core biochemical activity is ATP hydrolysis coupled to cycles of client binding and release, which enables folding/holding/refolding and quality control routing. ATP binding and hydrolysis in the NBD is allosterically coupled to SBD lid dynamics and client affinity (melikov2024heatshockprotein pages 5-6). In chaperone-mediated autophagy (CMA), the ADP-bound form is described as having the highest substrate affinity (huang2024selectiveproteindegradation pages 4-5).
1.3 Substrate recognition rules
HSC70/HSPA8 recognizes:
- Non-native protein segments, often hydrophobic patches exposed during misfolding/denaturation (general HSP70 feature) (pustovaya2026recentinsightsinto pages 1-2).
- 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 (yao2023chaperone‐mediatedautophagymolecular pages 1-3).
1.4 Co-chaperones: what “drives” specificity
HSC70 function is strongly shaped by co-chaperones:
- J-domain proteins (DNAJ/HSP40) stimulate HSC70 ATP hydrolysis and promote client handoff (melikov2024heatshockprotein pages 5-6, huang2024selectiveproteindegradation pages 4-5).
- Nucleotide exchange factors (NEFs) accelerate ADP→ATP exchange; multiple NEF families exist (e.g., BAG family, Hsp110-like) (melikov2024heatshockprotein pages 5-6, pustovaya2026recentinsightsinto pages 8-9).
- In CMA, additional modulators include Hip (stabilizes substrate-bound complexes), Hsp90 (notably described as stabilizing LAMP2A complexes), and others (huang2024selectiveproteindegradation pages 4-5).
2. Primary functions, pathways, and mechanisms
2.1 Proteostasis and protein quality control (PQC)
At a systems level, 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) (melikov2024heatshockprotein pages 5-6, pustovaya2026recentinsightsinto pages 2-3).
2.2 Chaperone-mediated autophagy (CMA): pathway role of Hspa8
CMA is a selective lysosomal degradation pathway in vertebrates in which HSC70/HSPA8 is the central recognition chaperone.
Mechanism (core steps):
1) HSC70 recognizes the substrate’s KFERQ-like motif and forms a chaperone–substrate complex (yao2023chaperone‐mediatedautophagymolecular pages 1-3).
2) The complex is delivered to lysosomal membranes, where it binds the cytosolic tail of LAMP-2A; LAMP-2A multimerizes to form the translocation complex (yao2023chaperone‐mediatedautophagymolecular pages 1-3, yao2023chaperone‐mediatedautophagymolecular media e1f481b9).
3) HSC70’s ATPase cycle supports substrate unfolding and translocation; the unfolded substrate is imported into the lysosomal lumen and degraded by lysosomal enzymes (huang2024selectiveproteindegradation pages 4-5, yao2023chaperone‐mediatedautophagymolecular media e1f481b9).
CMA evidence and regulatory context (recent review synthesis): A 2023 review highlights CMA regulation by signaling pathways including NRF2 and p38–TFEB axes, and positions CMA as activated by starvation, hypoxia, and oxidative stress (yao2023chaperone‐mediatedautophagymolecular pages 1-3). A 2024 CMA review adds mechanistic details including HSC70’s ATPase involvement and co-chaperone modulators (huang2024selectiveproteindegradation pages 4-5).
Figure evidence: The following schematic visualizes the HSC70/HSPA8-dependent CMA steps (substrate recognition, LAMP-2A multimerization, translocation, degradation) (yao2023chaperone‐mediatedautophagymolecular media e1f481b9).
2.3 Clathrin-mediated endocytosis (CME) and synaptic vesicle recycling: clathrin uncoating
HSC70/HSPA8 is a key ATPase that remodels and uncoats clathrin lattices after vesicle budding.
Primary evidence (brain and cells): 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). In this system, the clathrin-binding motif plus J-domain of GAK are necessary and sufficient to support Hsc70-dependent clathrin uncoating and rescue clathrin trafficking defects in knockout contexts, whereas the J-domain alone is insufficient (park2015theclathrinbindingand pages 1-2, park2015theclathrinbindingand pages 2-3). The study reports that a minimal GAK fragment (GAK-C62) can rescue lethality/histologic defects of GAK knockout and can support viability even when GAK and auxilin are both knocked out in brain (with smaller body size), implying these domains are the functional core for recruiting Hsc70 ATPase activity to clathrin coats (park2015theclathrinbindingand pages 1-2).
