Hspa8 (UniProt P63018; HSP7C_RAT) encodes the rat Heat shock cognate 71 kDa protein, the constitutively expressed cytosolic HSP70-family chaperone known as HSC70/HSC73. Unlike the stress-inducible Hspa1a/Hspa1b (HSP70) paralogs, HSC70 is expressed under basal conditions and is the housekeeping HSP70. Its core molecular function is an ATP-dependent (EC 3.6.4.10) protein-folding chaperone activity built on the canonical HSP70 architecture: an N-terminal nucleotide-binding/ATPase domain and a C-terminal substrate-binding domain with a helical lid, whose nucleotide state (ATP = low affinity/fast client exchange; ADP = high affinity) governs cyclic binding and release of unfolded/misfolded client polypeptides. The ATPase cycle is driven by J-domain (HSP40/DNAJ) co-chaperones that stimulate ATP hydrolysis and reset by nucleotide-exchange factors. Three best-supported, mechanistically distinct roles emerge: (1) general proteostasis - protein folding, refolding, unfolding and disassembly of protein complexes; (2) clathrin-coated vesicle uncoating - the clathrin-uncoating ATPase activity in which the J-domain co-chaperone auxilin (DNAJC6) recruits HSC70 to clathrin-coated vesicles and stimulates its ATPase to disassemble clathrin coats, central to clathrin-mediated endocytosis and synaptic vesicle recycling; and (3) chaperone-mediated autophagy (CMA) - cytosolic HSC70 recognizes KFERQ-like pentapeptide motifs in soluble client proteins and delivers them to LAMP-2A at the lysosomal membrane, with lysosomal HSC70 supporting translocation into the lysosomal lumen for degradation. HSC70 acts predominantly in the cytosol, with additional functional pools at the lysosomal membrane/lumen and at endocytic/synaptic trafficking structures. It is a highly pleiotropic protein; many of its annotated processes and locations reflect this pleiotropy rather than its evolved core function.
Summary: Manual review: HSC70 has documented nuclear/nucleolar pools (e.g. nuclear import roles), but the nucleus is not the site of its core chaperone, clathrin-uncoating, or CMA functions.
Reason: Valid localization but peripheral to the evolved cytosolic chaperone function.
Summary: Manual review: plasma membrane is not the site of the core chaperone function of HSC70, which acts in the cytosol; surface/extracellular pools are context-specific (e.g. exosomal/cell-surface) and do not represent the evolved function.
Reason: Localization over-annotation; the core HSC70 function is cytosolic, not at the plasma membrane.
Summary: Manual review: ATP hydrolysis activity underpins the ATP-dependent chaperone cycle of Hspa8/HSC70, in which the nucleotide state controls client affinity and is regulated by J-domain co-chaperones.
Reason: Retained as supporting the core ATP-driven chaperone cycle, corroborated by falcon deep research.
Supporting Evidence:
file:rat/Hspa8/Hspa8-deep-research-falcon.md
nucleotide state controls substrate affinity (ATP-bound low affinity/fast exchange; ADP-bound high affinity/slow exchange)
Summary: Manual review: protein folding chaperone is the core molecular function of Hspa8/HSC70; the constitutive HSP70-family ATP-dependent chaperone that assists folding, refolding, unfolding and complex disassembly of client proteins.
Reason: Retained as the core molecular function, corroborated by falcon deep research.
Supporting Evidence:
file:rat/Hspa8/Hspa8-deep-research-falcon.md
Hspa8/HSC70 is a **constitutive** HSP70-family **ATPase chaperone** that supports proteostasis by assisting **protein folding/refolding**, **unfolding**, and **disassembly of protein complexes**
Summary: Manual review: clathrin coat disassembly is a core process for Hspa8/HSC70; the auxilin (DNAJC6)-recruited HSC70 ATPase disassembles clathrin coats from clathrin-coated vesicles.
Reason: Retained as a core process, corroborated by falcon deep research.
Supporting Evidence:
file:rat/Hspa8/Hspa8-deep-research-falcon.md
the **J-domain co-chaperone auxilin (DNAJC6)** recruits HSC70 to CCVs and **stimulates HSC70 ATPase activity** to disassemble clathrin coats
Summary: Manual review: signal transduction is an over-broad inter-ontology IEA inference; HSC70 is a chaperone and does not act as a signal transducer. This generic term over-annotates the gene.
Reason: Over-broad IEA inference that does not reflect the evolved chaperone function of HSC70.
Summary: Manual review: the lysosomal membrane is a functional location of the core chaperone-mediated autophagy role of HSC70, where the chaperone-substrate complex engages LAMP-2A; this electronic annotation is consistent with the experimentally supported IDA annotations to the same term.
Reason: Lysosomal membrane is a bona fide functional location for the core CMA role of HSC70 (experimentally supported by PMID:18644871 and PMID:9038169); accepted for consistency with those IDA annotations.
Summary: Manual review: plasma membrane is not the site of the core chaperone function of HSC70; surface/extracellular pools are context-specific and do not represent the evolved function.
Reason: Localization over-annotation; the core HSC70 function is cytosolic, not at the plasma membrane.
Summary: Manual review: HSC70 is indeed a hydrolase (an ATPase, EC 3.6.4.10), so GO:0016787 is not factually wrong, but it is an over-broad parent term. The more specific GO:0016887 (ATP hydrolysis activity) is already ACCEPTed and captures the actual catalytic function.
Reason: GO:0016887 (ATP hydrolysis activity) is already ACCEPTed and is more specific; GO:0016787 (hydrolase activity) is the over-broad parent and is redundant.
Summary: Manual review: chaperone-mediated autophagy is a core process for Hspa8/HSC70, which selects KFERQ-motif clients and delivers them to LAMP-2A for lysosomal degradation.
Reason: Retained as a core process, corroborated by falcon deep research.
Supporting Evidence:
file:rat/Hspa8/Hspa8-deep-research-falcon.md
recognition of KFERQ-like pentapeptide motifs** in client proteins targeted for **chaperone-mediated autophagy (CMA)**
Summary: Manual review: the lysosomal membrane is a functional location of the core chaperone-mediated autophagy role of HSC70; this orthology-based annotation is consistent with the experimentally supported IDA annotations to the same term.
Reason: Lysosomal membrane is a bona fide functional location for the core CMA role of HSC70 (experimentally supported by PMID:18644871 and PMID:9038169); accepted for consistency with those IDA annotations.
Summary: Manual review: protein-macromolecule adaptor activity is consistent with known biology of Hspa8.
Reason: Retained as supported or plausible for this gene and evidence context.
GO:0061740
protein targeting to lysosome involved in chaperone-mediated autophagy
ISS
GO_REF:0000024
ACCEPT
Summary: Manual review: protein targeting to lysosome in CMA is a core process for Hspa8/HSC70; cytosolic HSC70 recognizes KFERQ-like motifs and delivers clients to LAMP-2A, and lysosomal HSC70 supports translocation into the lysosomal lumen.
Reason: Retained as a core CMA process, corroborated by falcon deep research.
Supporting Evidence:
file:rat/Hspa8/Hspa8-deep-research-falcon.md
recognition of KFERQ-like pentapeptide motifs** in client proteins targeted for **chaperone-mediated autophagy (CMA)**
file:rat/Hspa8/Hspa8-deep-research-falcon.md
Lysosomal HSC70 (LysβHSC70)** facilitates **substrate translocation** into the lysosome lumen
GO:1900226
negative regulation of NLRP3 inflammasome complex assembly
ISO
GO_REF:0000121
KEEP AS NON CORE
Summary: Manual review: negative regulation of NLRP3 inflammasome complex assembly may be context-dependent or peripheral for Hspa8.
Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
IDA
PMID:18644871
The chaperone-mediated autophagy receptor organizes in dynam...
ACCEPT
Summary: Manual review: this IDA derives from a key CMA mechanistic paper showing HSC70 organizes in dynamic protein complexes with LAMP-2A at the lysosomal membrane. The lysosomal membrane is a functional location of the core CMA role of HSC70 (also listed in the CMA core_function), so this experimental annotation is accepted as core.
Reason: The lysosomal membrane is a bona fide functional location for the core chaperone-mediated autophagy role of HSC70, directly demonstrated experimentally in PMID:18644871. Falcon corroboration is captured in the references findings block.
IDA
PMID:9038169
A population of rat liver lysosomes responsible for the sele...
ACCEPT
Summary: Manual review: PMID:9038169 (Cuervo, Dice & Knecht 1997) is a foundational CMA paper showing lysosomal hsc73 mediates selective uptake/degradation of cytosolic substrates in rat liver lysosomes. The lysosomal membrane is a functional location of the core CMA role of HSC70.
Reason: The lysosomal membrane is a bona fide functional location for the core chaperone-mediated autophagy role of HSC70, directly demonstrated experimentally in PMID:9038169.
IDA
PMID:8420978
Aspartyl residue 10 is essential for ATPase activity of rat ...
REMOVE
Summary: Manual review: PMID:8420978 (Huang et al. 1993, "Aspartyl residue 10 is essential for ATPase activity of rat hsc70") studies the ATPase activity of HSC70, not protein autophosphorylation. The annotation appears to be a database error.
Reason: Misannotation: PMID:8420978 reports ATPase activity (the catalytic mechanism of HSC70), not protein autophosphorylation; there is no evidence in this reference that HSC70 autophosphorylates.
IPI
PMID:10866672
The heat shock cognate protein hsc73 assembles with A(1) ade...
KEEP AS NON CORE
Summary: Manual review: PMID:10866672 documents a direct, specific rat hsc73-A1 adenosine receptor interaction (Kd ~0.5 nM by surface plasmon resonance, plus affinity chromatography, co-immunoprecipitation and confocal colocalization). This is a genuine documented interaction but is peripheral to the evolved core chaperone function.
Reason: Well-supported experimental rat interaction (PMID:10866672) but peripheral to the core HSC70 chaperone, clathrin-uncoating, and CMA functions; retained as non-core rather than removed.
Summary: Manual review: HSC70 has documented nuclear/nucleolar pools, but the nucleus is not the site of its core chaperone, clathrin-uncoating, or CMA functions.
Reason: Valid localization but peripheral to the evolved cytosolic chaperone function.
Summary: Manual review: HSC70 has documented nuclear/nucleolar pools, but the nucleus is not the site of its core chaperone, clathrin-uncoating, or CMA functions.
Reason: Valid localization but peripheral to the evolved cytosolic chaperone function.
GO:0045892
negative regulation of DNA-templated transcription
ISS
GO_REF:0000024
KEEP AS NON CORE
Summary: Manual review: negative regulation of DNA-templated transcription may be context-dependent or peripheral for Hspa8.
Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
Summary: Manual review: regulation of cell cycle may be context-dependent or peripheral for Hspa8.
Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
Core Functions
ATP-dependent (EC 3.6.4.10) protein-folding chaperone activity: cyclic, nucleotide-state-dependent binding and release of unfolded/misfolded client polypeptides to assist protein folding, refolding, unfolding and disassembly of protein complexes, with the ATPase cycle regulated by J-domain (HSP40/DNAJ) co-chaperones and nucleotide-exchange factors.
Hspa8/HSC70 is a **constitutive** HSP70-family **ATPase chaperone** that supports proteostasis by assisting **protein folding/refolding**, **unfolding**, and **disassembly of protein complexes**
file:rat/Hspa8/Hspa8-deep-research-falcon.md
nucleotide state controls substrate affinity (ATP-bound low affinity/fast exchange; ADP-bound high affinity/slow exchange)
file:rat/Hspa8/Hspa8-deep-research-falcon.md
J-domain proteins (HSP40/DNAJ)** stimulate ATP hydrolysis through engagement of the nucleotide-binding domain, and nucleotide exchange factors reset the cycle by promoting ADPβATP exchange
Clathrin-uncoating ATPase activity: HSC70, recruited by the J-domain co-chaperone auxilin (DNAJC6), hydrolyzes ATP to disassemble clathrin coats from clathrin-coated vesicles, recycling the pool of free clathrin in clathrin-mediated endocytosis and synaptic vesicle recycling.
the **J-domain co-chaperone auxilin (DNAJC6)** recruits HSC70 to CCVs and **stimulates HSC70 ATPase activity** to disassemble clathrin coats
Chaperone-mediated autophagy: cytosolic HSC70 recognizes KFERQ-like pentapeptide motifs in soluble client proteins and delivers them to LAMP-2A at the lysosomal membrane; lysosomal HSC70 supports substrate translocation into the lysosomal lumen for degradation. In this role HSC70 acts as a cargo selector/adaptor, bringing the client protein together with the LAMP-2A receptor.
recognition of KFERQ-like pentapeptide motifs** in client proteins targeted for **chaperone-mediated autophagy (CMA)**
file:rat/Hspa8/Hspa8-deep-research-falcon.md
Lysosomal HSC70 (LysβHSC70)** facilitates **substrate translocation** into the lysosome lumen
References
file:rat/Hspa8/Hspa8-deep-research-falcon.md
Falcon (Edison Scientific) deep research report: rat Hspa8 (HSC70/HSC73, UniProt P63018)
Hspa8 (UniProt P63018) is the constitutively expressed HSP70-family chaperone HSC70/HSC73, with an N-terminal nucleotide-binding/ATPase domain and a substrate-binding domain with a C-terminal lid whose nucleotide state controls substrate affinity.
"The UniProt accession **P63018** corresponds to **Rattus norvegicus Hspa8**, encoding the constitutively expressed HSP70-family chaperone commonly referred to as **HSC70/HSC73 (HSPA8)**."
