Heat shock 70 kDa protein 1A (HSPA1A/HSP72/HSP70-1) is a major stress-inducible member of the HSP70 molecular chaperone family. It functions as an ATP-dependent protein folding chaperone implicated in a wide variety of cellular processes including protection of the proteome from stress, folding and transport of newly synthesized polypeptides, refolding of misfolded proteins, activation of proteolysis of misfolded proteins, and the formation and dissociation of protein complexes. HSPA1A has genuine foldase activity, demonstrated by luciferase refolding assays, and also suppresses protein aggregation. Its acetylation/deacetylation state determines whether it functions in protein refolding (via HOPX co-chaperone) or protein degradation (via STUB1/CHIP ubiquitin ligase). Additionally, HSPA1A has roles in regulating apoptosis, centrosome integrity during mitosis, TGF-beta signaling, and can function as an extracellular signaling molecule (receptor ligand activity).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: HSPA1A nuclear localization is well-supported. During heat shock, Hsp70 translocates to the nucleus via Hikeshi (PMID:22024166), interacts with HSF1 transactivation domain to repress transcription (PMID:9499401), and localizes to nuclear speck-like structures (PMID:9553041). During erythropoiesis, Hsp70 accumulates in the nucleus where it protects GATA-1 from caspase-3 cleavage (PMID:17167422). Hsp70 also sequesters AUF1 in the perinucleus/nucleus during heat shock (PMID:10205060). IBA annotation is phylogenetically sound and experimentally confirmed by multiple IDA studies. Reason: Nuclear localization is well-established for HSPA1A under multiple conditions including heat stress (nuclear import via Hikeshi), transcriptional regulation (HSF1 repression), and erythropoiesis (GATA-1 protection). Supported by IDA evidence from PMID:17167422, PMID:10205060, PMID:9553041. Supporting Evidence: PMID:17167422 At the onset of caspase activation, Hsp70 co-localizes and interacts with GATA-1 in the nucleus of erythroid precursors undergoing terminal differentiation. PMID:9499401 the molecular chaperone Hsp70 and the cochaperone Hdj1 interact directly with the transactivation domain of HSF1 and repress heat shock gene transcription. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: HSPA1A is predominantly cytoplasmic under basal conditions. This is well-established by multiple IDA studies (PMID:24061851, PMID:10859165, PMID:11785981, PMID:24790089, PMID:9553041) and consistent with its role as a cytoplasmic chaperone. IBA annotation is phylogenetically sound and strongly supported. Reason: Cytoplasmic localization is the primary location of HSPA1A, confirmed by numerous independent studies and consistent with its core chaperone function. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: HSPA1A plasma membrane association is supported by evidence showing it can function as an extracellular receptor ligand via Tag7/PGLYRP1-Hsp70 complexes that interact with TNFR1 on cell surfaces (PMID:26183779), and is consistent with extracellular HSP70 signaling (PMID:17568691). The rotavirus receptor citation is not used here because the available local evidence points to Hsc70 rather than HSPA1A. Reason: Plasma membrane association is supported by extracellular HSP70 signaling evidence and phylogenetically consistent for HSP70 family members, without relying on the mismatched rotavirus receptor citation. Supporting Evidence: PMID:26183779 Tag7 (PGLYRP1) in Complex with Hsp70 Induces Alternative Cytotoxic Processes in Tumor Cells via TNFR1 Receptor |
| GO:0016887 ATP hydrolysis activity | IBA GO_REF:0000033 | ACCEPT | Summary: ATP hydrolysis activity is a core molecular function of HSPA1A. The N-terminal nucleotide binding domain (NBD) possesses intrinsic ATPase activity that is stimulated by J-domain co-chaperones (PMID:21231916). The ATPase cycle drives conformational changes between open (ATP-bound) and closed (ADP-bound) states of the substrate binding domain, which is essential for chaperone function. The ADP state of the Hsp70 NBD and its remodeling by the Hsp110 nucleotide-exchange factor are structurally defined in the Hsp70-Hsp110 (Sse1p) complex (PDB 3D2E/3D2F), where ATP-bound Hsp110 embraces the Hsp70 NBD and triggers release of bound ADP, resetting the ATPase cycle (PMID:18555782). Directly demonstrated by IDA evidence (PMID:21231916, PMID:23921388). IBA annotation is phylogenetically sound and represents a core function of all HSP70 family members. Reason: ATP hydrolysis is the fundamental enzymatic activity driving the HSPA1A chaperone cycle. Confirmed by direct assay (PMID:21231916). This is a core conserved function of the entire HSP70 family. Supporting Evidence: PMID:21231916 we assessed the effect of overexpression of each of these HSPs on refolding of heat-denatured luciferase and on the suppression of aggregation of a non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment PMID:18555782 Protein folding by Hsp70 is tightly controlled by cochaperones, including J-domain proteins that trigger ATP hydrolysis and nucleotide exchange factors (NEFs) that remove ADP from Hsp70. |