Disease-pathway linkage (2024 synthesis): A 2024 review on Parkinson’s disease emphasizes that defects in clathrin-uncoating-associated genes (e.g., DNAJC6/auxilin, SYNJ1) disrupt synaptic vesicle recycling, with mouse models showing dopamine terminal pathology and synergistic effects in combined models; it also flags GAK as a risk factor and notes emerging links between endocytic proteins and autophagy (ng2024dysfunctionofsynaptic pages 1-2).
3. Subcellular localization: where Hspa8 acts
3.1 Cytosol and cytosolic complexes
HSC70/HSPA8 is primarily a cytosolic chaperone supporting basal proteostasis, with cofactor engagement through its EEVD tail (melikov2024heatshockprotein pages 5-6).
3.2 Lysosomal membrane interface and lumen-associated CMA machinery
In CMA, HSC70 operates at the cytosolic face of lysosomes to recognize substrates and deliver them to LAMP-2A; luminal and membrane-associated co-chaperones (e.g., Hsp90 as described in one CMA review) participate in stabilizing the translocation complex (huang2024selectiveproteindegradation pages 4-5, yao2023chaperone‐mediatedautophagymolecular media e1f481b9).
3.3 Endocytic coats and synapses
In CME, HSC70/HSPA8 localizes functionally to clathrin-coated intermediates through recruitment by GAK/auxilin J-domain proteins, where ATP hydrolysis is coupled to clathrin lattice disassembly (park2015theclathrinbindingand pages 1-2, park2015theclathrinbindingand pages 2-3).
3.4 Neuronal dendrites: localized mRNA transport and local translation (2024)
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 (alecki2024localizedmolecularchaperone pages 1-3). Quantitatively, dendrites contained on average ~100 Hspa8 mRNAs vs ~5 Hspa1a mRNAs; MG132 stress increased the fraction of spines containing Hspa8 mRNAs from ~20% to ~40% (alecki2024localizedmolecularchaperone pages 3-5, alecki2024localizedmolecularchaperone pages 5-7). This work implicates ALS-linked RBPs (e.g., FUS; HNRNPA2B1) as regulators of the Hspa8 mRNA localization response (alecki2024localizedmolecularchaperone pages 1-3, alecki2024localizedmolecularchaperone pages 7-10).
3.5 Extracellular/EV-associated HSP70-family pools (context for HSPA8)
A 2024 review summarizes that HSP70-family proteins can translocate to membranes and extracellular space, including packaging into extracellular vesicles (EVs); mechanisms include lipid-raft association, endolysosomal trafficking, and exosome/ectosome release (hu2024diversityofextracellular pages 2-4). This literature is often not isoform-specific, but provides the current framework used for biomarker development around extracellular HSP70s.
4. Recent developments (prioritizing 2023–2024)
4.1 CMA: refined regulatory networks and disease connections
Recent CMA reviews (2023–2024) emphasize HSC70 as the recognition chaperone, LAMP-2A as the lysosomal receptor, and explore how CMA influences metabolism, aging, immunity, and inflammatory signaling; they highlight the continuing expansion of regulatory pathways (e.g., NRF2, p38–TFEB) (yao2023chaperone‐mediatedautophagymolecular pages 1-3, huang2024selectiveproteindegradation pages 4-5).
4.2 Neuronal compartment-specific proteostasis as an Hspa8-controlled stress response (2024)
The 2024 neuron-focused work provides a modern view of Hspa8 regulation: not just protein-level chaperoning, but spatiotemporally controlled dendritic mRNA localization and translation as a cell-biological mechanism to maintain local proteostasis in dendrites and spines under stress (alecki2024localizedmolecularchaperone pages 1-3, alecki2024localizedmolecularchaperone pages 5-7).
4.3 Therapeutic targeting: HSPA8 inhibition as a combination strategy (2024)
A 2024 Molecular Biology of the Cell study reports a noncanonical function of HSPA8 as an “amyloidase” that suppresses necroptosis by dismantling RHIM-containing fibrils, and shows that pharmacologic inhibition of HSPA8 can potentiate necroptosis and improve responses to microtubule-targeting chemotherapy (wu2024hspa8inhibitorsaugment pages 1-2). The study specifies two targeting modes: VER-155008 (ATP-competitive NBD binder) and PES/pifithrin-μ (SBD-interacting), both of which disrupted HSPA8–RHIM binding and enhanced necroptosis, with improved tumor regression in vivo when combined with MTAs (wu2024hspa8inhibitorsaugment pages 1-2).
5. Current applications and real-world implementations
5.1 Experimental biology and model systems
Endocytosis/synapse research: Hsc70/HSPA8 is used conceptually and experimentally as the ATPase core of clathrin uncoating, with GAK/auxilin as modulators; these mechanisms are used to interpret synaptic vesicle recycling phenotypes in neurological disease models (park2015theclathrinbindingand pages 1-2, ng2024dysfunctionofsynaptic pages 1-2).