The core molecular function is an ATP-dependent chaperone that assists protein folding, refolding, unfolding and disassembly of protein complexes, with the ATP/ADP cycle regulated by J-domain co-chaperones and nucleotide-exchange factors.
"Hspa8/HSC70 is a **constitutive** HSP70-family **ATPase chaperone** that supports proteostasis by assisting **protein folding/refolding**, **unfolding**, and **disassembly of protein complexes**"
A second core role is clathrin-coated vesicle uncoating, in which the J-domain co-chaperone auxilin (DNAJC6) recruits HSC70 and stimulates its ATPase to disassemble clathrin coats.
"the **J-domain co-chaperone auxilin (DNAJC6)** recruits HSC70 to CCVs and **stimulates HSC70 ATPase activity** to disassemble clathrin coats"
A third core role is chaperone-mediated autophagy: HSC70 recognizes KFERQ-like motifs in client proteins selected for CMA.
"recognition of KFERQ-like pentapeptide motifs** in client proteins targeted for **chaperone-mediated autophagy (CMA)**"
Lysosomal HSC70 facilitates substrate translocation into the lysosome lumen during CMA.
"Lysosomal HSC70 (LysβHSC70)** facilitates **substrate translocation** into the lysosome lumen"
The cytosol is the predominant compartment where HSC70 performs general chaperoning and recognizes CMA substrates.
"**Cytosol**: the predominant pool performing general chaperoning and recognizing CMA substrates (KFERQ-like motifs)"
During CMA, the HSC70-substrate complex binds LAMP-2A at the lysosomal membrane and HSC70 helps assemble the translocation complex there, corroborating the experimental lysosomal-membrane localization of HSC70 (GO:0005765) from PMID:18644871.
"The complex binds **LAMPβ2A** at the lysosomal membrane; HSC70 helps **assemble the translocation complex**."
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Increased striatal mRNA and protein levels of the immunophilin FKBP-12 in experimental Parkinson's disease and identification of FKBP-12-binding proteins.
Involvement of peptide antigens in the cytotoxicity between 70-kDa heat shock cognate protein-like molecule and CD3+, CD4-, CD8-, TCR-alpha beta- killer T cells.
Involvement of heat shock elements and basal transcription elements in the differential induction of the 70-kDa heat shock protein and its cognate by cadmium chloride in 9L rat brain tumor cells.
The 70-kDa heat shock cognate protein (Hsc73) gene is enhanced by ovarian hormones in the ventromedial hypothalamus.
Reactome:R-RNO-9613356
Plins bind Hspa8
Reactome:R-RNO-9615712
Hspa8 binds Rnase1
Reactome:R-RNO-9620205
Hspa8:Rnase1 binds Lamp2a
Reactome:R-RNO-9622832
Hspa8 dissociates from Lamp2a-bound substrate
Reactome:R-RNO-9625160
Hspa8 transports unfolded substrate to lysosomal lumen for degradation
Reactome:R-RNO-9625173
Unfolded substrate in Lamp2 multimeric complex binds Hspa8
Reactome:R-RNO-9626028
Hspa8:Substrate dissociates from Lamp2 multimer
Reactome:R-RNO-9626236
Hspa8 dissociates from Lamp2
Reactome:R-RNO-9626239
Hspa8 binds Lamp2 multimers
Reactome:R-RNO-9626254
Hspa8:Lamp2 multimers depolymerizes to monomers
Deep Research
Falcon
(Hspa8-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.FalconEdison Scientific Literature26 citations2 artifacts2026-06-01T00:45:31.576844
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.
Comprehensive Research Report: Rat Hspa8 (Heat shock cognate 71 kDa protein; HSC70/HSC73)
The UniProt accession P63018 corresponds to Rattus norvegicus Hspa8, encoding the constitutively expressed HSP70-family chaperone commonly referred to as HSC70/HSC73 (HSPA8). Recent literature consistently uses HSPA8 β‘ HSC70/HSC73 and describes the canonical HSP70 architecture and ATP-dependent cycle, supporting that the retrieved sources refer to the same protein family/function as UniProt P63018. Structurally, HSC70/HSPA8 is described as having an Nβterminal nucleotide-binding/ATPase domain plus a substrate-binding domain with a Cβterminal lid, whose nucleotide state controls substrate affinity (ATP-bound low affinity/fast exchange; ADP-bound high affinity/slow exchange). (chen2024mechanismandcomplex pages 1-2, adoff2024dnajc13localizationto pages 9-11)
2) Key concepts and definitions (current understanding)
Hspa8/HSC70 is a constitutive HSP70-family ATPase chaperone that supports proteostasis by assisting protein folding/refolding, unfolding, and disassembly of protein complexes, and can triage clients toward degradation pathways. The ATP/ADP cycle is regulated by co-chaperones: J-domain proteins (HSP40/DNAJ) stimulate ATP hydrolysis through engagement of the nucleotide-binding domain, and nucleotide exchange factors reset the cycle by promoting ADPβATP exchange. (chen2024mechanismandcomplex pages 1-2, adoff2024dnajc13localizationto pages 9-11)
2.2 Substrate selection and specificity in selective autophagy: KFERQ-like motifs
A major substrate-selectivity concept relevant to Hspa8 is recognition of KFERQ-like pentapeptide motifs in client proteins targeted for chaperone-mediated autophagy (CMA). This motif-based recognition is central to HSPA8βs role as a cargo selector for CMA. (yao2023chaperoneβmediatedautophagymolecular pages 3-5, yao2023chaperoneβmediatedautophagymolecular pages 1-3, endicott2024chaperonemediatedautophagyas pages 1-2)
2.3 Chaperone-mediated autophagy (CMA): definition and steps
CMA is a selective lysosomal protein degradation pathway (distinct from macroautophagy and microautophagy) in which individual soluble cytosolic proteins are chosen by motif recognition and delivered to the lysosome for translocation and degradation. Current mechanistic understanding emphasizes:
- Cytosolic HSC70/HSPA8 recognizes KFERQ-like motifs and forms a substrateβchaperone complex.
- The complex binds LAMPβ2A at the lysosomal membrane; HSC70 helps assemble the translocation complex.
- Lysosomal HSC70 (LysβHSC70) facilitates substrate translocation into the lysosome lumen.
- Substrates are degraded by lysosomal proteases; the chaperone is released for further cycles.
These steps are summarized in contemporary CMA reviews and schematics. (yao2023chaperoneβmediatedautophagymolecular pages 3-5, yao2023chaperoneβmediatedautophagymolecular pages 1-3, yao2023chaperoneβmediatedautophagymolecular media 2b520f72)
2.4 Clathrin-mediated endocytosis and clathrin-coated vesicle uncoating
A second primary, well-defined functional axis for Hspa8/HSC70 is clathrin-coated vesicle (CCV) uncoating in clathrin-mediated endocytosis (including synaptic vesicle recycling). Mechanistically, the J-domain co-chaperone auxilin (DNAJC6) recruits HSC70 to CCVs and stimulates HSC70 ATPase activity to disassemble clathrin coats, regulating the pool of free clathrin available for trafficking. (chiu2024downregulationofprotease pages 2-3, chiu2024downregulationofprotease pages 1-2)
3) Subcellular localization (where Hspa8 acts)
Across the 2023β2024 sources reviewed, Hspa8/HSC70 is functionally positioned in multiple compartments:
- Cytosol: the predominant pool performing general chaperoning and recognizing CMA substrates (KFERQ-like motifs). (yao2023chaperoneβmediatedautophagymolecular pages 3-5, yao2023chaperoneβmediatedautophagymolecular pages 1-3, endicott2024chaperonemediatedautophagyas pages 1-2)
- Lysosomal membrane/lumen interface: CMA requires delivery to LAMPβ2A and involves lysosomal HSC70 to support substrate translocation. (yao2023chaperoneβmediatedautophagymolecular pages 3-5, yao2023chaperoneβmediatedautophagymolecular media 2b520f72)
- Endocytic trafficking structures: association with clathrin-coated vesicles and AP2-regulated endocytosis; recent work highlights regulation of CCV lifetime by HSC70 phosphorylation/calmodulin in cited 2024 literature. (chen2024mechanismandcomplex pages 7-8, chen2024mechanismandcomplex pages 8-8)
- Cell surface/endocytosis entry sites in infection contexts: in viral entry literature, HSC70/HSPA8 is discussed at the interface of attachment and internalization pathways. (chen2024mechanismandcomplex pages 7-8, chen2024mechanismandcomplex pages 8-8)
4) Pathways and biological processes most directly supported by 2023β2024 literature
4.1 CMA in physiology and disease (metabolism, aging, immunity)
Recent reviews emphasize CMA as a vertebrate proteostasis pathway with broad physiological implications, including metabolism and immunity, with HSPA8 as the cargo-recognizing chaperone and LAMPβ2A as the essential receptor/translocation component. (yao2023chaperoneβmediatedautophagymolecular pages 1-3, endicott2024chaperonemediatedautophagyas pages 1-2)
Expert synthesis / current debate (aging): CMA decline with age has been a frequent model, but a 2023 primary study in genetically heterogeneous UMβHET3 mice found no evidence for age-related changes in LAMP2A levels, CMA substrate uptake, or whole liver levels of CMA targets, while noting sex differencesβhighlighting that CMA aging trajectories may be strain- and context-dependent. The same paper contrasts prior findings in more restricted genetic backgrounds, including reduced CMA substrate uptake in liver lysosomes from 22βmonth-old male Fisherβ344 rats reported in earlier work. (zhang2023lamp2aandother pages 1-2)
4.2 Clathrin uncoating, neuronal maintenance, and lysosome/autophagy coupling
A 2024 mechanistic neuron-focused study (DNAJC6/auxilin knockdown model) provides a pathway-level view linking auxilinβHSC70 uncoating dysfunction to broader homeostatic defects: reduced free clathrin, impaired autophagic lysosome reformation/lysosome number, downregulation of lysosomal cathepsin D, impaired macroautophagy/CMA clearance of pathological Ξ±-synuclein species, and downstream stress responses leading to neuronal degeneration. While HSPA8 itself was not knocked down in this experiment, the work reinforces that HSC70βs clathrin-uncoating activity (through its J-domain partner) is causally tied to lysosome/autophagy competence in dopaminergic neurons. (chiu2024downregulationofprotease pages 2-3, chiu2024downregulationofprotease pages 1-2)
A 2024 review synthesizes evidence that HSC70/HSPA8 contributes to viral entry by participating in endocytic uptake/trafficking pathways (including clathrin-mediated routes) and that post-translational regulation of HSC70 (e.g., phosphorylation patterns) may modulate clathrin-coated vesicle dynamics in relevant trafficking contexts, pointing to HSC70 as a candidate host factor in infection biology. (chen2024mechanismandcomplex pages 7-8, chen2024mechanismandcomplex pages 8-8)
5) Recent developments (prioritizing 2023β2024)
5.1 Mechanistic refinement of CMA and its regulation
A 2023 CMA review consolidates modern mechanistic steps (substrate recognition by HSC70, LAMPβ2A engagement, requirement for lysosomal HSC70 for translocation) and emphasizes the regulatory role of co-chaperones in tuning the HSC70 ATPase cycle during CMA. (yao2023chaperoneβmediatedautophagymolecular pages 3-5)
A 2024 aging-focused CMA review frames CMA as a modulator of aging and longevity, highlighting the centrality of HSPA8 recognition of KFERQ-like motifs and discussing CMAβs intersection with lysosomal dynamics and age-related proteostasis collapse models. (endicott2024chaperonemediatedautophagyas pages 1-2)
Recent (cited) 2024 work discussed in a 2024 review connects HSC70 phosphorylation patterns and calmodulin to AP2 clathrin-coated vesicle life span, pointing toward a signaling-regulated βtunableβ dimension of HSC70-mediated trafficking beyond the classical uncoating step. (chen2024mechanismandcomplex pages 7-8, chen2024mechanismandcomplex pages 8-8)
5.3 Rat-relevant disease biology: post-translational regulation in Huntingtonβs disease
A 2024 rat brain proteomics study (Huntingtonβs model) quantified site-specific ubiquitination changes on HSPA8/HSC70 in rat cortex and striatum, identifying altered ubiquitinated lysines K56, K507, K539. A key quantitative result: ubiquitination at K56 decreased ~16% in cortex and ~73% in striatum in the mutant HTT condition (significant in striatum), with K507 and K539 also decreased in diseased striatum but only minimally changed in cortex. This supports a model in which Hspa8 function in disease may be modulated by tissue-specific PTM remodeling, particularly in the striatum, rather than solely by expression changes. (panda2024elucidationofsitespecific pages 5-7)