| GO:0031072 heat shock protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: HSPA1A interacts with numerous heat shock proteins as part of its chaperone function. It binds HSP40/DNAJ co-chaperones (PMID:22219199, PMID:21231916), HSP90 via the HOP/STIP1 adapter (Reactome:R-HSA-3371503), HSP110 nucleotide exchange factors (PMID:24318877), and small HSPs. These interactions are central to its chaperone cycle. The Hsp70-Hsp110 interaction is structurally defined by the crystal structure of the Hsp110 NEF (yeast Sse1p) bound to the Hsp70 nucleotide-binding domain (PDB 3D2E/3D2F), in which Hsp110 (ATP-bound) embraces the Hsp70 NBD and drives ADP release (PMID:18555782). IBA annotation is well-supported and phylogenetically sound. Reason: Heat shock protein binding is a core property of HSPA1A, essential for its chaperone cycle. Binding to J-domain co-chaperones (HSP40s), HSP110/NEFs, and HSP90 are all well-documented. Supporting Evidence: PMID:22219199 The C-terminal helices of heat shock protein 70 are essential for J-domain binding and ATPase activation PMID:23921388 we identified the methyltransferase METTL21A as the enzyme responsible for trimethylation of a conserved lysine residue found in several human Hsp70 (HSPA) proteins. PMID:18555782 the crystal structure of the yeast NEF Sse1p (Hsp110) in complex with the nucleotide-binding domain (NBD) of Hsp70 PMID:18555782 together with the 3HBD it embraces the NBD of Hsp70, inducing opening and the release of bound ADP from Hsp70 |
| GO:0044183 protein folding chaperone | IBA GO_REF:0000033 | ACCEPT | Summary: Protein folding chaperone is the core molecular function of HSPA1A. Hageman et al. (2011) directly demonstrated that HSPA1A has foldase activity in luciferase refolding assays, and also suppresses polyQ aggregation and protects cells from heat-induced death (PMID:21231916). Kalia et al. (2004) also showed chaperone activity via refolding assays inhibited by BAG5 (PMID:15603737). IBA annotation is phylogenetically sound and confirmed by multiple IDA studies. Reason: This is the primary molecular function of HSPA1A. Directly demonstrated by multiple independent studies (PMID:21231916, PMID:15603737). Conserved across the HSP70 family. Supporting Evidence: PMID:21231916 Overexpressed chaperones that suppressed polyQ aggregation were found not to be able to stimulate luciferase refolding. Inversely, chaperones that supported luciferase refolding were poor suppressors of polyQ aggregation. file:human/HSPA1A/HSPA1A-deep-research-falcon.md HSPA1A is the stress-inducible cytosolic Hsp70-1A chaperone whose ATPase cycle drives client binding, folding/refolding, and proteostasis triage. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Cytosol is the primary subcellular location where HSPA1A functions as a chaperone. Confirmed by IDA (PMID:21231916) and multiple Reactome pathway annotations that place HSPA1A in the cytosol for chaperone cycle reactions. IBA annotation is phylogenetically sound. Reason: Cytosolic localization is the primary site of HSPA1A chaperone function. Confirmed by direct assay and consistent with all known chaperone cycle components. |
| GO:0042026 protein refolding | IBA GO_REF:0000033 | ACCEPT | Summary: Protein refolding is a core biological process for HSPA1A. Hageman et al. (2011) directly demonstrated luciferase refolding activity for HSPA1A (PMID:21231916). Kalia et al. (2004) showed BAG5 inhibits Hsp70-mediated refolding of denatured proteins (PMID:15603737). The refolding function is ATP-dependent and requires J-domain co-chaperones. IBA annotation is phylogenetically sound and confirmed by IDA evidence. Reason: Protein refolding is a core process carried out by HSPA1A. Directly demonstrated by luciferase refolding assays (PMID:21231916, PMID:15603737). Conserved function across HSP70 family. Supporting Evidence: PMID:21231916 we assessed the effect of overexpression of each of these HSPs on refolding of heat-denatured luciferase PMID:15603737 Within this complex, BAG5 inhibits both parkin E3 ubiquitin ligase activity and Hsp70-mediated refolding of misfolded proteins. |
| GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: HSPA1A promotes proteasomal degradation of substrates via its interaction with the CHIP/STUB1 ubiquitin ligase. Hsp70 delivers misfolded substrates to CHIP for ubiquitination and proteasomal degradation. Shang et al. (2014) showed Hsp70 enhances CHIP-induced ubiquitination and degradation of Smad3 (PMID:24613385). Imai et al. (2002) showed CHIP-Hsp70-Parkin complex promotes ubiquitination of Pael-R (PMID:12150907). The acetylation state of HSPA1A (by NAA10/ARD1) determines whether substrates are directed toward refolding or degradation (PMID:27708256). IBA annotation is well-supported. Reason: HSPA1A promotes proteasomal degradation of substrates through CHIP/STUB1, a well-established arm of the chaperone triage decision. Confirmed by IDA (PMID:24613385) and multiple studies showing CHIP-Hsp70 mediated ubiquitination. Supporting Evidence: PMID:24613385 over-expressed Hsp70 or inhibition of Hsp90 by geldanamycin (GA) leads to facilitated CHIP-induced ubiquitination and degradation of Smad3 |
| GO:0046718 symbiont entry into host cell | IEA GO_REF:0000108 | REMOVE | Summary: The source evidence for this rotavirus-entry inference is PMID:16537599, but the local UniProt citation describes recombinant hsc70 rather than HSPA1A/Hsp72. This is therefore a paralog/evidence mismatch for HSPA1A. Reason: The cited rotavirus receptor evidence does not establish HSPA1A-specific symbiont entry activity; it should not be retained for HSPA1A without HSPA1A-specific support. |