Autophagy pathway interrogation: CMA studies frequently track HSC70-mediated KFERQ recognition and LAMP-2A-dependent trafficking/translocation as a selective degradation route (yao2023chaperone‐mediatedautophagymolecular pages 1-3, yao2023chaperone‐mediatedautophagymolecular media e1f481b9).
5.2 Translational applications
Cancer therapy: Small-molecule HSPA8 inhibitors (e.g., VER-155008, PES/pifithrin-μ) are being investigated for synergistic effects with established chemotherapies by manipulating regulated cell death pathways (necroptosis) (wu2024hspa8inhibitorsaugment pages 1-2).
Biomarkers (extracellular HSP70s): EV-associated/extracellular HSP70-family proteins are being assessed as blood/urine biomarkers for diagnosis, metastasis, and treatment response in cancer; mechanistic models for how HSP70s are exported are actively reviewed (hu2024diversityofextracellular pages 2-4).
6. Expert opinions and analysis (authoritative synthesis)
6.1 Why Hspa8 is pleiotropic yet mechanistically coherent
The breadth of Hspa8 phenotypes across tissues and diseases is best understood as the downstream consequence of a conserved biochemical engine—ATP-driven binding/release cycles—deployed in diverse cellular contexts via distinct co-chaperones and targeting factors (J-domain proteins, NEFs, etc.) (melikov2024heatshockprotein pages 5-6, pustovaya2026recentinsightsinto pages 8-9).
6.2 Two especially well-supported “primary” pathway roles
Among Hspa8’s many reported functions, two are particularly mechanistically grounded and repeatedly supported:
1) CMA substrate recognition and delivery to LAMP-2A, central for selective lysosomal degradation (yao2023chaperone‐mediatedautophagymolecular pages 1-3, huang2024selectiveproteindegradation pages 4-5).
2) Clathrin uncoating and clathrin chaperoning via GAK/auxilin recruitment, crucial for endocytosis and synaptic vesicle recycling (park2015theclathrinbindingand pages 1-2, park2015theclathrinbindingand pages 2-3).
Neuronal compartmentalization (mouse neurons; 2024 preprint):
- Average dendritic abundance: ~100 Hspa8 vs ~5 Hspa1a mRNAs (alecki2024localizedmolecularchaperone pages 3-5).
- Fraction of spines containing Hspa8 mRNAs increased from ~20% (control) to ~40% (MG132 stress) (alecki2024localizedmolecularchaperone pages 5-7).
These quantitative readouts support a model in which Hspa8 is prioritized for local proteostasis support in neuronal projections during stress (alecki2024localizedmolecularchaperone pages 1-3, alecki2024localizedmolecularchaperone pages 5-7).
8. Summary table (evidence-based)
Category
Summary
Identity/Structure
- Mouse Hspa8/HSC70 (Hsc73) is the constitutive cytosolic HSP70-family paralog, distinct from stress-inducible HSP70s. - Domain architecture: N-terminal ATPase/NBD, C-terminal substrate-binding domain (SBD) with lid, interdomain linker, and EEVD-containing tail for cofactor interactions. - Functional annotation is consistent with an HSP70-family housekeeping chaperone/proteostasis factor (melikov2024heatshockprotein pages 5-6, pustovaya2026recentinsightsinto pages 1-2)
Enzymatic activity
- ATPase-driven molecular chaperone: ATP binding/hydrolysis in the NBD controls client capture and release. - ADP-bound state has high substrate affinity in CMA-related binding cycles. - Also functions in ATP-coupled clathrin coat remodeling/uncoating (huang2024selectiveproteindegradation pages 4-5, pustovaya2026recentinsightsinto pages 2-3, park2015theclathrinbindingand pages 1-2)
Substrate recognition