6) Current applications and real-world implementations
6.1 Human genetic risk markers (translational genetics)
A 2023 pilot human genetics study evaluated HSPA8 SNPs as ischemic stroke risk markers in 2,139 individuals (888 cases, 1,251 controls). Reported associations included:
- rs10892958 (G): higher ischemic stroke risk in smokers (OR 1.37, 95% CI 1.07β1.77, p=0.01) and in low fruit/vegetable intake (OR 1.36, 95% CI 1.14β1.63, Pbonf=0.002). (kobzeva2023associationbetweenhspa8 pages 1-2, kobzeva2023associationbetweenhspa8 pages 8-9)
- rs1136141 (A): higher risk in smokers (OR 1.68, 95% CI 1.23β2.28, p=7.0Γ10β4) and low fruit/vegetable intake (OR 1.29, 95% CI 1.05β1.60, Pbonf=0.04). (kobzeva2023associationbetweenhspa8 pages 1-2, kobzeva2023associationbetweenhspa8 pages 8-9)
The same study reports functional annotation/eQTL evidence for rs10892958βG associated with decreased HSPA8 expression in BrainβHippocampus (beta β0.44; p=1.9Γ10β7; FDR 5.8Γ10β5), supporting a plausible gene-regulatory mechanism. (kobzeva2023associationbetweenhspa8 pages 8-9)
Although this is not rat-specific, it represents real-world movement toward using HSPA8-related variation as a clinical risk-modifier and illustrates why Hspa8 biology is actively studied in mammalian disease contexts. (kobzeva2023associationbetweenhspa8 pages 1-2, kobzeva2023associationbetweenhspa8 pages 8-9)
A 2024 in silico study explored disrupting a SARS-CoV-2 spikeβHSPA8 interaction and reported docking metrics for candidate compounds, including NSC36398 with docking score β7.934 kcal/mol (binding free energy β39.52 kcal/mol) against spike and β8.029 kcal/mol (β38.61 kcal/mol) against the spikeβHSPA8 complex. While purely computational, it exemplifies a therapeutic strategy in which HSPA8-related interactions are targeted to modulate disease processes. (navhaya2024insilicodiscovery pages 1-2)
7) Relevant statistics and data highlights (2023β2024)
Rat Huntingtonβs disease PTM remodeling: HSPA8 ubiquitination at K56 decreased ~16% (cortex) and ~73% (striatum) in mutant HTT conditions; additional striatum-specific decreases at K507 and K539. (panda2024elucidationofsitespecific pages 5-7)
CMA aging heterogeneity: UMβHET3 mice showed no age-related decline in LAMP2A, CMA substrate uptake, or CMA target abundance; the same paper contrasts earlier reports of reduced CMA substrate uptake in 22βmonth male Fisherβ344 rat liver lysosomes. (zhang2023lamp2aandother pages 1-2)
Ischemic stroke genetics (human): rs10892958βG and rs1136141βA show ORs ~1.29β1.68 depending on subgroup, with multiple significant p-values and Bonferroni-corrected results; rs10892958βG linked to reduced HSPA8 expression in hippocampus (beta β0.44). (kobzeva2023associationbetweenhspa8 pages 1-2, kobzeva2023associationbetweenhspa8 pages 8-9)
8) Mechanism schematic (visual evidence)
The following figure schematizes the CMA pathway centered on HSC70/HSPA8 and LAMPβ2A, including recognition of KFERQ-like substrates, receptor engagement, translocation, and lysosomal degradation. (yao2023chaperoneβmediatedautophagymolecular media 2b520f72)
Rat Hspa8 (UniProt P63018) encodes a ubiquitous HSP70-family ATP-dependent chaperone whose most directly supported mechanistic roles in recent literature are:
1. ATPase-driven chaperone cycling governing client binding/release and co-chaperone-regulated proteostasis decisions. (chen2024mechanismandcomplex pages 1-2, adoff2024dnajc13localizationto pages 9-11)
2. CMA substrate selection and delivery via KFERQ-like motif recognition and cooperation with LAMPβ2A and lysosomal HSC70 to achieve translocation and lysosomal degradation. (yao2023chaperoneβmediatedautophagymolecular pages 3-5, yao2023chaperoneβmediatedautophagymolecular pages 1-3, yao2023chaperoneβmediatedautophagymolecular media 2b520f72)
3. Clathrin-coated vesicle uncoating through J-domain cochaperones (notably auxilin/DNAJC6) that stimulate HSC70 ATPase to disassemble clathrin coats; this trafficking role is coupled to lysosome/autophagy maintenance in neuronal systems. (chiu2024downregulationofprotease pages 2-3, chiu2024downregulationofprotease pages 1-2)
Direct rat-specific primary evidence in the retrieved 2023β2024 set is strongest for post-translational regulation in rat brain (Huntingtonβs model) via site-specific ubiquitination changes, and indirect rat-specific context appears in CMA aging assays performed historically in rat liver lysosomes (contrasted against newer genetically heterogeneous mouse findings). (zhang2023lamp2aandother pages 1-2, panda2024elucidationofsitespecific pages 5-7)
Source list (URLs and publication dates as available in evidence)
Yao R, Shen J. Chaperone-mediated autophagy: Molecular mechanisms, biological functions, and diseases.MedComm, Aug 2023. https://doi.org/10.1002/mco2.347 (yao2023chaperoneβmediatedautophagymolecular pages 3-5, yao2023chaperoneβmediatedautophagymolecular pages 1-3)
Zhang KK et al. LAMP2A, and other chaperone-mediated autophagy related proteins, do not decline with age in genetically heterogeneous UM-HET3 mice.Aging (Albany NY), Jun 2023. https://doi.org/10.18632/aging.204796 (zhang2023lamp2aandother pages 1-2)
Endicott SJ. Chaperone-mediated autophagy as a modulator of aging and longevity.Frontiers in Aging, Dec 2024. https://doi.org/10.3389/fragi.2024.1509400 (endicott2024chaperonemediatedautophagyas pages 1-2)
Chen Q et al. Mechanism and complex roles of HSC70/HSPA8 in viral entry.Virus Research, Sep 2024. https://doi.org/10.1016/j.virusres.2024.199433 (chen2024mechanismandcomplex pages 1-2, chen2024mechanismandcomplex pages 7-8)
Chiu C-C et al. Downregulation of Protease Cathepsin D and Upregulation of Pathologic Ξ±-Synuclein Mediate Paucity of DNAJC6-Induced Degeneration of Dopaminergic Neurons.Int J Mol Sci, Jun 2024. https://doi.org/10.3390/ijms25126711 (chiu2024downregulationofprotease pages 2-3, chiu2024downregulationofprotease pages 1-2)
Panda P et al. Elucidation of site-specific ubiquitination on chaperones in response to mutant huntingtin.Cellular and Molecular Neurobiology, Dec 2024. https://doi.org/10.1007/s10571-023-01446-1 (panda2024elucidationofsitespecific pages 5-7)
Kobzeva KA et al. Association between HSPA8 Gene Variants and Ischemic Stroke: A Pilot Studyβ¦Genes, May 2023. https://doi.org/10.3390/genes14061171 (kobzeva2023associationbetweenhspa8 pages 1-2, kobzeva2023associationbetweenhspa8 pages 8-9)
Navhaya LT et al. In Silico Discovery and Evaluation of Inhibitors of the SARS-CoV-2 Spike ProteinβHSPA8 Complexβ¦Viruses, Oct 2024. https://doi.org/10.3390/v16111726 (navhaya2024insilicodiscovery pages 1-2)
Adoff H et al. DNAJC13 localization to endosomes is opposed by its J domainβ¦bioRxiv, Dec 2024. https://doi.org/10.1101/2024.12.19.629517 (adoff2024dnajc13localizationto pages 9-11)
References
(chen2024mechanismandcomplex pages 1-2): Qiaoqiao Chen, Yiwen Chen, Chenxuan Bao, Huayuan Xiang, Qing Gao, and Lingxiang Mao. Mechanism and complex roles of hsc70/hspa8 in viral entry. Sep 2024. URL: https://doi.org/10.1016/j.virusres.2024.199433, doi:10.1016/j.virusres.2024.199433. This article has 8 citations and is from a peer-reviewed journal.
(adoff2024dnajc13localizationto pages 9-11): Hayden Adoff, Brandon Novy, Emily Holland, and Braden T Lobingier. Dnajc13 localization to endosomes is opposed by its j domain and its disordered c-terminal tail. bioRxiv, Dec 2024. URL: https://doi.org/10.1101/2024.12.19.629517, doi:10.1101/2024.12.19.629517. This article has 0 citations.
(yao2023chaperoneβmediatedautophagymolecular pages 3-5): Ruchen Yao and Jun Shen. Chaperoneβmediated 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.
(yao2023chaperoneβmediatedautophagymolecular pages 1-3): Ruchen Yao and Jun Shen. Chaperoneβmediated 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.
(endicott2024chaperonemediatedautophagyas pages 1-2): S. Joseph Endicott. Chaperone-mediated autophagy as a modulator of aging and longevity. Frontiers in Aging, Dec 2024. URL: https://doi.org/10.3389/fragi.2024.1509400, doi:10.3389/fragi.2024.1509400. This article has 10 citations.
(yao2023chaperoneβmediatedautophagymolecular media 2b520f72): Ruchen Yao and Jun Shen. Chaperoneβmediated 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.
(chiu2024downregulationofprotease pages 2-3): Ching-Chi Chiu, Ying-ling Chen, Yi-Hsin Weng, Shu-Yu Liu, Hon-Lun Li, Tu-Hsueh Yeh, and Hung-Li Wang. Downregulation of protease cathepsin d and upregulation of pathologic Ξ±-synuclein mediate paucity of dnajc6-induced degeneration of dopaminergic neurons. International Journal of Molecular Sciences, 25:6711, Jun 2024. URL: https://doi.org/10.3390/ijms25126711, doi:10.3390/ijms25126711. This article has 10 citations.
(chiu2024downregulationofprotease pages 1-2): Ching-Chi Chiu, Ying-ling Chen, Yi-Hsin Weng, Shu-Yu Liu, Hon-Lun Li, Tu-Hsueh Yeh, and Hung-Li Wang. Downregulation of protease cathepsin d and upregulation of pathologic Ξ±-synuclein mediate paucity of dnajc6-induced degeneration of dopaminergic neurons. International Journal of Molecular Sciences, 25:6711, Jun 2024. URL: https://doi.org/10.3390/ijms25126711, doi:10.3390/ijms25126711. This article has 10 citations.
(chen2024mechanismandcomplex pages 7-8): Qiaoqiao Chen, Yiwen Chen, Chenxuan Bao, Huayuan Xiang, Qing Gao, and Lingxiang Mao. Mechanism and complex roles of hsc70/hspa8 in viral entry. Sep 2024. URL: https://doi.org/10.1016/j.virusres.2024.199433, doi:10.1016/j.virusres.2024.199433. This article has 8 citations and is from a peer-reviewed journal.
(chen2024mechanismandcomplex pages 8-8): Qiaoqiao Chen, Yiwen Chen, Chenxuan Bao, Huayuan Xiang, Qing Gao, and Lingxiang Mao. Mechanism and complex roles of hsc70/hspa8 in viral entry. Sep 2024. URL: https://doi.org/10.1016/j.virusres.2024.199433, doi:10.1016/j.virusres.2024.199433. This article has 8 citations and is from a peer-reviewed journal.
(zhang2023lamp2aandother pages 1-2): Katherine K. Zhang, Peichuan Zhang, Anagha Kodur, Ilkim Erturk, Calvin M. Burns, Cynthia Kenyon, Richard A. Miller, and S. Joseph Endicott. Lamp2a, and other chaperone-mediated autophagy related proteins, do not decline with age in genetically heterogeneous um-het3 mice. Aging (Albany NY), 15:4685-4698, Jun 2023. URL: https://doi.org/10.18632/aging.204796, doi:10.18632/aging.204796. This article has 8 citations.
(panda2024elucidationofsitespecific pages 5-7): Prajnadipta Panda, Vivek Sarohi, Trayambak Basak, and Prasad Kasturi. Elucidation of site-specific ubiquitination on chaperones in response to mutant huntingtin. Cellular and molecular neurobiology, 44 1:3, Dec 2024. URL: https://doi.org/10.1007/s10571-023-01446-1, doi:10.1007/s10571-023-01446-1. This article has 8 citations and is from a peer-reviewed journal.
(kobzeva2023associationbetweenhspa8 pages 1-2): Ksenia A. Kobzeva, Maria O. Soldatova, Tatiana A. Stetskaya, Vladislav O. Soldatov, Alexey V. Deykin, Maxim B. Freidin, Marina A. Bykanova, Mikhail I. Churnosov, Alexey V. Polonikov, and Olga Y. Bushueva. Association between hspa8 gene variants and ischemic stroke: a pilot study providing additional evidence for the role of heat shock proteins in disease pathogenesis. Genes, 14:1171, May 2023. URL: https://doi.org/10.3390/genes14061171, doi:10.3390/genes14061171. This article has 16 citations.
(kobzeva2023associationbetweenhspa8 pages 8-9): Ksenia A. Kobzeva, Maria O. Soldatova, Tatiana A. Stetskaya, Vladislav O. Soldatov, Alexey V. Deykin, Maxim B. Freidin, Marina A. Bykanova, Mikhail I. Churnosov, Alexey V. Polonikov, and Olga Y. Bushueva. Association between hspa8 gene variants and ischemic stroke: a pilot study providing additional evidence for the role of heat shock proteins in disease pathogenesis. Genes, 14:1171, May 2023. URL: https://doi.org/10.3390/genes14061171, doi:10.3390/genes14061171. This article has 16 citations.
(navhaya2024insilicodiscovery pages 1-2): Liberty T. Navhaya, Thabe M. Matsebatlela, Mokgerwa Z. Monama, and Xolani H. Makhoba. In silico discovery and evaluation of inhibitors of the sars-cov-2 spike proteinβhspa8 complex towards developing covid-19 therapeutic drugs. Viruses, 16:1726, Oct 2024. URL: https://doi.org/10.3390/v16111726, doi:10.3390/v16111726. This article has 9 citations.