| GO:0000166 nucleotide binding | IEA GO_REF:0000043 | ACCEPT | Summary: HSPA1A binds ATP and ADP as part of its core chaperone cycle. The N-terminal nucleotide-binding domain (NBD) binds and hydrolyzes ATP, which drives the conformational changes essential for chaperone function (PMID:21231916, PMID:23921388). The nucleotide-bound (ADP) state of the Hsp70 NBD and its remodeling by the Hsp110 nucleotide-exchange factor are structurally defined in the Hsp70-Hsp110 (Sse1p) complex (PDB 3D2E/3D2F), where Hsp110 binding induces opening and release of bound ADP from the Hsp70 NBD (PMID:18555782). Nucleotide binding is a correct but very broad parent term; the more specific GO:0005524 ATP binding is already annotated. Reason: Nucleotide binding is accurate for HSPA1A. While broader than GO:0005524 (ATP binding), it is acceptable as an IEA annotation that captures the fundamental nucleotide-binding property of the NBD. Supporting Evidence: PMID:18555782 together with the 3HBD it embraces the NBD of Hsp70, inducing opening and the release of bound ADP from Hsp70 PMID:18555782 Protein folding by Hsp70 is tightly controlled by cochaperones, including J-domain proteins that trigger ATP hydrolysis and nucleotide exchange factors (NEFs) that remove ADP from Hsp70. |
| GO:0001618 virus receptor activity | IEA GO_REF:0000043 | REMOVE | Summary: The rotavirus receptor evidence cited for this annotation is PMID:16537599, but the local UniProt citation identifies the tested protein as recombinant hsc70 rather than HSPA1A/Hsp72. The annotation therefore appears to transfer an HSPA8/Hsc70-related observation onto HSPA1A. Reason: Virus receptor activity is not supported by HSPA1A-specific evidence in the available local citation and should not be retained for HSPA1A. |
| GO:0001664 G protein-coupled receptor binding | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: This IEA annotation likely derives from the Hsp70-Pael-R interaction described in PMID:12150907. Pael-R (GPR37) is a GPCR, and Hsp70 forms a complex with CHIP, Parkin, and unfolded Pael-R. However, Hsp70 binds the unfolded Pael-R as a chaperone substrate, not as a GPCR ligand engaging in canonical receptor binding. The term "G protein-coupled receptor binding" is misleading here. Reason: Hsp70 binds unfolded Pael-R (a GPCR) in the context of chaperone-mediated quality control and CHIP/Parkin-directed ubiquitination (PMID:12150907), not as a functional GPCR binding partner. This is chaperone-substrate interaction, not receptor binding in the signaling sense. Supporting Evidence: PMID:12150907 CHIP, Hsp70, Parkin, and Pael-R formed a complex in vitro and in vivo. The amount of CHIP in the complex was increased during ER stress. |
| GO:0005524 ATP binding | IEA GO_REF:0000120 | ACCEPT | Summary: ATP binding is a core molecular function of HSPA1A. The N-terminal NBD binds ATP, and crystal structures of HSPA1A in complex with ATP analogs have been solved (PDB:2E88, 2E8A). Directly confirmed by IDA (PMID:23921388). Reason: ATP binding is fundamental to the HSPA1A chaperone cycle and is confirmed by structural and biochemical evidence. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: HSPA1A is released extracellularly and detected in exosomes, blood microparticles, and as free protein in necrotic cell supernatants (PMID:17568691, PMID:26183779). UniProt annotates HSPA1A as secreted. Confirmed by IDA evidence from PMID:17568691 and PMID:26183779. Reason: Extracellular localization is supported by multiple independent studies showing HSPA1A release from cells and its presence in extracellular fluids and exosomes. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Duplicate of the IBA-reviewed nuclear localization annotation. HSPA1A nuclear localization is well-established by multiple IDA studies (PMID:17167422, PMID:10205060, PMID:9553041) and the IBA annotation is already accepted. Reason: IEA annotation consistent with the already-accepted IBA annotation and multiple IDA confirmations. Nuclear localization is well-established for HSPA1A. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Duplicate of the IBA-reviewed cytoplasm annotation. Cytoplasm is the primary location of HSPA1A under basal conditions. Confirmed by numerous IDA studies. Reason: IEA annotation consistent with the already-accepted IBA annotation and multiple IDA confirmations. |
| GO:0005813 centrosome | IEA GO_REF:0000044 | ACCEPT | Summary: HSPA1A accumulates at mitotic centrosomes during prometaphase to metaphase and is required for bipolar spindle assembly (PMID:27137183). UniProt confirms centrosome localization. Also confirmed by IDA (PMID:27137183). Reason: Centrosome localization is experimentally confirmed by Fang et al. 2016 (PMID:27137183) who demonstrated HSP70 accumulation at mitotic centrosomes and its role in centrosome integrity. Supporting Evidence: PMID:27137183 heat shock protein (HSP) 70 considerably accumulates at the mitotic centrosome during prometaphase to metaphase and is required for bipolar spindle assembly. |
| GO:0005814 centriole | IEA GO_REF:0000117 | ACCEPT | Summary: HSPA1A localizes to centrioles upon thermal stress in human neuronal cells (PMID:24061851). Specifically targets the proximal end of centrioles identified by gamma-tubulin marker. Confirmed by IDA (PMID:24061851) and GO_REF:0000052 (immunofluorescence-based). Reason: Centriole localization is experimentally confirmed by Khalouei et al. 2014 (PMID:24061851) using YFP-tagged HSPA1A in neuronal cells. Supporting Evidence: PMID:24061851 Following a brief period of thermal stress, YFP-tagged HSPA6 and HSPA1A rapidly appeared at centrioles in the cytoplasm of human neuronal cells |
| GO:0006402 mRNA catabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Hsp70 participates in AU-rich element-mediated mRNA decay. Heat shock induces Hsp70 sequestration of AUF1 into the perinucleus/nucleus, blocking decay of AU-rich mRNAs (PMID:10205060). However, Hsp70 blocks mRNA decay rather than promoting it. The role is indirect and regulatory rather than direct participation in mRNA catabolism. Reason: HSPA1A modulates mRNA decay through the AUF1-ubiquitin-proteasome pathway (PMID:10205060), but this is an indirect regulatory role secondary to its primary chaperone function. Supporting Evidence: PMID:10205060 Induction of hsp70 by heat shock, down-regulation of the ubiquitin-proteasome network, or inactivation of ubiquitinating enzyme E1 all result in hsp70 sequestration of AUF1 in the perinucleus-nucleus, and all three processes block decay of AU-rich mRNAs and AUF1 protein. |