- Binds exposed hydrophobic peptide segments typical of non-native proteins. - In chaperone-mediated autophagy (CMA), recognizes KFERQ-like motifs and delivers substrates to lysosomes. - 2024 mechanistic evidence highlighted direct HSC70 interaction with KFERQ-like motifs in CMA/microautophagy context (huang2024selectiveproteindegradation pages 4-5, yao2023chaperone‐mediatedautophagymolecular pages 1-3, pustovaya2026recentinsightsinto pages 11-12)
Key co-chaperones
- J-domain proteins/HSP40s stimulate ATP hydrolysis and client handoff. - NEFs (e.g., BAG family, HSP110 class) promote ADP→ATP exchange. - In CMA/endocytosis contexts, reported partners include Hip, Hsp40, Hsp90, BAG proteins, GAK, auxilin (melikov2024heatshockprotein pages 5-6, huang2024selectiveproteindegradation pages 4-5, pustovaya2026recentinsightsinto pages 8-9, park2015theclathrinbindingand pages 1-2)
Major pathways
- Core proteostasis/PQC: folding, refolding, anti-aggregation, routing clients toward degradation. - CMA: HSC70 binds KFERQ-bearing substrates, docks at LAMP2A, and supports unfolding/translocation. - Clathrin-mediated endocytosis/synaptic vesicle recycling: HSC70 works with GAK/auxilin to uncoat clathrin-coated vesicles (huang2024selectiveproteindegradation pages 4-5, yao2023chaperone‐mediatedautophagymolecular pages 1-3, park2015theclathrinbindingand pages 1-2, ng2024dysfunctionofsynaptic pages 1-2)
Localization
- Predominantly cytosolic, but functionally engages lysosomal membranes/lumen-associated CMA machinery. - Also implicated at endocytic/synaptic vesicle coats and in neuronal dendrites via local Hspa8 mRNA translation. - Broader HSP70 literature supports extracellular/endolysosomal/exosomal trafficking, though HSPA8-specific extracellular evidence here is more limited than for total eHSP70 (huang2024selectiveproteindegradation pages 4-5, pustovaya2026recentinsightsinto pages 11-12, alecki2024localizedmolecularchaperone pages 1-3, hu2024diversityofextracellular pages 2-4)
2023-2024 developments
- 2023–2024 CMA reviews emphasize HSC70 as the central substrate-recognition chaperone and discuss newer regulators such as NRF2 and p38–TFEB pathways. - 2024 neuronal work identifies Hspa8 as the most abundant dendritic chaperone mRNA and shows stress-induced local translation in mouse/human neurons. - 2024 cancer study shows HSPA8 inhibitors can potentiate necroptosis and chemotherapy response (yao2023chaperone‐mediatedautophagymolecular pages 1-3, alecki2024localizedmolecularchaperone pages 1-3, alecki2024localizedmolecularchaperone pages 7-10, wu2024hspa8inhibitorsaugment pages 1-2)
Applications/therapeutic targeting
- Pharmacologic inhibitors include VER-155008 (ATP-competitive, NBD) and PES/pifithrin-μ (SBD-directed). - In 2024 cancer models, HSPA8 inhibition increased sensitivity to microtubule-targeting agents and enhanced necroptosis-driven tumor regression. - HSP70-family extracellular vesicle biology is being explored for biomarker and therapeutic applications, though much of that literature is not HSPA8-specific (wu2024hspa8inhibitorsaugment pages 1-2, hu2024diversityofextracellular pages 2-4)
Quantitative findings
- In stressed neurons, dendrites contained roughly ~100 Hspa8 mRNAs vs ~5 Hspa1a mRNAs on average. - MG132 stress increased spines containing Hspa8 mRNA from about ~20% to ~40%. - MG132 increased translated Hspa8 mRNAs by about 20–45% in reporter assays; differential-expression thresholds included >1.7-fold, p<0.01 in one analysis (alecki2024localizedmolecularchaperone pages 10-12, alecki2024localizedmolecularchaperone pages 5-7, alecki2024localizedmolecularchaperone pages 3-5)
Table: This table condenses the current evidence-based functional annotation for mouse Hspa8/HSC70 (UniProt P63017). It highlights validated structural features, core biochemical roles, major pathways, localization, and recent 2023–2024 developments useful for a final gene report.