I begin with the InterPro architecture. The N-terminus carries IPR043129 (ATPase, nucleotide binding domain homologous_superfamily, residues 5β382), which establishes a P-loop NBD that binds and hydrolyzes ATP. This region overlaps with IPR013126 (Heat shock protein 70 family, residues 6β612) and IPR018181 (Heat shock protein 70, conserved site, residues 9β348), reinforcing that the NBD is characteristic of Hsp70-class chaperones and dictates ATP-coupled conformational switching. Immediately downstream, the polypeptide transitions into IPR029047 (Heat shock protein 70kD, peptide-binding domain superfamily, residues 383β543), defining the canonical substrate-binding domain that clamps non-native polypeptides. The C-terminus is annotated by IPR029048 (Heat shock protein 70kD, C-terminal domain superfamily, residues 532β646), which forms the βlidβ and often encodes regulatory motifs that tune cochaperone interactions. The ordered layoutβNBD (5β382), followed by peptide-binding core (383β543) and C-terminal lid (532β646)βis the textbook Hsp70 architecture that couples ATP hydrolysis to high- and low-affinity states for unfolded protein binding.
This domain arrangement causes three core molecular functions. First, the NBD mandates GO:0005524 ATP binding and supports ATP hydrolysis that powers allostery. Second, the peptide-binding domain and lid directly produce GO:0051082 unfolded protein binding by capturing exposed hydrophobic segments of non-native substrates. Third, the integrated Hsp70 scaffold supports multivalent GO:0005515 protein binding, including interactions with J-domain cochaperones and nucleotide-exchange factors.
Coupling ATP-driven conformational cycles to substrate capture mechanistically yields protein folding and refolding. Thus, the architecture inherently drives GO:0006457 protein folding, including ATP-dependent cycles that stabilize native states and rescue stress-denatured proteins. Because this cycle is particularly engaged during thermal and proteotoxic stress, the same mechanism underlies cellular recovery pathways often formalized as cellular response to unfolded protein and stress, but the core, specific process here is protein folding.
Cellular location follows from function and regulation. Hsp70 chaperones typically operate in soluble compartments and shuttle between cytosol and nucleus depending on demand. The absence of transmembrane segments and the soluble chaperone architecture support a non-membranous localization. Consequently, the protein resides in the cytoplasm and transits to the nucleus; this corresponds to GO:0005737 cytoplasm and GO:0005634 nucleus, matching its role in cytosolic proteostasis and nuclear protein quality control.
These features suggest a mechanism and partners. The NBD and conserved Hsp70 motifs recruit J-domain cochaperones that stimulate ATP hydrolysis and target specific substrates; the peptide-binding domain and lid hold substrates until nucleotide exchange factors release them. Therefore, likely interaction partners include J-domain proteins (e.g., DNAJ/Hsp40 family) that deliver clients, and nucleotide-exchange factors that accelerate ADP release. Downstream, cooperation with other chaperones such as Hsp90 and small heat shock proteins would funnel clients through hierarchical folding pathways. In the cytoplasm and nucleus, this ensemble triages nascent and stress-labile proteins, ensuring folding fidelity and preventing aggregation.
Functional Summary
An ATP-dependent molecular chaperone that cycles between ATP-bound and ADP-bound states to capture and release non-native polypeptides, thereby promoting folding and refolding of stress-labile proteins in the cytoplasm and nucleus. Its N-terminal nucleotide-binding module powers conformational switching, a central peptide-binding region secures unfolded clients, and a C-terminal lid regulates substrate dwell time. Through coordinated action with cochaperones and exchange factors, it maintains proteostasis and restores native structures after stress.
UniProt Summary
Molecular chaperone implicated in a wide variety of cellular processes, including protection of the proteome from stress, folding and transport of proteins, assembly of molecular complexes, and modulation of protein degradation.
Biological Process: biological_process (GO:0008150), localization (GO:0051179), positive regulation of biological process (GO:0048518), regulation of biological process (GO:0050789), reproduction (GO:0000003), multicellular organismal process (GO:0032501), biological regulation (GO:0065007), rhythmic process (GO:0048511), response to stimulus (GO:0050896), developmental process (GO:0032502), cellular process (GO:0009987), metabolic process (GO:0008152), reproductive process (GO:0022414), negative regulation of biological process (GO:0048519), response to external stimulus (GO:0009605), cellular localization (GO:0051641), anatomical structure development (GO:0048856), transmembrane transport (GO:0055085), response to chemical (GO:0042221), cell cycle process (GO:0022402), nitrogen compound metabolic process (GO:0006807), positive regulation of immune system process (GO:0002684), cellular component organization or biogenesis (GO:0071840), multicellular organism reproduction (GO:0032504), positive regulation of transport (GO:0051050), regulation of biological quality (GO:0065008), response to endogenous stimulus (GO:0009719), regulation of cellular process (GO:0050794), regulation of response to stimulus (GO:0048583), cellular response to stimulus (GO:0051716), process utilizing autophagic mechanism (GO:0061919), aging (GO:0007568), negative regulation of cellular process (GO:0048523), response to abiotic stimulus (GO:0009628), multicellular organism development (GO:0007275), positive regulation of response to stimulus (GO:0048584), regulation of metabolic process (GO:0019222), regulation of localization (GO:0032879), cell cycle (GO:0007049), establishment of localization (GO:0051234), regulation of immune system process (GO:0002682), organic substance metabolic process (GO:0071704), response to activity (GO:0014823), catabolic process (GO:0009056), system process (GO:0003008), macromolecule localization (GO:0033036), cellular metabolic process (GO:0044237), ovulation cycle (GO:0042698), protein folding (GO:0006457), positive regulation of metabolic process (GO:0009893), regulation of molecular function (GO:0065009), response to stress (GO:0006950), microtubule-based process (GO:0007017), multicellular organismal reproductive process (GO:0048609), negative regulation of response to stimulus (GO:0048585), primary metabolic process (GO:0044238), positive regulation of cellular process (GO:0048522), response to temperature stimulus (GO:0009266), negative regulation of cell death (GO:0060548), response to xenobiotic stimulus (GO:0009410), regulation of response to stress (GO:0080134), cellular catabolic process (GO:0044248), system development (GO:0048731), animal organ development (GO:0048513), positive regulation of phagocytosis (GO:0050766), regulation of macromolecule metabolic process (GO:0060255), regulation of vesicle-mediated transport (GO:0060627), estrous cycle (GO:0044849), response to hormone (GO:0009725), establishment of protein localization (GO:0045184), autophagy (GO:0006914), phosphorus metabolic process (GO:0006793), response to heat (GO:0009408), regulation of cell killing (GO:0031341), cerebellum development (GO:0021549), response to inorganic substance (GO:0010035), intracellular transport (GO:0046907), regulation of immune effector process (GO:0002697), forebrain development (GO:0030900), protein transmembrane transport (GO:0071806), response to odorant (GO:1990834), regulation of nitrogen compound metabolic process (GO:0051171), positive regulation of immune response (GO:0050778), cellular component organization (GO:0016043), organic substance catabolic process (GO:1901575), positive regulation of nitrogen compound metabolic process (GO:0051173), regulation of membrane permeability (GO:0090559), regulation of catalytic activity (GO:0050790), positive regulation of molecular function (GO:0044093), regulation of transport (GO:0051049), organonitrogen compound metabolic process (GO:1901564), mitotic cell cycle process (GO:1903047), positive regulation of macromolecule metabolic process (GO:0010604), protein metabolic process (GO:0019538), positive regulation of cell killing (GO:0031343), regulation of cellular response to stress (GO:0080135), hindbrain development (GO:0030902), establishment of localization in cell (GO:0051649), response to oxygen-containing compound (GO:1901700), chaperone-mediated protein folding (GO:0061077), metencephalon development (GO:0022037), macromolecule metabolic process (GO:0043170), response to organic substance (GO:0010033), microtubule-based movement (GO:0007018), response to extracellular stimulus (GO:0009991), muscle structure development (GO:0061061), negative regulation of response to oxidative stress (GO:1902883), regulation of immune response (GO:0050776), response to starvation (GO:0042594), regulation of cell death (GO:0010941), tissue development (GO:0009888), head development (GO:0060322), cellular response to stress (GO:0033554), cellular response to chemical stimulus (GO:0070887), transport (GO:0006810), cell cycle phase transition (GO:0044770), cellular macromolecule localization (GO:0070727), nervous system process (GO:0050877), positive regulation of immune effector process (GO:0002699), regulation of primary metabolic process (GO:0080090), mitotic cell cycle (GO:0000278), response to alcohol (GO:0097305), nitrogen compound transport (GO:0071705), response to ketone (GO:1901654), response to estradiol (GO:0032355), cell cycle G1/S phase transition (GO:0044843), regulation of protein metabolic process (GO:0051246), negative regulation of programmed cell death (GO:0043069), regulation of programmed cell death (GO:0043067), regulation of leukocyte mediated immunity (GO:0002703), cytoskeleton-dependent intracellular transport (GO:0030705), protein catabolic process (GO:0030163), cellular component maintenance (GO:0043954), negative regulation of response to reactive oxygen species (GO:1901032), response to steroid hormone (GO:0048545), organic substance transport (GO:0071702), nuclear transport (GO:0051169), positive regulation of leukocyte mediated immunity (GO:0002705), protein transmembrane import into intracellular organelle (GO:0044743), microtubule-based transport (GO:0099111), regulation of gene expression (GO:0010468), positive regulation of leukocyte mediated cytotoxicity (GO:0001912), regulation of cellular response to oxidative stress (GO:1900407), brain development (GO:0007420), macromolecule catabolic process (GO:0009057), synaptic vesicle cycle (GO:0099504), intracellular protein transport (GO:0006886), macromolecule modification (GO:0043412), nervous system development (GO:0007399), regulation of oxidative stress-induced cell death (GO:1903201), protein transport (GO:0015031), response to nutrient levels (GO:0031667), regulation of response to oxidative stress (GO:1902882), cellular response to heat (GO:0034605), central nervous system development (GO:0007417), protein-containing complex organization (GO:0043933), positive regulation of catalytic activity (GO:0043085), cellular component disassembly (GO:0022411), regulation of adaptive immune response (GO:0002819), membrane organization (GO:0061024), response to metal ion (GO:0010038), renal system development (GO:0072001), synaptic vesicle recycling (GO:0036465), transport along microtubule (GO:0010970), organonitrogen compound catabolic process (GO:1901565), establishment of protein localization to organelle (GO:0072594), positive regulation of membrane permeability (GO:1905710), positive regulation of gene expression (GO:0010628), phosphate-containing compound metabolic process (GO:0006796), negative regulation of oxidative stress-induced cell death (GO:1903202), sensory perception (GO:0007600), protein modification process (GO:0036211), mitotic cell cycle phase transition (GO:0044772), regulation of phagocytosis (GO:0050764), presynaptic endocytosis (GO:0140238), cellular response to inorganic substance (GO:0071241), regulation of leukocyte mediated cytotoxicity (GO:0001910), response to lipid (GO:0033993), muscle tissue development (GO:0060537), positive regulation of protein metabolic process (GO:0051247), positive regulation of adaptive immune response (GO:0002821), vesicle-mediated transport (GO:0016192), protein localization (GO:0008104), response to organic cyclic compound (GO:0014070), postsynapse organization (GO:0099173), muscle organ development (GO:0007517), organelle organization (GO:0006996), cell junction organization (GO:0034330), kidney development (GO:0001822), protein import into nucleus (GO:0006606), response to nickel cation (GO:0010045), regulation of apoptotic process (GO:0042981), regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains (GO:0002822), response to ethanol (GO:0045471), regulation of proteolysis (GO:0030162), regulation of response to reactive oxygen species (GO:1901031), phosphorylation (GO:0016310), skeletal muscle tissue development (GO:0007519), response to progesterone (GO:0032570), G1/S transition of mitotic cell cycle (GO:0000082), vesicle-mediated transport in synapse (GO:0099003), response to cadmium ion (GO:0046686), regulation of hydrogen peroxide-induced cell death (GO:1903205), positive regulation of T cell mediated cytotoxicity (GO:0001916), nucleocytoplasmic transport (GO:0006913), protein localization to organelle (GO:0033365), positive regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains (GO:0002824), positive regulation of lymphocyte mediated immunity (GO:0002708), skeletal muscle organ development (GO:0060538), axo-dendritic transport (GO:0008088), negative regulation of apoptotic process (GO:0043066), synaptic vesicle endocytosis (GO:0048488), protein phosphorylation (GO:0006468), sensory perception of chemical stimulus (GO:0007606), postsynaptic specialization organization (GO:0099084), cell junction maintenance (GO:0034331), regulation of T cell mediated cytotoxicity (GO:0001914), negative regulation of hydrogen peroxide-induced cell death (GO:1903206), cellular response to metal ion (GO:0071248), positive regulation of proteolysis (GO:0045862), vacuole organization (GO:0007033), endocytosis (GO:0006897), regulation of lymphocyte mediated immunity (GO:0002706), protein-containing complex disassembly (GO:0032984), synapse organization (GO:0050808), protein localization to nucleus (GO:0034504), import into nucleus (GO:0051170), regulation of muscle cell apoptotic process (GO:0010660), postsynaptic density organization (GO:0097106), regulation of T cell mediated immunity (GO:0002709), sensory perception of smell (GO:0007608), cellular response to cadmium ion (GO:0071276), protein depolymerization (GO:0051261), positive regulation of T cell mediated immunity (GO:0002711), maintenance of synapse structure (GO:0099558), lytic vacuole organization (GO:0080171), negative regulation of muscle cell apoptotic process (GO:0010656), protein autophosphorylation (GO:0046777), regulation of striated muscle cell apoptotic process (GO:0010662), negative regulation of striated muscle cell apoptotic process (GO:0010664), lysosome organization (GO:0007040), negative regulation of cardiac muscle cell apoptotic process (GO:0010667), regulation of cardiac muscle cell apoptotic process (GO:0010665)
An ATP-dependent molecular chaperone that cycles between ATP-bound and ADP-bound states to capture and release non-native polypeptides, thereby promoting folding and refolding of stress-labile proteins in the cytoplasm and nucleus. Its N-terminal nucleotide-binding module powers conformational switching, a central peptide-binding region secures unfolded clients, and a C-terminal lid regulates substrate dwell time. Through coordinated action with cochaperones and exchange factors, it maintains proteostasis and restores native structures after stress.