| GO:0008285 negative regulation of cell population proliferation | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: This derives from the WT1-Hsp70 interaction study (PMID:9553041) where Hsp70 is required for WT1-mediated growth suppression. However, the antiproliferative effect is mediated by WT1, not by Hsp70 itself; Hsp70 acts as a cofactor/chaperone for WT1. This is not a direct function of HSPA1A. Reason: The negative regulation of cell proliferation requires WT1, with Hsp70 serving as a cofactor (PMID:9553041). This represents a chaperone client effect, not a direct HSPA1A function in proliferation control. Supporting Evidence: PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires association with the inducible chaperone Hsp70. |
| GO:0016235 aggresome | IEA GO_REF:0000117 | ACCEPT | Summary: HSPA1A localizes to aggresomes. PMID:15885686 shows TRIM37 forms ubiquitin- and chaperone-positive aggresomes. Confirmed by IDA (PMID:15885686). Reason: Aggresome localization is confirmed by IDA evidence (PMID:15885686) and is consistent with HSPA1A's role in protein quality control and handling of misfolded proteins. |
| GO:0016607 nuclear speck | IEA GO_REF:0000117 | ACCEPT | Summary: HSPA1A localizes to nuclear speck-like structures upon association with WT1 (PMID:9553041). Maheswaran et al. showed Hsp70 is recruited to characteristic subnuclear clusters containing WT1. Confirmed by IDA (PMID:9553041). Reason: Nuclear speck localization is confirmed by IDA (PMID:9553041) showing colocalization of Hsp70 with WT1 in subnuclear clusters. Supporting Evidence: PMID:9553041 Hsp70 is recruited to the characteristic subnuclear clusters that contain WT1. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate of the IBA-reviewed ATP hydrolysis annotation. ATP hydrolysis is a core enzymatic activity of HSPA1A confirmed by IDA (PMID:21231916). Reason: IEA annotation consistent with the already-accepted IBA annotation and confirmed by direct assay. |
| GO:0030308 negative regulation of cell growth | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Similar to GO:0008285, this likely derives from the WT1-Hsp70 study (PMID:9553041). The growth inhibition is a property of WT1 that requires Hsp70 as a cofactor. Hsp70 does not directly regulate cell growth. Reason: As with negative regulation of cell proliferation, the cell growth effect is mediated by WT1 with Hsp70 as a chaperone cofactor (PMID:9553041). This is an over-annotation of HSPA1A function. |
| GO:0031072 heat shock protein binding | IEA GO_REF:0000117 | ACCEPT | Summary: Duplicate of the IBA-reviewed heat shock protein binding annotation. HSPA1A interacts with multiple HSPs including DNAJ/HSP40 co-chaperones, HSP90, and HSP110/HSPH1. Core property confirmed by numerous IPI studies. Reason: IEA annotation consistent with the already-accepted IBA annotation and extensive experimental evidence. |
| GO:0031397 negative regulation of protein ubiquitination | IEA GO_REF:0000117 | ACCEPT | Summary: HSPA1A can inhibit protein ubiquitination by competing with CHIP/STUB1 for substrate binding. In the CHIP-Hsp70-Parkin complex, Hsp70 can sequester substrates and prevent their ubiquitination until CHIP promotes Hsp70 dissociation (PMID:12150907). Confirmed by IDA (PMID:12150907). Reason: Negative regulation of ubiquitination is a genuine property of Hsp70 chaperone triage. Hsp70 binding to substrates can shield them from ubiquitin ligases until the appropriate signal triggers degradation (PMID:12150907). Supporting Evidence: PMID:12150907 CHIP promoted the dissociation of Hsp70 from Parkin and Pael-R, thus facilitating Parkin-mediated Pael-R ubiquitination. |
| GO:0031625 ubiquitin protein ligase binding | IEA GO_REF:0000117 | ACCEPT | Summary: HSPA1A interacts directly with ubiquitin ligases including CHIP/STUB1 (via TPR repeats) and Parkin (PMID:12150907, PMID:15603737, PMID:24613385). This is a core interaction mediating chaperone-directed degradation. Confirmed by multiple IPI studies. Reason: Ubiquitin protein ligase binding is a core property of HSPA1A, mediating the chaperone triage decision between refolding and degradation. The HSPA1A-CHIP/STUB1 interaction is well-established. |
| GO:0032757 positive regulation of interleukin-8 production | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: HSPA1A stabilizes NOD2, which activates NF-kappaB signaling and downstream IL-8 production (PMID:24790089). This is an indirect effect mediated through NOD2 stabilization. Confirmed by IMP (PMID:24790089). Reason: Positive regulation of IL-8 production is an indirect downstream consequence of HSPA1A's chaperone-mediated stabilization of NOD2, not a direct function of HSPA1A (PMID:24790089). |
| GO:0034599 cellular response to oxidative stress | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: HSPA1A is induced by oxidative stress and provides cytoprotection. The TAS reference PMID:24252804 (a review on oxidative stress in Parkinson's disease) discusses the role of chaperones including Hsp70 in response to oxidative damage. This is a well-established general stress response. Reason: HSPA1A responds to and provides protection against oxidative stress as part of its general cytoprotective role, but this is a secondary response, not its core function. |