Key sources (with URLs and publication dates)
Yao R, Shen J. Chaperone-mediated autophagy: Molecular mechanisms, biological functions, and diseases.MedComm. Aug 2023. https://doi.org/10.1002/mco2.347 (yao2023chaperone‐mediatedautophagymolecular pages 1-3, yao2023chaperone‐mediatedautophagymolecular media e1f481b9)
Huang J, Wang J. Selective protein degradation through chaperone-mediated autophagy: Implications for cellular homeostasis and disease (Review).Molecular Medicine Reports. Oct 2024. https://doi.org/10.3892/mmr.2024.13378 (huang2024selectiveproteindegradation pages 4-5)
Melikov A, Novák P. Heat Shock Protein Network: the Mode of Action, the Role in Protein Folding and Human Pathologies.Folia Biologica. Jan 2024. https://doi.org/10.14712/fb2024070030152 (melikov2024heatshockprotein pages 5-6)
Alecki C et al. Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis.bioRxiv preprint. Oct 2024. https://doi.org/10.1101/2023.10.03.560761 (alecki2024localizedmolecularchaperone pages 1-3, alecki2024localizedmolecularchaperone pages 5-7, alecki2024localizedmolecularchaperone pages 3-5)
Wu E et al. HSPA8 inhibitors augment cancer chemotherapeutic effectiveness via potentiating necroptosis.Molecular Biology of the Cell. Aug 2024. https://doi.org/10.1091/mbc.e24-04-0194 (wu2024hspa8inhibitorsaugment pages 1-2)
Park B-C et al. The clathrin-binding and J-domains of GAK support the uncoating and chaperoning of clathrin by Hsc70 in the brain.Journal of Cell Science. Oct 2015. https://doi.org/10.1242/jcs.171058 (park2015theclathrinbindingand pages 1-2, park2015theclathrinbindingand pages 2-3)
Hu B et al. Diversity of extracellular HSP70 in cancer: advancing from a molecular biomarker to a novel therapeutic target.Frontiers in Oncology. Apr 2024. https://doi.org/10.3389/fonc.2024.1388999 (hu2024diversityofextracellular pages 2-4)
References
(melikov2024heatshockprotein pages 5-6): Aleksandr Melikov and Petr Novák. Heat shock protein network: the mode of action, the role in protein folding and human pathologies. Folia biologica, 70 3:152-165, Jan 2024. URL: https://doi.org/10.14712/fb2024070030152, doi:10.14712/fb2024070030152. This article has 11 citations and is from a peer-reviewed journal.
(park2015theclathrinbindingand pages 1-2): Bum-Chan Park, Yang-In Yim, Xiaohong Zhao, Maciej B. Olszewski, Evan Eisenberg, and Lois E. Greene. The clathrin-binding and j-domains of gak support the uncoating and chaperoning of clathrin by hsc70 in the brain. Journal of Cell Science, 128:3811-3821, Oct 2015. URL: https://doi.org/10.1242/jcs.171058, doi:10.1242/jcs.171058. This article has 36 citations and is from a domain leading peer-reviewed journal.
(huang2024selectiveproteindegradation pages 4-5): Jiahui Huang and Jiazhen Wang. Selective protein degradation through chaperone‑mediated autophagy: implications for cellular homeostasis and disease (review). Molecular Medicine Reports, Oct 2024. URL: https://doi.org/10.3892/mmr.2024.13378, doi:10.3892/mmr.2024.13378. This article has 24 citations and is from a peer-reviewed journal.
(pustovaya2026recentinsightsinto pages 1-2): Kristina Pustovaya, Artem Venediktov, Vladislav Soldatov, Egor Kuzmin, Ksenia Pokidova, Viktoria Gartzeva, Olga Payushina, Vassiliy Tsytsarev, Igor Meglinski, and Gennadii Piavchenko. Recent insights into hsp70: proteostasis and beyond. Frontiers in Molecular Biosciences, Apr 2026. URL: https://doi.org/10.3389/fmolb.2026.1791536, doi:10.3389/fmolb.2026.1791536. This article has 1 citations.
(yao2023chaperone‐mediatedautophagymolecular pages 1-3): Ruchen Yao and Jun Shen. Chaperone‐mediated autophagy: molecular mechanisms, biological functions, and diseases. MedComm, Aug 2023. URL: https://doi.org/10.1002/mco2.347, doi:10.1002/mco2.347. This article has 101 citations.
(pustovaya2026recentinsightsinto pages 8-9): Kristina Pustovaya, Artem Venediktov, Vladislav Soldatov, Egor Kuzmin, Ksenia Pokidova, Viktoria Gartzeva, Olga Payushina, Vassiliy Tsytsarev, Igor Meglinski, and Gennadii Piavchenko. Recent insights into hsp70: proteostasis and beyond. Frontiers in Molecular Biosciences, Apr 2026. URL: https://doi.org/10.3389/fmolb.2026.1791536, doi:10.3389/fmolb.2026.1791536. This article has 1 citations.
(pustovaya2026recentinsightsinto pages 2-3): Kristina Pustovaya, Artem Venediktov, Vladislav Soldatov, Egor Kuzmin, Ksenia Pokidova, Viktoria Gartzeva, Olga Payushina, Vassiliy Tsytsarev, Igor Meglinski, and Gennadii Piavchenko. Recent insights into hsp70: proteostasis and beyond. Frontiers in Molecular Biosciences, Apr 2026. URL: https://doi.org/10.3389/fmolb.2026.1791536, doi:10.3389/fmolb.2026.1791536. This article has 1 citations.