This is accurate and consistent with the curated review. The ai-review.yaml confirms ATP hydrolysis activity (GO:0016887), protein folding chaperone (GO:0044183), unfolded protein binding (GO:0051082), protein refolding (GO:0042026), heat shock protein binding (GO:0031072), cytoplasm (GO:0005737), cytosol (GO:0005829), and nucleus (GO:0005634).
The description of the Hsp70 chaperone cycle (ATP/ADP states, conformational switching, co-chaperone coordination) is mechanistically sound and matches the UniProt summary.
However, the BioReason summary misses several important and distinctive functions of Hspa8/Hsc70. The curated review includes clathrin coat disassembly (GO:0072318), which is a hallmark function of Hsc70 that distinguishes it from inducible Hsp70. Hspa8 is also annotated for autophagy (GO:0006914) via chaperone-mediated autophagy (CMA), lysosomal membrane association (GO:0005765), plasma membrane (GO:0005886), and signal transduction (GO:0007165, kept as non-core). These represent the distinctive biology of the constitutive Hsc70 isoform versus general Hsp70 function.
The BioReason summary reads as a generic Hsp70 description that could apply equally to any Hsp70 family member. It does not capture the specific identity of Hspa8 as the constitutive cognate chaperone with unique roles in clathrin uncoating and CMA.
Comparison with interpro2go:
There are no GO_REF:0000002 annotations in the Hspa8 ai-review.yaml. BioReason's summary derives from the standard Hsp70 family domains (IPR013126, IPR018181, IPR043129, IPR029047, IPR029048). The inferences are correct but generic -- they match what any Hsp70 domain-based mapping would produce. BioReason does not add specificity beyond interpro2go-level annotation for distinguishing Hspa8 from other Hsp70 family members.
Notes on thinking trace
The trace is solid but formulaic. It correctly describes the three-domain Hsp70 architecture and derives appropriate molecular functions. The hypothesized interaction partners (DNAJ/Hsp40 family, nucleotide exchange factors, Hsp90) are accurate. However, the trace lacks any mention of clathrin uncoating or CMA -- functions that are specific to the constitutive Hsc70 and well-established in the literature.
π View Raw YAML
id: P63018
gene_symbol: Hspa8
product_type: PROTEIN
status: DRAFT
taxon:
id: NCBITaxon:10116
label: Rattus norvegicus
description: >-
Hspa8 (UniProt P63018; HSP7C_RAT) encodes the rat Heat shock cognate 71 kDa
protein, the constitutively expressed cytosolic HSP70-family chaperone known as
HSC70/HSC73. Unlike the stress-inducible Hspa1a/Hspa1b (HSP70) paralogs, HSC70 is
expressed under basal conditions and is the housekeeping HSP70. Its core molecular
function is an ATP-dependent (EC 3.6.4.10) protein-folding chaperone activity built
on the canonical HSP70 architecture: an N-terminal nucleotide-binding/ATPase domain
and a C-terminal substrate-binding domain with a helical lid, whose nucleotide state
(ATP = low affinity/fast client exchange; ADP = high affinity) governs cyclic binding
and release of unfolded/misfolded client polypeptides. The ATPase cycle is driven by
J-domain (HSP40/DNAJ) co-chaperones that stimulate ATP hydrolysis and reset by
nucleotide-exchange factors. Three best-supported, mechanistically distinct roles
emerge: (1) general proteostasis - protein folding, refolding, unfolding and
disassembly of protein complexes; (2) clathrin-coated vesicle uncoating - the
clathrin-uncoating ATPase activity in which the J-domain co-chaperone auxilin
(DNAJC6) recruits HSC70 to clathrin-coated vesicles and stimulates its ATPase to
disassemble clathrin coats, central to clathrin-mediated endocytosis and synaptic
vesicle recycling; and (3) chaperone-mediated autophagy (CMA) - cytosolic HSC70
recognizes KFERQ-like pentapeptide motifs in soluble client proteins and delivers
them to LAMP-2A at the lysosomal membrane, with lysosomal HSC70 supporting
translocation into the lysosomal lumen for degradation. HSC70 acts predominantly in
the cytosol, with additional functional pools at the lysosomal membrane/lumen and
at endocytic/synaptic trafficking structures. It is a highly pleiotropic protein;
many of its annotated processes and locations reflect this pleiotropy rather than its
evolved core function.
existing_annotations:
- term:
id: GO:0005634
label: nucleus
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'Manual review: HSC70 has documented nuclear/nucleolar pools (e.g. nuclear import roles), but the nucleus is not the site of its core chaperone, clathrin-uncoating, or CMA functions.'
action: KEEP_AS_NON_CORE
reason: Valid localization but peripheral to the evolved cytosolic chaperone function.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'Manual review: cytoplasm is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'Manual review: plasma membrane is not the site of the core chaperone function of HSC70, which acts in the cytosol; surface/extracellular pools are context-specific (e.g. exosomal/cell-surface) and do not represent the evolved function.'
action: MARK_AS_OVER_ANNOTATED
reason: Localization over-annotation; the core HSC70 function is cytosolic, not at the plasma membrane.
- term:
id: GO:0016887
label: ATP hydrolysis activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'Manual review: ATP hydrolysis activity underpins the ATP-dependent chaperone cycle of Hspa8/HSC70, in which the nucleotide state controls client affinity and is regulated by J-domain co-chaperones.'
action: ACCEPT
reason: Retained as supporting the core ATP-driven chaperone cycle, corroborated by falcon deep research.
supported_by:
- reference_id: file:rat/Hspa8/Hspa8-deep-research-falcon.md
reference_section_type: OTHER
supporting_text: |-
nucleotide state controls substrate affinity (ATP-bound low affinity/fast exchange; ADP-bound high affinity/slow exchange)
- term:
id: GO:0031072
label: heat shock protein binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'Manual review: heat shock protein binding is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0044183
label: protein folding chaperone
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'Manual review: protein folding chaperone is the core molecular function of Hspa8/HSC70; the constitutive HSP70-family ATP-dependent chaperone that assists folding, refolding, unfolding and complex disassembly of client proteins.'
action: ACCEPT
reason: Retained as the core molecular function, corroborated by falcon deep research.
supported_by:
- reference_id: file:rat/Hspa8/Hspa8-deep-research-falcon.md
reference_section_type: OTHER
supporting_text: |-
Hspa8/HSC70 is a **constitutive** HSP70-family **ATPase chaperone** that supports proteostasis by assisting **protein folding/refolding**, **unfolding**, and **disassembly of protein complexes**
- term:
id: GO:0005829
label: cytosol
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'Manual review: cytosol is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0072318
label: clathrin coat disassembly
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'Manual review: clathrin coat disassembly is a core process for Hspa8/HSC70; the auxilin (DNAJC6)-recruited HSC70 ATPase disassembles clathrin coats from clathrin-coated vesicles.'
action: ACCEPT
reason: Retained as a core process, corroborated by falcon deep research.
supported_by:
- reference_id: file:rat/Hspa8/Hspa8-deep-research-falcon.md
reference_section_type: OTHER
supporting_text: |-
the **J-domain co-chaperone auxilin (DNAJC6)** recruits HSC70 to CCVs and **stimulates HSC70 ATPase activity** to disassemble clathrin coats
- term:
id: GO:0042026
label: protein refolding
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'Manual review: protein refolding is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0007165
label: signal transduction
evidence_type: IEA
original_reference_id: GO_REF:0000108
review:
summary: 'Manual review: signal transduction is an over-broad inter-ontology IEA inference; HSC70 is a chaperone and does not act as a signal transducer. This generic term over-annotates the gene.'
action: MARK_AS_OVER_ANNOTATED
reason: Over-broad IEA inference that does not reflect the evolved chaperone function of HSC70.
- term:
id: GO:0000166
label: nucleotide binding
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: 'Manual review: nucleotide binding is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0001916
label: positive regulation of T cell mediated cytotoxicity
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: 'Manual review: positive regulation of T cell mediated cytotoxicity may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005524
label: ATP binding
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: 'Manual review: ATP binding is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0005681
label: spliceosomal complex
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: 'Manual review: spliceosomal complex may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005730
label: nucleolus
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: 'Manual review: nucleolus may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: 'Manual review: cytoplasm is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0005765
label: lysosomal membrane
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: 'Manual review: the lysosomal membrane is a functional location of the core chaperone-mediated autophagy role of HSC70, where the chaperone-substrate complex engages LAMP-2A; this electronic annotation is consistent with the experimentally supported IDA annotations to the same term.'
action: ACCEPT
reason: Lysosomal membrane is a bona fide functional location for the core CMA role of HSC70 (experimentally supported by PMID:18644871 and PMID:9038169); accepted for consistency with those IDA annotations.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: 'Manual review: plasma membrane is not the site of the core chaperone function of HSC70; surface/extracellular pools are context-specific and do not represent the evolved function.'
action: MARK_AS_OVER_ANNOTATED
reason: Localization over-annotation; the core HSC70 function is cytosolic, not at the plasma membrane.
- term:
id: GO:0006397
label: mRNA processing
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: 'Manual review: mRNA processing may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0006914
label: autophagy
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: 'Manual review: autophagy may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0008289
label: lipid binding
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: 'Manual review: lipid binding may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0008380
label: RNA splicing
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: 'Manual review: RNA splicing may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0016787
label: hydrolase activity
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: 'Manual review: HSC70 is indeed a hydrolase (an ATPase, EC 3.6.4.10), so GO:0016787 is not factually wrong, but it is an over-broad parent term. The more specific GO:0016887 (ATP hydrolysis activity) is already ACCEPTed and captures the actual catalytic function.'
action: MARK_AS_OVER_ANNOTATED
reason: GO:0016887 (ATP hydrolysis activity) is already ACCEPTed and is more specific; GO:0016787 (hydrolase activity) is the over-broad parent and is redundant.
- term:
id: GO:0016887
label: ATP hydrolysis activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: 'Manual review: ATP hydrolysis activity is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0042470
label: melanosome
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: 'Manual review: melanosome may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0043066
label: negative regulation of apoptotic process
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: 'Manual review: negative regulation of apoptotic process may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0043168
label: anion binding
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: 'Manual review: anion binding may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0001786
label: phosphatidylserine binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'Manual review: phosphatidylserine binding may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005770
label: late endosome
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'Manual review: late endosome may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005829
label: cytosol
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'Manual review: cytosol is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0030674
label: protein-macromolecule adaptor activity
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'Manual review: protein-macromolecule adaptor activity is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0035651
label: AP-3 adaptor complex binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'Manual review: AP-3 adaptor complex binding may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0044788
label: host-mediated perturbation of viral process
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'Manual review: host-mediated perturbation of viral process may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0044829
label: host-mediated activation of viral genome replication
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'Manual review: host-mediated activation of viral genome replication may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0048471
label: perinuclear region of cytoplasm
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'Manual review: perinuclear region of cytoplasm may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0051082
label: unfolded protein binding
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: 'Manual review: unfolded protein binding is better represented by a more specific replacement term for Hspa8.'
action: MODIFY
reason: Modified to align with current curation guidance and improve term specificity.
proposed_replacement_terms:
- id: GO:0044183
label: protein folding chaperone
- term:
id: GO:0061684
label: chaperone-mediated autophagy
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'Manual review: chaperone-mediated autophagy is a core process for Hspa8/HSC70, which selects KFERQ-motif clients and delivers them to LAMP-2A for lysosomal degradation.'
action: ACCEPT
reason: Retained as a core process, corroborated by falcon deep research.
supported_by:
- reference_id: file:rat/Hspa8/Hspa8-deep-research-falcon.md
reference_section_type: OTHER
supporting_text: |-
recognition of KFERQ-like pentapeptide motifs** in client proteins targeted for **chaperone-mediated autophagy (CMA)**
- term:
id: GO:0061738
label: late endosomal microautophagy
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'Manual review: late endosomal microautophagy is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0070062
label: extracellular exosome
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'Manual review: extracellular exosome may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0072318
label: clathrin coat disassembly
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: 'Manual review: clathrin coat disassembly is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0098684
label: photoreceptor ribbon synapse
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'Manual review: photoreceptor ribbon synapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098690
label: glycinergic synapse
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: 'Manual review: glycinergic synapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098793
label: presynapse
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'Manual review: presynapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098978
label: glutamatergic synapse
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'Manual review: glutamatergic synapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0099175
label: regulation of postsynapse organization
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'Manual review: regulation of postsynapse organization may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0099634
label: postsynaptic specialization membrane
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'Manual review: postsynaptic specialization membrane may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0160020
label: positive regulation of ferroptosis
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: 'Manual review: positive regulation of ferroptosis may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0030674
label: protein-macromolecule adaptor activity
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: protein-macromolecule adaptor activity is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0061684
label: chaperone-mediated autophagy
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: chaperone-mediated autophagy is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0160020
label: positive regulation of ferroptosis
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: positive regulation of ferroptosis may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: cytoplasm is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0101031
label: protein folding chaperone complex
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: protein folding chaperone complex is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0005615
label: extracellular space
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: extracellular space may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0030335
label: positive regulation of cell migration
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: positive regulation of cell migration may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0048018
label: receptor ligand activity
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: receptor ligand activity is not sufficiently supported as a direct function of Hspa8.'
action: REMOVE
reason: Removed due weak mechanistic support or likely misannotation for this gene.