| GO:0042026 protein refolding | IEA GO_REF:0000117 | ACCEPT | Summary: Duplicate of the IBA-reviewed protein refolding annotation. Protein refolding is a core process carried out by HSPA1A, confirmed by IDA (PMID:21231916, PMID:15603737). Reason: IEA annotation consistent with the already-accepted IBA annotation and confirmed by direct assay evidence. |
| GO:0042826 histone deacetylase binding | IEA GO_REF:0000117 | ACCEPT | Summary: HSPA1A interacts with HDAC4, which deacetylates Hsp70 at Lys-77 during the later stages of the stress response. This deacetylation switches Hsp70 from protein refolding to protein degradation mode (PMID:27708256). Also, HDAC8-phosphorylated form recruits Hsp70 to a complex (PMID:16809764). Confirmed by IPI (PMID:16809764). Reason: Histone deacetylase binding is confirmed by experimental evidence. HDAC4 deacetylates Hsp70 at K77 to switch its co-chaperone preference (PMID:27708256), and HDAC8 recruits Hsp70 to the hEST1B complex (PMID:16809764). Supporting Evidence: PMID:27708256 Here, we demonstrate that Hsp70 preferentially facilitates protein refolding after stress, gradually switching to protein degradation via a mechanism dependent on ARD1-mediated Hsp70 acetylation PMID:16809764 Phosphorylated HDAC8 preferentially recruits Hsp70 to a complex that inhibits the CHIP (C-terminal heat shock protein interacting protein) E3 ligase-mediated degradation of hEST1B. |
| GO:0044183 protein folding chaperone | IEA GO_REF:0000117 | ACCEPT | Summary: Duplicate of the IBA-reviewed protein folding chaperone annotation. This is the core molecular function of HSPA1A. Confirmed by IDA (PMID:21231916, PMID:15603737). Reason: IEA annotation consistent with the already-accepted IBA annotation and confirmed by direct assay evidence. Core molecular function of HSPA1A. |
| GO:0045648 positive regulation of erythrocyte differentiation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: HSPA1A protects GATA-1 from caspase-3 cleavage during erythroid terminal differentiation, enabling proper erythropoiesis (PMID:17167422). Confirmed by IMP (PMID:17167422). Reason: Positive regulation of erythrocyte differentiation is experimentally supported (PMID:17167422) but represents a tissue-specific non-core function of HSPA1A, where its chaperone activity protects GATA-1 during erythropoiesis. Supporting Evidence: PMID:17167422 during differentiation, but not during apoptosis, the chaperone protein Hsp70 protects GATA-1 from caspase-mediated proteolysis. |
| GO:0046034 ATP metabolic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: HSPA1A hydrolyzes ATP as part of its chaperone cycle, but ATP metabolic process is a broad biological-process term. The actual molecular activity is captured by ATP hydrolysis activity and ATP-dependent chaperone terms. Reason: This broad BP term is less informative than the molecular-function terms describing HSPA1A's ATPase-driven chaperone cycle. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000117 | ACCEPT | Summary: Hsp70 sequesters AUF1 in the perinucleus/nucleus during heat shock (PMID:10205060). Also confirmed by IDA showing BAG5-Hsp70 perinuclear localization (PMID:15603737). Confirmed by multiple IDA studies. Reason: Perinuclear localization is confirmed by IDA (PMID:10205060, PMID:15603737) and consistent with HSPA1A's role in mRNA decay regulation and client protein handling. Supporting Evidence: PMID:10205060 Induction of hsp70 by heat shock [...] result in hsp70 sequestration of AUF1 in the perinucleus-nucleus |
| GO:0050821 protein stabilization | IEA GO_REF:0000117 | ACCEPT | Summary: HSPA1A stabilizes client proteins, including NOD2 (PMID:24790089) and intrinsically disordered proteins (PMID:21909508). Hsp70 binding increases NOD2 half-life. Confirmed by IDA (PMID:21909508) and IMP (PMID:24790089). Reason: Protein stabilization is a genuine function of HSPA1A chaperone activity, demonstrated for multiple substrates including NOD2 (PMID:24790089). Supporting Evidence: PMID:24790089 HSP70 to regulate the half-life of NOD2, as increasing the HSP70 level in cells increased the half-life of NOD2, and down-regulating HSP70 decreased the half-life of NOD2. |
| GO:0051082 unfolded protein binding | IEA GO_REF:0000117 | MODIFY | Summary: GO:0051082 "unfolded protein binding" is now formally obsolete (go-ontology#30962). HSPA1A is a bona fide molecular chaperone with demonstrated foldase activity (luciferase refolding) and aggregation suppression (PMID:21231916). The term "unfolded protein binding" describes only the substrate-binding aspect and misses the active chaperone function. HSPA1A already has an IBA annotation to GO:0044183 "protein folding chaperone" which accurately captures its core molecular function. This IEA annotation from ARBA machine learning should be replaced with GO:0044183. Reason: GO:0051082 is now formally obsolete. HSPA1A has genuine protein folding chaperone activity, not merely unfolded protein binding. The protein actively refolds substrates in an ATP-dependent manner, as demonstrated by Hageman et al. (PMID:21231916). The IBA annotation to GO:0044183 already correctly captures this function. This IEA annotation should be modified to GO:0044183 to align with the term obsoletion and to more accurately represent the molecular function. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:21231916 Overexpressed chaperones that suppressed polyQ aggregation were found not to be able to stimulate luciferase refolding. Inversely, chaperones that supported luciferase refolding were poor suppressors of polyQ aggregation. [...] overexpression of HSPA1A protected cells from heat-induced cell death |
