Gene Ontology annotation by the MGI curatorial staff, curated orthology
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Automated transfer of experimentally-verified manual GO annotation data to mouse-rat orthologs
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Automatic assignment of GO terms using logical inference, based on on inter-ontology links
Electronic Gene Ontology annotations created by ARBA machine learning models
Automated transfer of experimentally-verified manual GO annotation data to mouse-human orthologs
Combined Automated Annotation using Multiple IEA Methods
Hsc70 regulates accumulation of cyclin D1 and cyclin D1-dependent protein kinase.
Emerging role for autophagy in the removal of aggresomes in Schwann cells.
Hsp105 but not Hsp70 family proteins suppress the aggregation of heat-denatured protein in the presence of ADP.
Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration.
Proteolipid protein is required for transport of sirtuin 2 into CNS myelin.
A novel calcium-binding protein is associated with tau proteins in tauopathy.
Hermansky-Pudlak syndrome protein complexes associate with phosphatidylinositol 4-kinase type II alpha in neuronal and non-neuronal cells.
The water channel aquaporin-1 partitions into exosomes during reticulocyte maturation: implication for the regulation of cell volume.
Chaperone-assisted selective autophagy is essential for muscle maintenance.
Kinesin-1/Hsc70-dependent mechanism of slow axonal transport and its relation to fast axonal transport.
Endocytosis and clathrin-uncoating defects at synapses of auxilin knockout mice.
CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity.
Heat shock cognate protein 70 regulates gephyrin clustering.
Microautophagy of cytosolic proteins by late endosomes.
RAB-like 2 has an essential role in male fertility, sperm intra-flagellar transport, and tail assembly.
A broadly applicable high-throughput screening strategy identifies new regulators of Dlg4 (Psd-95) alternative splicing.
Splicing and beyond: the many faces of the Prp19 complex.
Evidence for a Clathrin-independent mode of endocytosis at a continuously active sensory synapse.
Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis.
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.
Subcellular distribution of non-muscle myosin IIb is controlled by FILIP through Hsc70.
Chaperone-mediated autophagy is involved in the execution of ferroptosis.
Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
Role of auxilin in uncoating clathrin-coated vesicles.
Prkaa2 phosphorylates Plins
Prkaa2 dissociate from p-Plins:Hspa8
p-Plins translocate from lipid droplet surface to cytosol
Hspa8:substrate binds late endosomal phospholipids
Substrate translocates into late endosomal lumen
Falcon deep research report on mouse Hspa8 (HSC70/HSC73, UniProt P63017)
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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."
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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"
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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"
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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"
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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)."
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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"
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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)"
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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"
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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"
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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"