- term:
id: GO:0006457
label: protein folding
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: protein folding is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0014069
label: postsynaptic density
evidence_type: IEP
original_reference_id: PMID:11230095
review:
summary: 'Manual review: postsynaptic density may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0014069
label: postsynaptic density
evidence_type: IDA
original_reference_id: PMID:11230095
review:
summary: 'Manual review: postsynaptic density may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0014069
label: postsynaptic density
evidence_type: IDA
original_reference_id: PMID:9878698
review:
summary: 'Manual review: postsynaptic density may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098684
label: photoreceptor ribbon synapse
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: photoreceptor ribbon synapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098690
label: glycinergic synapse
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: glycinergic synapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098690
label: glycinergic synapse
evidence_type: IDA
original_reference_id: PMID:21209184
review:
summary: 'Manual review: glycinergic synapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098690
label: glycinergic synapse
evidence_type: EXP
original_reference_id: PMID:21209184
review:
summary: 'Manual review: glycinergic synapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098690
label: glycinergic synapse
evidence_type: IMP
original_reference_id: PMID:21209184
review:
summary: 'Manual review: glycinergic synapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098793
label: presynapse
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: presynapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098793
label: presynapse
evidence_type: IEP
original_reference_id: PMID:9878698
review:
summary: 'Manual review: presynapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098793
label: presynapse
evidence_type: IDA
original_reference_id: PMID:9878698
review:
summary: 'Manual review: presynapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098794
label: postsynapse
evidence_type: IEP
original_reference_id: PMID:9878698
review:
summary: 'Manual review: postsynapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098794
label: postsynapse
evidence_type: IDA
original_reference_id: PMID:9878698
review:
summary: 'Manual review: postsynapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098880
label: maintenance of postsynaptic specialization structure
evidence_type: IDA
original_reference_id: PMID:21209184
review:
summary: 'Manual review: maintenance of postsynaptic specialization structure may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098880
label: maintenance of postsynaptic specialization structure
evidence_type: EXP
original_reference_id: PMID:21209184
review:
summary: 'Manual review: maintenance of postsynaptic specialization structure may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098880
label: maintenance of postsynaptic specialization structure
evidence_type: IMP
original_reference_id: PMID:21209184
review:
summary: 'Manual review: maintenance of postsynaptic specialization structure may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098978
label: glutamatergic synapse
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: glutamatergic synapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098978
label: glutamatergic synapse
evidence_type: IEP
original_reference_id: PMID:11230095
review:
summary: 'Manual review: glutamatergic synapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098978
label: glutamatergic synapse
evidence_type: IDA
original_reference_id: PMID:11230095
review:
summary: 'Manual review: glutamatergic synapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098978
label: glutamatergic synapse
evidence_type: IEP
original_reference_id: PMID:9878698
review:
summary: 'Manual review: glutamatergic synapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0098978
label: glutamatergic synapse
evidence_type: IDA
original_reference_id: PMID:9878698
review:
summary: 'Manual review: glutamatergic synapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0099175
label: regulation of postsynapse organization
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: regulation of postsynapse organization may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0099634
label: postsynaptic specialization membrane
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: postsynaptic specialization membrane may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0072318
label: clathrin coat disassembly
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: clathrin coat disassembly is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0072318
label: clathrin coat disassembly
evidence_type: IDA
original_reference_id: PMID:8524399
review:
summary: 'Manual review: clathrin coat disassembly is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0005765
label: lysosomal membrane
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: the lysosomal membrane is a functional location of the core chaperone-mediated autophagy role of HSC70; this orthology-based annotation is consistent with the experimentally supported IDA annotations to the same term.'
action: ACCEPT
reason: Lysosomal membrane is a bona fide functional location for the core CMA role of HSC70 (experimentally supported by PMID:18644871 and PMID:9038169); accepted for consistency with those IDA annotations.
- term:
id: GO:0030674
label: protein-macromolecule adaptor activity
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: 'Manual review: protein-macromolecule adaptor activity is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- 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: 'Manual review: protein targeting to lysosome in CMA is a core process for Hspa8/HSC70; cytosolic HSC70 recognizes KFERQ-like motifs and delivers clients to LAMP-2A, and lysosomal HSC70 supports translocation into the lysosomal lumen.'
action: ACCEPT
reason: Retained as a core CMA process, corroborated by falcon deep research.
supported_by:
- reference_id: file:rat/Hspa8/Hspa8-deep-research-falcon.md
reference_section_type: OTHER
supporting_text: |-
recognition of KFERQ-like pentapeptide motifs** in client proteins targeted for **chaperone-mediated autophagy (CMA)**
- reference_id: file:rat/Hspa8/Hspa8-deep-research-falcon.md
reference_section_type: OTHER
supporting_text: |-
Lysosomal HSC70 (LysβHSC70)** facilitates **substrate translocation** into the lysosome lumen
- term:
id: GO:1900226
label: negative regulation of NLRP3 inflammasome complex assembly
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: negative regulation of NLRP3 inflammasome complex assembly may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0001786
label: phosphatidylserine binding
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: phosphatidylserine binding may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0061635
label: regulation of protein complex stability
evidence_type: IDA
original_reference_id: PMID:18644871
review:
summary: 'Manual review: regulation of protein complex stability may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0140545
label: ATP-dependent protein disaggregase activity
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: ATP-dependent protein disaggregase activity is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0061684
label: chaperone-mediated autophagy
evidence_type: IGI
original_reference_id: PMID:18644871
review:
summary: 'Manual review: chaperone-mediated autophagy is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0043202
label: lysosomal lumen
evidence_type: TAS
original_reference_id: Reactome:R-RNO-9625160
review:
summary: 'Manual review: lysosomal lumen may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0043202
label: lysosomal lumen
evidence_type: TAS
original_reference_id: Reactome:R-RNO-9625173
review:
summary: 'Manual review: lysosomal lumen may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0043202
label: lysosomal lumen
evidence_type: TAS
original_reference_id: Reactome:R-RNO-9626028
review:
summary: 'Manual review: lysosomal lumen may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0048471
label: perinuclear region of cytoplasm
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: perinuclear region of cytoplasm may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-RNO-9613356
review:
summary: 'Manual review: cytosol is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-RNO-9615712
review:
summary: 'Manual review: cytosol is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-RNO-9620205
review:
summary: 'Manual review: cytosol is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-RNO-9622832
review:
summary: 'Manual review: cytosol is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-RNO-9626236
review:
summary: 'Manual review: cytosol is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-RNO-9626239
review:
summary: 'Manual review: cytosol is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-RNO-9626254
review:
summary: 'Manual review: cytosol is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0043195
label: terminal bouton
evidence_type: HDA
original_reference_id: PMID:24876496
review:
summary: 'Manual review: terminal bouton may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0031625
label: ubiquitin protein ligase binding
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: ubiquitin protein ligase binding may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0051087
label: protein-folding chaperone binding
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: protein-folding chaperone binding is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15708368
review:
summary: 'Manual review: protein binding is too generic or over-extended for Hspa8.'
action: MARK_AS_OVER_ANNOTATED
reason: Marked over-annotated because more specific terms capture the biology more accurately.
- term:
id: GO:0030425
label: dendrite
evidence_type: IDA
original_reference_id: PMID:9878698
review:
summary: 'Manual review: dendrite may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0044309
label: neuron spine
evidence_type: IDA
original_reference_id: PMID:9878698
review:
summary: 'Manual review: neuron spine may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0061740
label: protein targeting to lysosome involved in chaperone-mediated autophagy
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: protein targeting to lysosome involved in chaperone-mediated autophagy is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0044788
label: host-mediated perturbation of viral process
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: host-mediated perturbation of viral process may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0044829
label: host-mediated activation of viral genome replication
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: host-mediated activation of viral genome replication may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005765
label: lysosomal membrane
evidence_type: IDA
original_reference_id: PMID:18644871
review:
summary: 'Manual review: this IDA derives from a key CMA mechanistic paper showing HSC70 organizes in dynamic protein complexes with LAMP-2A at the lysosomal membrane. The lysosomal membrane is a functional location of the core CMA role of HSC70 (also listed in the CMA core_function), so this experimental annotation is accepted as core.'
action: ACCEPT
reason: The lysosomal membrane is a bona fide functional location for the core chaperone-mediated autophagy role of HSC70, directly demonstrated experimentally in PMID:18644871. Falcon corroboration is captured in the references findings block.
- term:
id: GO:0032984
label: protein-containing complex disassembly
evidence_type: IMP
original_reference_id: PMID:18644871
review:
summary: 'Manual review: protein-containing complex disassembly may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:1990836
label: lysosomal matrix
evidence_type: IDA
original_reference_id: PMID:18644871
review:
summary: 'Manual review: lysosomal matrix may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005770
label: late endosome
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: late endosome may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0061738
label: late endosomal microautophagy
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: late endosomal microautophagy is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0016887
label: ATP hydrolysis activity
evidence_type: IDA
original_reference_id: PMID:20060297
review:
summary: 'Manual review: ATP hydrolysis activity is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:1904764
label: chaperone-mediated autophagy translocation complex disassembly
evidence_type: IDA
original_reference_id: PMID:18644871
review:
summary: 'Manual review: chaperone-mediated autophagy translocation complex disassembly may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0042026
label: protein refolding
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: 'Manual review: protein refolding is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0061684
label: chaperone-mediated autophagy
evidence_type: IDA
original_reference_id: PMID:18644871
review:
summary: 'Manual review: chaperone-mediated autophagy is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0031647
label: regulation of protein stability
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: regulation of protein stability may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0097214
label: positive regulation of lysosomal membrane permeability
evidence_type: IMP
original_reference_id: PMID:9038169
review:
summary: 'Manual review: positive regulation of lysosomal membrane permeability may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:1990832
label: slow axonal transport
evidence_type: IEP
original_reference_id: PMID:11933046
review:
summary: 'Manual review: slow axonal transport may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:1990833
label: clathrin-uncoating ATPase activity
evidence_type: IDA
original_reference_id: PMID:8363588
review:
summary: 'Manual review: clathrin-uncoating ATPase activity is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:1990834
label: response to odorant
evidence_type: IEP
original_reference_id: PMID:11268007
review:
summary: 'Manual review: response to odorant may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0000082
label: G1/S transition of mitotic cell cycle
evidence_type: IEP
original_reference_id: PMID:10198213
review:
summary: 'Manual review: G1/S transition of mitotic cell cycle may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0070301
label: cellular response to hydrogen peroxide
evidence_type: IEP
original_reference_id: PMID:10329212
review:
summary: 'Manual review: cellular response to hydrogen peroxide may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:1904593
label: prostaglandin binding
evidence_type: IPI
original_reference_id: PMID:21445266
review:
summary: 'Manual review: prostaglandin binding is not sufficiently supported as a direct function of Hspa8.'
action: REMOVE
reason: Removed due weak mechanistic support or likely misannotation for this gene.
- term:
id: GO:0001916
label: positive regulation of T cell mediated cytotoxicity
evidence_type: IMP
original_reference_id: PMID:8871636
review:
summary: 'Manual review: positive regulation of T cell mediated cytotoxicity may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005776
label: autophagosome
evidence_type: IDA
original_reference_id: PMID:20392947
review:
summary: 'Manual review: autophagosome may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005874
label: microtubule
evidence_type: IDA
original_reference_id: PMID:2527848
review:
summary: 'Manual review: microtubule may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005882
label: intermediate filament
evidence_type: IDA
original_reference_id: PMID:7721954
review:
summary: 'Manual review: intermediate filament may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0009986
label: cell surface
evidence_type: IDA
original_reference_id: PMID:8228242
review:
summary: 'Manual review: cell surface may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0010628
label: positive regulation of gene expression
evidence_type: IMP
original_reference_id: PMID:8734434
review:
summary: 'Manual review: positive regulation of gene expression may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0032279
label: asymmetric synapse
evidence_type: IDA
original_reference_id: PMID:11230095
review:
summary: 'Manual review: asymmetric synapse may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0043197
label: dendritic spine
evidence_type: IDA
original_reference_id: PMID:11230095
review:
summary: 'Manual review: dendritic spine may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0043198
label: dendritic shaft
evidence_type: IDA
original_reference_id: PMID:11230095
review:
summary: 'Manual review: dendritic shaft may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0043204
label: perikaryon
evidence_type: IDA
original_reference_id: PMID:11230095
review:
summary: 'Manual review: perikaryon may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0045471
label: response to ethanol
evidence_type: IEP
original_reference_id: PMID:12170112
review:
summary: 'Manual review: response to ethanol may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0050766
label: positive regulation of phagocytosis
evidence_type: IMP
original_reference_id: PMID:9886410
review:
summary: 'Manual review: positive regulation of phagocytosis may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:1904592
label: positive regulation of protein refolding
evidence_type: IDA
original_reference_id: PMID:11360998
review:
summary: 'Manual review: positive regulation of protein refolding may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0001822
label: kidney development
evidence_type: IEP
original_reference_id: PMID:9764759
review:
summary: 'Manual review: kidney development may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0001917
label: photoreceptor inner segment
evidence_type: IDA
original_reference_id: PMID:10549657
review:
summary: 'Manual review: photoreceptor inner segment may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005765
label: lysosomal membrane
evidence_type: IDA
original_reference_id: PMID:9038169
review:
summary: 'Manual review: PMID:9038169 (Cuervo, Dice & Knecht 1997) is a foundational CMA paper showing lysosomal hsc73 mediates selective uptake/degradation of cytosolic substrates in rat liver lysosomes. The lysosomal membrane is a functional location of the core CMA role of HSC70.'
action: ACCEPT
reason: The lysosomal membrane is a bona fide functional location for the core chaperone-mediated autophagy role of HSC70, directly demonstrated experimentally in PMID:9038169.