| GO:0055131 C3HC4-type RING finger domain binding | IEA GO_REF:0000117 | ACCEPT | Summary: HSPA1A interacts with RING finger E3 ubiquitin ligases including CHIP/STUB1, which contains a U-box domain (structurally related to RING), and TRIM37, a RING E3 ligase (PMID:15885686). The annotation captures the binding of Hsp70 to RING-type E3 ligases as part of the chaperone-ubiquitin triage system. Reason: HSPA1A binding to RING-type E3 ubiquitin ligases is a well-established aspect of chaperone-mediated protein quality control. Supported by interactions with CHIP/STUB1 and TRIM37 (PMID:15885686, PMID:12150907). Supporting Evidence: PMID:15885686 TRIM37 defective in mulibrey nanism is a novel RING finger ubiquitin E3 ligase. PMID:12150907 CHIP, Hsp70, Parkin, and Pael-R formed a complex in vitro and in vivo. |
| GO:0070370 cellular heat acclimation | IEA GO_REF:0000117 | ACCEPT | Summary: HSPA1A is a central effector of thermotolerance/heat acclimation. Hageman et al. (2011) showed that overexpression of HSPA1A protected cells from heat-induced cell death (PMID:21231916). Hsp70 is a primary effector of acquired thermotolerance. Reason: Cellular heat acclimation (thermotolerance) is a core function of HSPA1A. Directly demonstrated by PMID:21231916 showing HSPA1A overexpression protects from heat-induced cell death. Supporting Evidence: PMID:21231916 whereas overexpression of HSPA1A protected cells from heat-induced cell death, overexpression of HSPA6 did not |
| GO:0070434 positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: HSPA1A stabilizes NOD2 and enhances its signaling capacity. Mohanan & Grimes (2014) showed that HSP70 binds and stabilizes NOD2, increasing its half-life and NF-kappaB signaling in response to bacterial cell wall fragments (PMID:24790089). Reason: Positive regulation of NOD2 signaling is experimentally supported (PMID:24790089) but is a downstream effect of HSPA1A's chaperone-mediated stabilization of NOD2, not a core function. Supporting Evidence: PMID:24790089 Induced HSP70 expression in cells increased the response of NOD2 to bacterial cell wall fragments. |
| GO:0071383 cellular response to steroid hormone stimulus | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: HSPA1A participates in the HSP90 chaperone cycle for steroid hormone receptors (SHR). Hsp70 binds nascent/misfolded steroid hormone receptors and transfers them to HSP90 via HOP/STIP1 (Reactome:R-HSA-3371497). This is part of the general chaperone pathway rather than a specific response to steroid hormones. Reason: HSPA1A participates in the HSP90 chaperone cycle for steroid hormone receptors as a general chaperone, not as a specific steroid hormone response gene. Supported by Reactome pathway R-HSA-3371497. |
| GO:0090063 positive regulation of microtubule nucleation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Fang et al. (2016) showed HSP70 accumulates at mitotic centrosomes and is required for microtubule nucleation and bipolar spindle assembly. Loss of HSP70 reduced accumulation of NEDD1 and gamma-tubulin at mitotic centrosomes, disrupting MT nucleation (PMID:27137183). Reason: Positive regulation of microtubule nucleation is experimentally confirmed (PMID:27137183) but represents a specific cell-cycle role rather than the core chaperone function of HSPA1A. Supporting Evidence: PMID:27137183 Inhibition or depletion of HSP70 impaired the function of mitotic centrosome and disrupted MT nucleation and polymerization from the spindle pole |
| GO:0090084 negative regulation of inclusion body assembly | IEA GO_REF:0000117 | ACCEPT | Summary: HSPA1A suppresses aggregation and inclusion body formation. Hageman et al. (2011) showed HSPA1A suppresses polyQ aggregation (PMID:21231916). Kalia et al. (2004) showed BAG5 inhibits Hsp70-mediated suppression of protein aggregation, and that BAG5 enhances parkin sequestration within protein aggregates (PMID:15603737). Reason: Suppression of inclusion body/aggregate formation is a core chaperone function of HSPA1A, directly demonstrated by multiple studies (PMID:21231916, PMID:15603737). Supporting Evidence: PMID:21231916 we assessed the effect of overexpression of each of these HSPs on refolding of heat-denatured luciferase and on the suppression of aggregation of a non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment. |
| GO:0140545 ATP-dependent protein disaggregase activity | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: This ARBA inference cites PMID:23921388, but the local paper describes METTL21A methylation and altered HSPA8/Hsc70 affinity for alpha-synuclein, not direct HSPA1A ATP-dependent disaggregase activity. HSP70-family disaggregation can require HSP110/HSP40 systems, but this evidence does not establish HSPA1A-specific disaggregase activity. Reason: The annotation overextends family-level proteostasis biology and HSPA8-focused evidence to HSPA1A. HSPA1A's accepted core role should remain ATP-dependent folding/refolding and client triage unless direct HSPA1A disaggregase evidence is available. Supporting Evidence: PMID:23921388 we show that trimethylation of HSPA8 (Hsc70) has functional consequences, as it alters the affinity of the chaperone for both the monomeric and fibrillar forms of the Parkinson disease-associated protein alpha-synuclein. |
| GO:1901673 regulation of mitotic spindle assembly | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Fang et al. (2016) demonstrated HSP70 is required for bipolar mitotic spindle assembly. Inhibition or depletion of HSP70 disrupted MT nucleation from spindle poles and resulted in abnormal mitotic spindles (PMID:27137183). Reason: Regulation of mitotic spindle assembly is experimentally supported (PMID:27137183) but represents a cell-cycle-specific role, not the core chaperone function. Supporting Evidence: PMID:27137183 In this study, we showed that heat shock protein (HSP) 70 considerably accumulates at the mitotic centrosome during prometaphase to metaphase and is required for bipolar spindle assembly. |