(yao2023chaperone‐mediatedautophagymolecular media e1f481b9): Ruchen Yao and Jun Shen. Chaperone‐mediated autophagy: molecular mechanisms, biological functions, and diseases. MedComm, Aug 2023. URL: https://doi.org/10.1002/mco2.347, doi:10.1002/mco2.347. This article has 101 citations.
(park2015theclathrinbindingand pages 2-3): Bum-Chan Park, Yang-In Yim, Xiaohong Zhao, Maciej B. Olszewski, Evan Eisenberg, and Lois E. Greene. The clathrin-binding and j-domains of gak support the uncoating and chaperoning of clathrin by hsc70 in the brain. Journal of Cell Science, 128:3811-3821, Oct 2015. URL: https://doi.org/10.1242/jcs.171058, doi:10.1242/jcs.171058. This article has 36 citations and is from a domain leading peer-reviewed journal.
(ng2024dysfunctionofsynaptic pages 1-2): Xin Yi Ng and Mian Cao. Dysfunction of synaptic endocytic trafficking in parkinson’s disease. Neural Regeneration Research, 19(12):2649-2660, Mar 2024. URL: https://doi.org/10.4103/nrr.nrr-d-23-01624, doi:10.4103/nrr.nrr-d-23-01624. This article has 32 citations and is from a peer-reviewed journal.
(alecki2024localizedmolecularchaperone pages 1-3): Célia Alecki, Javeria Rizwan, Phuong Le, Suleima Jacob-Tomas, Mario Fernandez-Comaduran, Morgane Verbrugghe, Jia Ming Stella Xu, Sandra Minotti, James Lynch, Tad Wu, Heather Durham, Gene W. Yeo, and Maria Vera. Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis. bioRxiv, Oct 2024. URL: https://doi.org/10.1101/2023.10.03.560761, doi:10.1101/2023.10.03.560761. This article has 13 citations.
(alecki2024localizedmolecularchaperone pages 3-5): Célia Alecki, Javeria Rizwan, Phuong Le, Suleima Jacob-Tomas, Mario Fernandez-Comaduran, Morgane Verbrugghe, Jia Ming Stella Xu, Sandra Minotti, James Lynch, Tad Wu, Heather Durham, Gene W. Yeo, and Maria Vera. Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis. bioRxiv, Oct 2024. URL: https://doi.org/10.1101/2023.10.03.560761, doi:10.1101/2023.10.03.560761. This article has 13 citations.
(alecki2024localizedmolecularchaperone pages 5-7): Célia Alecki, Javeria Rizwan, Phuong Le, Suleima Jacob-Tomas, Mario Fernandez-Comaduran, Morgane Verbrugghe, Jia Ming Stella Xu, Sandra Minotti, James Lynch, Tad Wu, Heather Durham, Gene W. Yeo, and Maria Vera. Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis. bioRxiv, Oct 2024. URL: https://doi.org/10.1101/2023.10.03.560761, doi:10.1101/2023.10.03.560761. This article has 13 citations.
(alecki2024localizedmolecularchaperone pages 7-10): Célia Alecki, Javeria Rizwan, Phuong Le, Suleima Jacob-Tomas, Mario Fernandez-Comaduran, Morgane Verbrugghe, Jia Ming Stella Xu, Sandra Minotti, James Lynch, Tad Wu, Heather Durham, Gene W. Yeo, and Maria Vera. Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis. bioRxiv, Oct 2024. URL: https://doi.org/10.1101/2023.10.03.560761, doi:10.1101/2023.10.03.560761. This article has 13 citations.
(hu2024diversityofextracellular pages 2-4): Binbin Hu, Guihong Liu, Kejia Zhao, and Gao Zhang. Diversity of extracellular hsp70 in cancer: advancing from a molecular biomarker to a novel therapeutic target. Frontiers in Oncology, Apr 2024. URL: https://doi.org/10.3389/fonc.2024.1388999, doi:10.3389/fonc.2024.1388999. This article has 30 citations.
(wu2024hspa8inhibitorsaugment pages 1-2): Erpeng Wu, Chenlu Wu, Kelong Jia, Shen’ao Zhou, and Liming Sun. Hspa8 inhibitors augment cancer chemotherapeutic effectiveness via potentiating necroptosis. Molecular Biology of the Cell, Aug 2024. URL: https://doi.org/10.1091/mbc.e24-04-0194, doi:10.1091/mbc.e24-04-0194. This article has 9 citations and is from a domain leading peer-reviewed journal.