- term:
id: GO:0006606
label: protein import into nucleus
evidence_type: IMP
original_reference_id: PMID:8892974
review:
summary: 'Manual review: protein import into nucleus may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0007519
label: skeletal muscle tissue development
evidence_type: IEP
original_reference_id: PMID:12909603
review:
summary: 'Manual review: skeletal muscle tissue development may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0008088
label: axo-dendritic transport
evidence_type: IEP
original_reference_id: PMID:11933046
review:
summary: 'Manual review: axo-dendritic transport may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0009410
label: response to xenobiotic stimulus
evidence_type: IEP
original_reference_id: PMID:10425221
review:
summary: 'Manual review: response to xenobiotic stimulus may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0014823
label: response to activity
evidence_type: IEP
original_reference_id: PMID:10606824
review:
summary: 'Manual review: response to activity may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0021549
label: cerebellum development
evidence_type: IEP
original_reference_id: PMID:9764759
review:
summary: 'Manual review: cerebellum development may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0034605
label: cellular response to heat
evidence_type: IEP
original_reference_id: PMID:8955942
review:
summary: 'Manual review: cellular response to heat may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0042277
label: peptide binding
evidence_type: IDA
original_reference_id: PMID:8363588
review:
summary: 'Manual review: peptide binding may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0042594
label: response to starvation
evidence_type: IEP
original_reference_id: PMID:9038169
review:
summary: 'Manual review: response to starvation may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0044743
label: protein transmembrane import into intracellular organelle
evidence_type: IEP
original_reference_id: PMID:9038169
review:
summary: 'Manual review: protein transmembrane import into intracellular organelle may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0045862
label: positive regulation of proteolysis
evidence_type: IDA
original_reference_id: PMID:9987077
review:
summary: 'Manual review: positive regulation of proteolysis may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0046777
label: protein autophosphorylation
evidence_type: IDA
original_reference_id: PMID:8420978
review:
summary: 'Manual review: PMID:8420978 (Huang et al. 1993, "Aspartyl residue 10 is essential for ATPase activity of rat hsc70") studies the ATPase activity of HSC70, not protein autophosphorylation. The annotation appears to be a database error.'
action: REMOVE
reason: 'Misannotation: PMID:8420978 reports ATPase activity (the catalytic mechanism of HSC70), not protein autophosphorylation; there is no evidence in this reference that HSC70 autophosphorylates.'
- term:
id: GO:0048471
label: perinuclear region of cytoplasm
evidence_type: IDA
original_reference_id: PMID:10549657
review:
summary: 'Manual review: perinuclear region of cytoplasm may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0071276
label: cellular response to cadmium ion
evidence_type: IEP
original_reference_id: PMID:9736451
review:
summary: 'Manual review: cellular response to cadmium ion may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0072318
label: clathrin coat disassembly
evidence_type: IDA
original_reference_id: PMID:8363588
review:
summary: 'Manual review: clathrin coat disassembly is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:1990836
label: lysosomal matrix
evidence_type: IDA
original_reference_id: PMID:9038169
review:
summary: 'Manual review: lysosomal matrix may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0010045
label: response to nickel cation
evidence_type: IEP
original_reference_id: PMID:15736156
review:
summary: 'Manual review: response to nickel cation may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0010667
label: negative regulation of cardiac muscle cell apoptotic process
evidence_type: IMP
original_reference_id: PMID:21958194
review:
summary: 'Manual review: negative regulation of cardiac muscle cell apoptotic process may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0019899
label: enzyme binding
evidence_type: IPI
original_reference_id: PMID:21958194
review:
summary: 'Manual review: enzyme binding may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0030424
label: axon
evidence_type: IDA
original_reference_id: PMID:9878698
review:
summary: 'Manual review: axon may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0030900
label: forebrain development
evidence_type: IEP
original_reference_id: PMID:9878698
review:
summary: 'Manual review: forebrain development may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0031686
label: A1 adenosine receptor binding
evidence_type: IPI
original_reference_id: PMID:10866672
review:
summary: 'Manual review: PMID:10866672 documents a direct, specific rat hsc73-A1 adenosine receptor interaction (Kd ~0.5 nM by surface plasmon resonance, plus affinity chromatography, co-immunoprecipitation and confocal colocalization). This is a genuine documented interaction but is peripheral to the evolved core chaperone function.'
action: KEEP_AS_NON_CORE
reason: Well-supported experimental rat interaction (PMID:10866672) but peripheral to the core HSC70 chaperone, clathrin-uncoating, and CMA functions; retained as non-core rather than removed.
- term:
id: GO:0032355
label: response to estradiol
evidence_type: IEP
original_reference_id: PMID:9990085
review:
summary: 'Manual review: response to estradiol may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0032570
label: response to progesterone
evidence_type: IEP
original_reference_id: PMID:9990085
review:
summary: 'Manual review: response to progesterone may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0043025
label: neuronal cell body
evidence_type: IDA
original_reference_id: PMID:9878698
review:
summary: 'Manual review: neuronal cell body may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0043085
label: positive regulation of catalytic activity
evidence_type: IMP
original_reference_id: PMID:21958194
review:
summary: 'Manual review: positive regulation of catalytic activity may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0043195
label: terminal bouton
evidence_type: IDA
original_reference_id: PMID:9878698
review:
summary: 'Manual review: terminal bouton may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0044849
label: estrous cycle
evidence_type: IEP
original_reference_id: PMID:9990085
review:
summary: 'Manual review: estrous cycle may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0032991
label: protein-containing complex
evidence_type: IDA
original_reference_id: PMID:20596529
review:
summary: 'Manual review: protein-containing complex may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0003723
label: RNA binding
evidence_type: IDA
original_reference_id: PMID:23159318
review:
summary: 'Manual review: RNA binding may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23159318
review:
summary: 'Manual review: protein binding is too generic or over-extended for Hspa8.'
action: MARK_AS_OVER_ANNOTATED
reason: Marked over-annotated because more specific terms capture the biology more accurately.
- term:
id: GO:0046034
label: ATP metabolic process
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: ATP metabolic process may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0055131
label: C3HC4-type RING finger domain binding
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: C3HC4-type RING finger domain binding may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0048026
label: positive regulation of mRNA splicing, via spliceosome
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: positive regulation of mRNA splicing, via spliceosome may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0001664
label: G protein-coupled receptor binding
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: G protein-coupled receptor binding is not sufficiently supported as a direct function of Hspa8.'
action: REMOVE
reason: Removed due weak mechanistic support or likely misannotation for this gene.
- term:
id: GO:0070062
label: extracellular exosome
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: extracellular exosome may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18307834
review:
summary: 'Manual review: protein binding is too generic or over-extended for Hspa8.'
action: MARK_AS_OVER_ANNOTATED
reason: Marked over-annotated because more specific terms capture the biology more accurately.
- term:
id: GO:0005524
label: ATP binding
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: ATP binding is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0019899
label: enzyme binding
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: enzyme binding may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0031072
label: heat shock protein binding
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: heat shock protein binding is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:1902904
label: negative regulation of supramolecular fiber organization
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: negative regulation of supramolecular fiber organization may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005829
label: cytosol
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: cytosol is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0042026
label: protein refolding
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: protein refolding is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0051082
label: unfolded protein binding
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: unfolded protein binding is better represented by a more specific replacement term for Hspa8.'
action: MODIFY
reason: Modified to align with current curation guidance and improve term specificity.
proposed_replacement_terms:
- id: GO:0044183
label: protein folding chaperone
- term:
id: GO:0000974
label: Prp19 complex
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: 'Manual review: Prp19 complex may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0000974
label: Prp19 complex
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: Prp19 complex may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005634
label: nucleus
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: 'Manual review: HSC70 has documented nuclear/nucleolar pools, but the nucleus is not the site of its core chaperone, clathrin-uncoating, or CMA functions.'
action: KEEP_AS_NON_CORE
reason: Valid localization but peripheral to the evolved cytosolic chaperone function.
- term:
id: GO:0005634
label: nucleus
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: HSC70 has documented nuclear/nucleolar pools, but the nucleus is not the site of its core chaperone, clathrin-uncoating, or CMA functions.'
action: KEEP_AS_NON_CORE
reason: Valid localization but peripheral to the evolved cytosolic chaperone function.
- term:
id: GO:0045892
label: negative regulation of DNA-templated transcription
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: 'Manual review: negative regulation of DNA-templated transcription may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19457116
review:
summary: 'Manual review: protein binding is too generic or over-extended for Hspa8.'
action: MARK_AS_OVER_ANNOTATED
reason: Marked over-annotated because more specific terms capture the biology more accurately.
- term:
id: GO:0008021
label: synaptic vesicle
evidence_type: IDA
original_reference_id: PMID:19457116
review:
summary: 'Manual review: synaptic vesicle may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0043025
label: neuronal cell body
evidence_type: IDA
original_reference_id: PMID:19457116
review:
summary: 'Manual review: neuronal cell body may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0045892
label: negative regulation of DNA-templated transcription
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: negative regulation of DNA-templated transcription may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17877381
review:
summary: 'Manual review: protein binding is too generic or over-extended for Hspa8.'
action: MARK_AS_OVER_ANNOTATED
reason: Marked over-annotated because more specific terms capture the biology more accurately.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:9528774
review:
summary: 'Manual review: protein binding is too generic or over-extended for Hspa8.'
action: MARK_AS_OVER_ANNOTATED
reason: Marked over-annotated because more specific terms capture the biology more accurately.
- term:
id: GO:0016887
label: ATP hydrolysis activity
evidence_type: IDA
original_reference_id: PMID:9528774
review:
summary: 'Manual review: ATP hydrolysis activity is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0032991
label: protein-containing complex
evidence_type: IDA
original_reference_id: PMID:9528774
review:
summary: 'Manual review: protein-containing complex may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005102
label: signaling receptor binding
evidence_type: IPI
original_reference_id: PMID:11133993
review:
summary: 'Manual review: signaling receptor binding may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:10198213
review:
summary: 'Manual review: protein binding is too generic or over-extended for Hspa8.'
action: MARK_AS_OVER_ANNOTATED
reason: Marked over-annotated because more specific terms capture the biology more accurately.
- term:
id: GO:0032991
label: protein-containing complex
evidence_type: IDA
original_reference_id: PMID:10198213
review:
summary: 'Manual review: protein-containing complex may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0051082
label: unfolded protein binding
evidence_type: IDA
original_reference_id: PMID:11133993
review:
summary: 'Manual review: unfolded protein binding is better represented by a more specific replacement term for Hspa8.'
action: MODIFY
reason: Modified to align with current curation guidance and improve term specificity.
proposed_replacement_terms:
- id: GO:0044183
label: protein folding chaperone
- term:
id: GO:1990904
label: ribonucleoprotein complex
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: 'Manual review: ribonucleoprotein complex may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:1990904
label: ribonucleoprotein complex
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: ribonucleoprotein complex may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12514190
review:
summary: 'Manual review: protein binding is too generic or over-extended for Hspa8.'
action: MARK_AS_OVER_ANNOTATED
reason: Marked over-annotated because more specific terms capture the biology more accurately.
- term:
id: GO:0016887
label: ATP hydrolysis activity
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: ATP hydrolysis activity is consistent with known biology of Hspa8.'
action: ACCEPT
reason: Retained as supported or plausible for this gene and evidence context.