| GO:1903265 positive regulation of tumor necrosis factor-mediated signaling pathway | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Extracellular Hsp70 promotes TNF signaling. Tag7/PGLYRP1-Hsp70 complex induces cytotoxic processes in tumor cells via TNFR1 (PMID:26183779). Also, necrotic cell-released Hsp70 augments TNF-alpha responses (PMID:17568691). Reason: Positive regulation of TNF signaling is supported for extracellular Hsp70 (PMID:26183779, PMID:17568691) but is a non-core extracellular signaling function distinct from the primary intracellular chaperone role. Supporting Evidence: PMID:26183779 Tag7 (PGLYRP1) in Complex with Hsp70 Induces Alternative Cytotoxic Processes in Tumor Cells via TNFR1 Receptor. |
| GO:1904813 ficolin-1-rich granule lumen | IEA GO_REF:0000117 | ACCEPT | Summary: HSPA1A is found in ficolin-1-rich granule lumen, a neutrophil granule compartment. This localization is supported by Reactome pathway R-HSA-6800434 and consistent with the detection of Hsp70 in immune cell granules. Reason: Ficolin-1-rich granule lumen localization is supported by Reactome and consistent with known immune cell biology of extracellular Hsp70. |
| GO:1990904 ribonucleoprotein complex | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: HSPA1A associates with IMP1 ribonucleoprotein granules. Jonson et al. (2007) identified Hsp70 among the molecular composition of IMP1 RNP granules by mass spectrometry (PMID:17289661). This is consistent with Hsp70's known role in mRNA metabolism via AUF1. Reason: Ribonucleoprotein complex association is experimentally supported (PMID:17289661) but represents a secondary localization rather than a core function. Supporting Evidence: PMID:17289661 Molecular composition of IMP1 ribonucleoprotein granules. |
| GO:2001240 negative regulation of extrinsic apoptotic signaling pathway in absence of ligand | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: HSPA1A inhibits the extrinsic apoptotic signaling pathway. During erythropoiesis, Hsp70 protects GATA-1 from caspase-3 cleavage, preventing apoptosis during differentiation. Erythropoietin starvation induces nuclear export of Hsp70, leading to GATA-1 cleavage and apoptosis (PMID:17167422). Reason: Negative regulation of extrinsic apoptotic signaling is experimentally supported (PMID:17167422) but represents an indirect anti-apoptotic effect of the chaperone, not a core molecular function. Supporting Evidence: PMID:17167422 during differentiation, but not during apoptosis, the chaperone protein Hsp70 protects GATA-1 from caspase-mediated proteolysis. |
| GO:0005515 protein binding | IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0005515 protein binding | IPI PMID:24338975 Discovery of multiple interacting partners of gankyrin, a pr... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0005515 protein binding | IPI PMID:24428437 Mutations in the substrate binding site of human heat-shock ... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IMP PMID:24790089 The molecular chaperone HSP70 binds to and stabilizes NOD2, ... | KEEP AS NON CORE | Summary: Mohanan & Grimes (2014) showed HSP70 stabilizes NOD2 which activates NF-kappaB. HSP70 overexpression increased NOD2-mediated NF-kappaB activation in response to bacterial cell wall fragments. HSP70 inhibitor KNK437 decreased NOD2-mediated NF-kappaB activation (PMID:24790089). Reason: Positive regulation of NF-kappaB is an indirect downstream effect of HSPA1A stabilizing NOD2 (PMID:24790089). Not a core chaperone function. Supporting Evidence: PMID:24790089 an HSP70 inhibitor, KNK437, was capable of decreasing NOD2-mediated NF-kappaB activation in response to bacterial cell wall stimulation. |
| GO:0070434 positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway | IMP PMID:24790089 The molecular chaperone HSP70 binds to and stabilizes NOD2, ... | KEEP AS NON CORE | Summary: Mohanan & Grimes (2014) showed HSP70 binds and stabilizes NOD2, increasing its half-life and enhancing signaling capacity in response to bacterial cell wall fragments (PMID:24790089). Confirmed by IMP evidence. Reason: Experimentally confirmed (PMID:24790089) but represents a downstream effect of HSPA1A chaperone-mediated NOD2 stabilization, not a core function. Supporting Evidence: PMID:24790089 Induced HSP70 expression in cells increased the response of NOD2 to bacterial cell wall fragments. |
| GO:0005814 centriole | IDA GO_REF:0000052 | ACCEPT | Summary: HSPA1A localizes to centrioles upon thermal stress in human neuronal cells. Khalouei et al. (2014) showed YFP-tagged HSPA1A rapidly appeared at centrioles following thermal stress, targeting the proximal end identified by gamma-tubulin marker (PMID:24061851). Confirmed by IDA (immunofluorescence-based). Reason: Centriole localization is experimentally confirmed by immunofluorescence (PMID:24061851). Supporting Evidence: PMID:24061851 Following a brief period of thermal stress, YFP-tagged HSPA6 and HSPA1A rapidly appeared at centrioles in the cytoplasm of human neuronal cells |
| GO:0071383 cellular response to steroid hormone stimulus | TAS Reactome:R-HSA-3371497 | KEEP AS NON CORE | Summary: HSPA1A participates in the HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand (Reactome:R-HSA-3371497). Hsp70 binds nascent/misfolded steroid hormone receptors and hands them off to HSP90 via HOP/STIP1. Reason: HSPA1A participates in the HSP90 chaperone cycle for SHRs as a general chaperone; this is not a specific steroid hormone response. Supported by Reactome pathway. |