(pustovaya2026recentinsightsinto pages 11-12): Kristina Pustovaya, Artem Venediktov, Vladislav Soldatov, Egor Kuzmin, Ksenia Pokidova, Viktoria Gartzeva, Olga Payushina, Vassiliy Tsytsarev, Igor Meglinski, and Gennadii Piavchenko. Recent insights into hsp70: proteostasis and beyond. Frontiers in Molecular Biosciences, Apr 2026. URL: https://doi.org/10.3389/fmolb.2026.1791536, doi:10.3389/fmolb.2026.1791536. This article has 1 citations.
(alecki2024localizedmolecularchaperone pages 10-12): Célia Alecki, Javeria Rizwan, Phuong Le, Suleima Jacob-Tomas, Mario Fernandez-Comaduran, Morgane Verbrugghe, Jia Ming Stella Xu, Sandra Minotti, James Lynch, Tad Wu, Heather Durham, Gene W. Yeo, and Maria Vera. Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis. bioRxiv, Oct 2024. URL: https://doi.org/10.1101/2023.10.03.560761, doi:10.1101/2023.10.03.560761. This article has 13 citations.
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. Falcon deep research confirms ATP hydrolysis as the core biochemical engine driving client binding/release cycles.
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"
- reference_id: file:mouse/Hspa8/Hspa8-deep-research-falcon.md
supporting_text: |-
HSC70’s core biochemical activity is **ATP hydrolysis coupled to cycles of client binding and release**, which enables folding/holding/refolding and quality control routing.
- 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. Falcon deep research emphasizes that J-domain proteins (DNAJ/HSP40) stimulate HSC70 ATP hydrolysis and promote client handoff.
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"
- reference_id: file:mouse/Hspa8/Hspa8-deep-research-falcon.md
supporting_text: |-
**J-domain proteins/HSP40s** stimulate ATP hydrolysis and client handoff.
- 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. Falcon deep research independently identifies this housekeeping foldase/proteostasis activity as the primary, mechanistically coherent function from which Hspa8's pleiotropy derives.
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"
- reference_id: file:mouse/Hspa8/Hspa8-deep-research-falcon.md
supporting_text: |-
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)
- 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). Falcon deep research confirms HSC70/HSPA8 is primarily a cytosolic chaperone supporting basal proteostasis.
action: ACCEPT
reason: Cytosol is the primary subcellular location where Hspa8 performs its housekeeping chaperone functions.
supported_by:
- reference_id: file:mouse/Hspa8/Hspa8-deep-research-falcon.md
supporting_text: |-
HSC70/HSPA8 is primarily a **cytosolic** chaperone supporting basal proteostasis, with cofactor engagement through its EEVD tail
- 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. 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.
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"
- reference_id: file:mouse/Hspa8/Hspa8-deep-research-falcon.md
supporting_text: |-
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).
- 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. 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.
- 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. Falcon deep research confirms HSC70 operates at the cytosolic face of lysosomes to recognize substrates and deliver them to LAMP-2A.
action: ACCEPT
reason: Lysosomal membrane localization is a core feature of Hspa8's role in CMA.
supported_by:
- reference_id: file:mouse/Hspa8/Hspa8-deep-research-falcon.md
supporting_text: |-
In CMA, HSC70 operates at the **cytosolic face of lysosomes** to recognize substrates and deliver them to LAMP-2A
- 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). Falcon deep research confirms HSC70/HSPA8 as the central recognition chaperone of CMA, recognizing KFERQ-like motifs and delivering substrates to the lysosomal surface.
action: ACCEPT
reason: Autophagy involvement is a core function of Hspa8 through its essential role in CMA and endosomal microautophagy.
supported_by:
- reference_id: file:mouse/Hspa8/Hspa8-deep-research-falcon.md
supporting_text: |-
**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
- 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). 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.
action: ACCEPT
reason: Consistent with documented dendritic and postsynaptic functions of Hspa8.
supported_by:
- reference_id: file:mouse/Hspa8/Hspa8-deep-research-falcon.md
supporting_text: |-
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
- 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). Falcon deep research confirms Hsc70/HSPA8 is a key ATPase that remodels and uncoats clathrin lattices after vesicle budding.
action: ACCEPT
reason: Clathrin-uncoating ATPase activity is a specific and well-documented molecular function of Hspa8.
supported_by:
- reference_id: file:mouse/Hspa8/Hspa8-deep-research-falcon.md
supporting_text: |-
HSC70/HSPA8 is a key ATPase that remodels and **uncoats clathrin lattices** after vesicle budding.
- 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. Falcon deep research confirms the substrate complex docks at the cytosolic tail of LAMP-2A, whose multimerization forms the translocation complex.