- term:
id: GO:0051726
label: regulation of cell cycle
evidence_type: ISO
original_reference_id: GO_REF:0000121
review:
summary: 'Manual review: regulation of cell cycle may be context-dependent or peripheral for Hspa8.'
action: KEEP_AS_NON_CORE
reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
core_functions:
- description: >-
ATP-dependent (EC 3.6.4.10) protein-folding chaperone activity: cyclic, nucleotide-state-dependent
binding and release of unfolded/misfolded client polypeptides to assist protein folding, refolding,
unfolding and disassembly of protein complexes, with the ATPase cycle regulated by J-domain (HSP40/DNAJ)
co-chaperones and nucleotide-exchange factors.
molecular_function:
id: GO:0044183
label: protein folding chaperone
directly_involved_in:
- id: GO:0042026
label: protein refolding
- id: GO:0006457
label: protein folding
locations:
- id: GO:0005829
label: cytosol
supported_by:
- reference_id: file:rat/Hspa8/Hspa8-deep-research-falcon.md
reference_section_type: OTHER
supporting_text: |-
Hspa8/HSC70 is a **constitutive** HSP70-family **ATPase chaperone** that supports proteostasis by assisting **protein folding/refolding**, **unfolding**, and **disassembly of protein complexes**
- reference_id: file:rat/Hspa8/Hspa8-deep-research-falcon.md
reference_section_type: OTHER
supporting_text: |-
nucleotide state controls substrate affinity (ATP-bound low affinity/fast exchange; ADP-bound high affinity/slow exchange)
- reference_id: file:rat/Hspa8/Hspa8-deep-research-falcon.md
reference_section_type: OTHER
supporting_text: |-
J-domain proteins (HSP40/DNAJ)** stimulate ATP hydrolysis through engagement of the nucleotide-binding domain, and nucleotide exchange factors reset the cycle by promoting ADPβATP exchange
- description: >-
Clathrin-uncoating ATPase activity: HSC70, recruited by the J-domain co-chaperone auxilin (DNAJC6),
hydrolyzes ATP to disassemble clathrin coats from clathrin-coated vesicles, recycling the pool of free
clathrin in clathrin-mediated endocytosis and synaptic vesicle recycling.
molecular_function:
id: GO:1990833
label: clathrin-uncoating ATPase activity
directly_involved_in:
- id: GO:0072318
label: clathrin coat disassembly
locations:
- id: GO:0005829
label: cytosol
supported_by:
- reference_id: file:rat/Hspa8/Hspa8-deep-research-falcon.md
reference_section_type: OTHER
supporting_text: |-
the **J-domain co-chaperone auxilin (DNAJC6)** recruits HSC70 to CCVs and **stimulates HSC70 ATPase activity** to disassemble clathrin coats
- description: >-
Chaperone-mediated autophagy: cytosolic HSC70 recognizes KFERQ-like pentapeptide motifs in soluble
client proteins and delivers them to LAMP-2A at the lysosomal membrane; lysosomal HSC70 supports
substrate translocation into the lysosomal lumen for degradation. In this role HSC70 acts as a
cargo selector/adaptor, bringing the client protein together with the LAMP-2A receptor.
molecular_function:
id: GO:0030674
label: protein-macromolecule adaptor activity
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:0005829
label: cytosol
- id: GO:0005765
label: lysosomal membrane
supported_by:
- reference_id: file:rat/Hspa8/Hspa8-deep-research-falcon.md
reference_section_type: OTHER
supporting_text: |-
recognition of KFERQ-like pentapeptide motifs** in client proteins targeted for **chaperone-mediated autophagy (CMA)**
- reference_id: file:rat/Hspa8/Hspa8-deep-research-falcon.md
reference_section_type: OTHER
supporting_text: |-
Lysosomal HSC70 (LysβHSC70)** facilitates **substrate translocation** into the lysosome lumen
references:
- id: file:rat/Hspa8/Hspa8-deep-research-falcon.md
title: 'Falcon (Edison Scientific) deep research report: rat Hspa8 (HSC70/HSC73, UniProt P63018)'
findings:
- statement: >-
Hspa8 (UniProt P63018) is the constitutively expressed HSP70-family chaperone HSC70/HSC73,
with an N-terminal nucleotide-binding/ATPase domain and a substrate-binding domain with a
C-terminal lid whose nucleotide state controls substrate affinity.
supporting_text: |-
The UniProt accession **P63018** corresponds to **Rattus norvegicus Hspa8**, encoding the constitutively expressed HSP70-family chaperone commonly referred to as **HSC70/HSC73 (HSPA8)**.
reference_section_type: OTHER
- statement: >-
The core molecular function is an ATP-dependent chaperone that assists protein folding,
refolding, unfolding and disassembly of protein complexes, with the ATP/ADP cycle regulated
by J-domain co-chaperones and nucleotide-exchange factors.
supporting_text: |-
Hspa8/HSC70 is a **constitutive** HSP70-family **ATPase chaperone** that supports proteostasis by assisting **protein folding/refolding**, **unfolding**, and **disassembly of protein complexes**
reference_section_type: OTHER
- statement: >-
A second core role is clathrin-coated vesicle uncoating, in which the J-domain co-chaperone
auxilin (DNAJC6) recruits HSC70 and stimulates its ATPase to disassemble clathrin coats.
supporting_text: |-
the **J-domain co-chaperone auxilin (DNAJC6)** recruits HSC70 to CCVs and **stimulates HSC70 ATPase activity** to disassemble clathrin coats
reference_section_type: OTHER
- statement: >-
A third core role is chaperone-mediated autophagy: HSC70 recognizes KFERQ-like motifs in
client proteins selected for CMA.
supporting_text: |-
recognition of KFERQ-like pentapeptide motifs** in client proteins targeted for **chaperone-mediated autophagy (CMA)**
reference_section_type: OTHER
- statement: >-
Lysosomal HSC70 facilitates substrate translocation into the lysosome lumen during CMA.
supporting_text: |-
Lysosomal HSC70 (LysβHSC70)** facilitates **substrate translocation** into the lysosome lumen
reference_section_type: OTHER
- statement: >-
The cytosol is the predominant compartment where HSC70 performs general chaperoning and
recognizes CMA substrates.
supporting_text: |-
**Cytosol**: the predominant pool performing general chaperoning and recognizing CMA substrates (KFERQ-like motifs)
reference_section_type: OTHER
- statement: >-
During CMA, the HSC70-substrate complex binds LAMP-2A at the lysosomal membrane and HSC70
helps assemble the translocation complex there, corroborating the experimental
lysosomal-membrane localization of HSC70 (GO:0005765) from PMID:18644871.
supporting_text: |-
The complex binds **LAMPβ2A** at the lysosomal membrane; HSC70 helps **assemble the translocation complex**.
reference_section_type: OTHER
- 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: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:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: GO_REF:0000121
title: RGD ISO annotations to rat from other mammalian species
findings: []
- id: PMID:10198213
title: 73-kDa heat shock cognate protein interacts directly with P27Kip1, a cyclin-dependent kinase inhibitor, during G1/S transition.
findings: []
- id: PMID:10329212
title: A physiologically relevant hyperthermia selectively activates constitutive hsp70 in H9c2 cardiac myoblasts and confers oxidative protection.
findings: []
- id: PMID:10425221
title: Identification of a novel splice variant of heat shock cognate protein 70 after chronic antidepressant treatment in rat frontal cortex.
findings: []
- id: PMID:10549657
title: Constitutive and inducible heat shock protein 70 immunoreactivity in the normal rat eye.
findings: []
- id: PMID:10606824
title: The effects of exercise duration on adrenal HSP72/73 induction in rats.
findings: []
- id: PMID:10866672
title: The heat shock cognate protein hsc73 assembles with A(1) adenosine receptors to form functional modules in the cell membrane.
findings: []
- id: PMID:11133993
title: Characteristics of the interaction between Hsc70 and the transferrin receptor in exosomes released during reticulocyte maturation.
findings: []
- id: PMID:11230095
title: Presence of both constitutive and inducible forms of heat shock protein 70 in the cerebral cortex and hippocampal synapses.
findings: []
- id: PMID:11268007
title: Odorants as cell-type specific activators of a heat shock response in the rat olfactory mucosa.
findings: []
- id: PMID:11360998
title: The effect of mutating arginine-469 on the substrate binding and refolding activities of 70-kDa heat shock cognate protein.
findings: []
- id: PMID:11933046
title: Slow axonal transport of the cytosolic chaperonin CCT with Hsc73 and actin in motor neurons.
findings: []
- id: PMID:12170112
title: Stress response caused by chronic alcohol intake in aged rat brain.
findings: []
- id: PMID:12514190
title: Cloning and characterization of a novel GRP78-binding protein in the rat brain.
findings: []
- id: PMID:12909603
title: Endogenous expression and developmental changes of HSP72 in rat skeletal muscles.
findings: []
- id: PMID:15708368
title: Small glutamine-rich tetratricopeptide repeat-containing protein is composed of three structural units with distinct functions.
findings: []
- id: PMID:15736156
title: Effects of nickel poisoning on expression pattern of the 72/73 and 94 kDa stress proteins in rat organs and in the COS-7, HepG2, and A549 cell lines.
findings: []
- id: PMID:17877381
title: Increased striatal mRNA and protein levels of the immunophilin FKBP-12 in experimental Parkinson's disease and identification of FKBP-12-binding proteins.
findings: []
- id: PMID:18307834
title: Cathepsin C propeptide interacts with intestinal alkaline phosphatase and heat shock cognate protein 70 in human Caco-2 cells.
findings: []
- id: PMID:18644871
title: The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane.
findings: []
- id: PMID:19457116
title: The molecular chaperone Hsc70 interacts with the vesicular monoamine transporter-2.
findings: []
- id: PMID:20060297
title: Chaperone-assisted selective autophagy is essential for muscle maintenance.
findings: []
- id: PMID:20392947
title: Essential role of the redox-sensitive kinase p66shc in determining energetic and oxidative status and cell fate in neuronal preconditioning.
findings: []
- id: PMID:20596529
title: Molecular composition of staufen2-containing ribonucleoproteins in embryonic rat brain.
findings: []
- id: PMID:21209184
title: Heat shock cognate protein 70 regulates gephyrin clustering.
findings: []
- id: PMID:21445266
title: Proteomic identification of protein targets for 15-deoxy-Ξ(12,14)-prostaglandin J2 in neuronal plasma membrane.
findings: []
- id: PMID:21958194
title: Constitutive heat shock protein 70 interacts with Ξ±-enolase and protects cardiomyocytes against oxidative stress.
findings: []
- id: PMID:23159318
title: Identification in the rat brain of a set of nuclear proteins interacting with H1Β° mRNA.
findings: []
- id: PMID:24876496
title: Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins.
findings: []
- id: PMID:2527848
title: Beta-internexin is a microtubule-associated protein identical to the 70-kDa heat-shock cognate protein and the clathrin uncoating ATPase.
findings: []
- id: PMID:7721954
title: Integrity of intermediate filaments is associated with the development of acquired thermotolerance in 9L rat brain tumor cells.
findings: []
- id: PMID:8228242
title: 70 kDa heat shock cognate protein is a transformation-associated antigen and a possible target for the host's anti-tumor immunity.
findings: []
- id: PMID:8363588
title: 'High-level expression of soluble rat hsc70 in Escherichia coli: purification and characterization of the cloned enzyme.'
findings: []
- id: PMID:8420978
title: Aspartyl residue 10 is essential for ATPase activity of rat hsc70.
findings: []
- id: PMID:8524399
title: Role of auxilin in uncoating clathrin-coated vesicles.
findings: []
- id: PMID:8734434
title: Antisense oligonucleotide to the 70-kDa heat shock cognate protein inhibits synthesis of myelin basic protein.
findings: []
- id: PMID:8871636
title: Involvement of peptide antigens in the cytotoxicity between 70-kDa heat shock cognate protein-like molecule and CD3+, CD4-, CD8-, TCR-alpha beta- killer T cells.
findings: []
- id: PMID:8892974
title: Evidence for the existence of a novel mechanism for the nuclear import of Hsc70.
findings: []
- id: PMID:8955942
title: Differential expression of heat shock 70 proteins in primary cultures from rat cerebellum.
findings: []
- id: PMID:9038169
title: A population of rat liver lysosomes responsible for the selective uptake and degradation of cytosolic proteins.
findings: []
- id: PMID:9528774
title: The carboxy-terminal domain of Hsc70 provides binding sites for a distinct set of chaperone cofactors.
findings: []
- id: PMID:9736451
title: Involvement of heat shock elements and basal transcription elements in the differential induction of the 70-kDa heat shock protein and its cognate by cadmium chloride in 9L rat brain tumor cells.
findings: []
- id: PMID:9764759
title: Constitutive expression of heat shock proteins Hsp90, Hsc70, Hsp70 and Hsp60 in neural and non-neural tissues of the rat during postnatal development.
findings: []
- id: PMID:9878698
title: Presence of molecular chaperones, heat shock cognate (Hsc) 70 and heat shock proteins (Hsp) 40, in the postsynaptic structures of rat brain.
findings: []
- id: PMID:9886410
title: Clathrin-coated pit-associated proteins are required for alveolar macrophage phagocytosis.
findings: []
- id: PMID:9987077
title: Direct lysosomal uptake of alpha 2-microglobulin contributes to chemically induced nephropathy.
findings: []
- id: PMID:9990085
title: The 70-kDa heat shock cognate protein (Hsc73) gene is enhanced by ovarian hormones in the ventromedial hypothalamus.
findings: []
- id: Reactome:R-RNO-9613356
title: Plins bind Hspa8
findings: []
- id: Reactome:R-RNO-9615712
title: Hspa8 binds Rnase1
findings: []
- id: Reactome:R-RNO-9620205
title: Hspa8:Rnase1 binds Lamp2a
findings: []
- id: Reactome:R-RNO-9622832
title: Hspa8 dissociates from Lamp2a-bound substrate
findings: []
- id: Reactome:R-RNO-9625160
title: Hspa8 transports unfolded substrate to lysosomal lumen for degradation
findings: []
- id: Reactome:R-RNO-9625173
title: Unfolded substrate in Lamp2 multimeric complex binds Hspa8
findings: []
- id: Reactome:R-RNO-9626028
title: Hspa8:Substrate dissociates from Lamp2 multimer
findings: []
- id: Reactome:R-RNO-9626236
title: Hspa8 dissociates from Lamp2
findings: []
- id: Reactome:R-RNO-9626239
title: Hspa8 binds Lamp2 multimers
findings: []
- id: Reactome:R-RNO-9626254
title: Hspa8:Lamp2 multimers depolymerizes to monomers
findings: []