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
- reference_id: file:mouse/Hspa8/Hspa8-deep-research-falcon.md
supporting_text: |-
The complex is delivered to lysosomal membranes, where it binds the cytosolic tail of **LAMP-2A**; LAMP-2A multimerizes to form the translocation complex
- 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: []
- id: file:mouse/Hspa8/Hspa8-deep-research-falcon.md
title: Falcon deep research report on mouse Hspa8 (HSC70/HSC73, UniProt P63017)
findings:
- statement: |-
Mouse Hspa8 (HSC70/HSC73) is the constitutively expressed cytosolic HSP70-family
chaperone whose core biochemical activity is ATP hydrolysis (EC 3.6.4.10) coupled to
cycles of client binding and release, with an N-terminal nucleotide-binding domain
(NBD) and a C-terminal substrate-binding domain (SBD).
reference_section_type: OTHER
supporting_text: |-
HSC70’s core biochemical activity is **ATP hydrolysis coupled to cycles of client binding and release**, which enables folding/holding/refolding and quality control routing.
- statement: |-
HSC70/HSPA8 contains an N-terminal nucleotide-binding domain (NBD) that binds and
hydrolyzes ATP and a C-terminal substrate-binding domain (SBD) that binds client
peptides; the ADP-bound state has highest substrate affinity.
reference_section_type: OTHER
supporting_text: |-
Structurally, HSP70s (including HSC70/HSPA8) contain an **N-terminal nucleotide-binding domain (NBD)** that binds/hydrolyzes ATP and a **C-terminal substrate-binding domain (SBD)** that binds client peptides; a C-terminal tail containing **EEVD** mediates cofactor interactions
- statement: |-
In chaperone-mediated autophagy (CMA), HSC70 recognizes substrates bearing a
KFERQ-like pentapeptide motif and delivers them to the lysosomal surface, where the
complex binds the cytosolic tail of LAMP-2A.
reference_section_type: OTHER
supporting_text: |-
**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
- statement: |-
HSC70/HSPA8 is the central substrate-recognition chaperone of CMA, recognizing the
KFERQ-like motif and docking substrates at LAMP-2A, whose multimerization forms the
translocation complex.
reference_section_type: OTHER
supporting_text: |-
The complex is delivered to lysosomal membranes, where it binds the cytosolic tail of **LAMP-2A**; LAMP-2A multimerizes to form the translocation complex
- statement: |-
HSC70/HSPA8 is a key ATPase that uncoats clathrin lattices after vesicle budding,
an activity that requires the J-domain cochaperones GAK (ubiquitous) or auxilin
(neuronal).
reference_section_type: OTHER
supporting_text: |-
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).
- statement: |-
J-domain proteins (DNAJ/HSP40) stimulate HSC70 ATP hydrolysis and promote client
handoff, while nucleotide exchange factors (NEFs, e.g. BAG family, Hsp110-like)
accelerate ADP-to-ATP exchange.
reference_section_type: OTHER
supporting_text: |-
**J-domain proteins (DNAJ/HSP40)** stimulate HSC70 ATP hydrolysis and promote client handoff
- statement: |-
As a core proteostasis factor, HSC70/HSPA8 assists folding of nascent and
stress-denatured proteins, prevents aggregation, and helps route damaged clients
toward proteasome/autophagy degradation pathways.
reference_section_type: OTHER
supporting_text: |-
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)
- statement: |-
HSC70/HSPA8 acts predominantly in the cytosol as the constitutive housekeeping
chaperone, also operating at the cytosolic face of lysosomes during CMA.
reference_section_type: OTHER
supporting_text: |-
HSC70/HSPA8 is primarily a **cytosolic** chaperone supporting basal proteostasis, with cofactor engagement through its EEVD tail
- statement: |-
A 2024 study reports a noncanonical 'amyloidase' function of HSPA8 that suppresses
necroptosis by dismantling RHIM-containing fibrils; pharmacologic HSPA8 inhibition
can potentiate necroptosis.
reference_section_type: OTHER
supporting_text: |-
A 2024 Molecular Biology of the Cell study reports a noncanonical function of HSPA8 as an “amyloidase” that suppresses necroptosis by dismantling RHIM-containing fibrils, and shows that **pharmacologic inhibition** of HSPA8 can potentiate necroptosis and improve responses to microtubule-targeting chemotherapy
- statement: |-
In mouse neurons, Hspa8 mRNA is the most abundant dendritic chaperone mRNA, and
proteotoxic stress increases its dendritic localization and local translation.
reference_section_type: OTHER
supporting_text: |-
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
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