| GO:0030968 endoplasmic reticulum unfolded protein response | IDA PMID:20625543 HSP72 protects cells from ER stress-induced apoptosis via en... | KEEP AS NON CORE | Summary: Gupta et al. (2010) showed Hsp72 (HSPA1A) enhances the IRE1alpha-XBP1 arm of the UPR. Hsp72 forms a stable complex with the cytosolic domain of IRE1alpha and enhances its RNase activity, promoting XBP1 mRNA splicing and cell survival under ER stress (PMID:20625543). Reason: Participation in the ER UPR is experimentally confirmed (PMID:20625543) but represents a secondary cytoprotective function of HSPA1A rather than its core chaperone activity. Supporting Evidence: PMID:20625543 binding of Hsp72 to IRE1alpha enhances IRE1alpha/XBP1 signaling at the ER and inhibits ER stress-induced apoptosis. |
| GO:0016887 ATP hydrolysis activity | TAS Reactome:R-HSA-3371422 | ACCEPT | Summary: ATP hydrolysis by HSP70 is a Reactome-curated reaction (R-HSA-3371422). This is the core enzymatic activity of HSPA1A, confirmed by IDA (PMID:21231916) and IBA evidence. Reason: ATP hydrolysis is a core enzymatic activity of HSPA1A. Consistent with already-accepted IBA and IDA annotations. Reactome pathway correctly represents this activity. |
| GO:0005515 protein binding | IPI PMID:17182002 HDJC9, a novel human type C DnaJ/HSP40 member interacts with... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0005515 protein binding | IPI PMID:21231916 The diverse members of the mammalian HSP70 machine show dist... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:9499401 Molecular chaperones as HSF1-specific transcriptional repres... | KEEP AS NON CORE | Summary: Shi et al. (1998) showed Hsp70 and Hdj1 directly interact with the transactivation domain of HSF1 and repress heat shock gene transcription. Overexpression of Hsp70 represses transcriptional activity of endogenous HSF1 without affecting its DNA binding (PMID:9499401). This represents a bona fide transcriptional repression function. Reason: Negative regulation of transcription is experimentally confirmed for HSF1-dependent gene transcription (PMID:9499401). This represents the autoregulatory feedback loop of the heat shock response, a well-established but non-core regulatory function. Supporting Evidence: PMID:9499401 the molecular chaperone Hsp70 and the cochaperone Hdj1 interact directly with the transactivation domain of HSF1 and repress heat shock gene transcription. |
| GO:0034605 cellular response to heat | IDA PMID:9499401 Molecular chaperones as HSF1-specific transcriptional repres... | ACCEPT | Summary: HSPA1A is a primary effector of the cellular response to heat. Shi et al. (1998) demonstrated Hsp70 represses HSF1 transcriptional activity during heat shock attenuation (PMID:9499401). HSPA1A is strongly induced by heat stress and is the canonical heat shock response gene. Reason: Cellular response to heat is a defining biological process for HSPA1A. It is both induced by and a primary effector of the heat shock response (PMID:9499401, PMID:21231916). Supporting Evidence: PMID:9499401 the repression of heat shock gene transcription, which occurs during attenuation, is due to the association of Hsp70 with the HSF1 transactivation domain |
| GO:0140416 transcription regulator inhibitor activity | IDA PMID:9499401 Molecular chaperones as HSF1-specific transcriptional repres... | KEEP AS NON CORE | Summary: Shi et al. (1998) showed Hsp70 directly interacts with the HSF1 transactivation domain and represses its transcriptional activity. This is a genuine transcription regulator inhibitor activity (PMID:9499401). Reason: Transcription regulator inhibitor activity toward HSF1 is experimentally confirmed (PMID:9499401). This is part of the autoregulatory heat shock response loop, not a core chaperone function per se. Supporting Evidence: PMID:9499401 Overexpression of either chaperone represses the transcriptional activity of a transfected GAL4-HSF1 activation domain fusion protein and endogenous HSF1. |
| GO:0140545 ATP-dependent protein disaggregase activity | IDA PMID:23921388 Identification and characterization of a novel human methylt... | REMOVE | Summary: PMID:23921388 shows METTL21A-mediated methylation effects on HSPA8/Hsc70 binding to alpha-synuclein, not direct HSPA1A disaggregase activity. The evidence is therefore mismatched for an HSPA1A IDA annotation. Reason: The cited IDA evidence does not support HSPA1A-specific ATP-dependent protein disaggregase activity and should not be accepted for this gene. Supporting Evidence: PMID:23921388 trimethylation of HSPA8 (Hsc70) has functional consequences, as it alters the affinity of the chaperone for both the monomeric and fibrillar forms of the Parkinson disease-associated protein alpha-synuclein. |
| GO:0016887 ATP hydrolysis activity | IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist... | ACCEPT | Summary: Hageman et al. (2011) directly assayed HSPA1A ATPase activity and showed it possesses intrinsic ATPase activity stimulated by J-proteins (PMID:21231916). Core enzymatic function. Reason: ATP hydrolysis activity directly demonstrated by Hageman et al. (PMID:21231916). Core enzymatic function of HSPA1A. Supporting Evidence: PMID:21231916 HSPA6 has a functional substrate-binding domain and possesses intrinsic ATPase activity that is as high as that of the canonical HSPA1A when stimulated by J-proteins. |
| GO:0005615 extracellular space | IDA PMID:17568691 Endogenous signals released from necrotic cells augment infl... | ACCEPT | Summary: El Mezayen et al. (2007) showed HSP70 is released from necrotic cells into the extracellular space and acts as a danger signal to activate innate immune cells (PMID:17568691). Reason: Extracellular space localization is experimentally confirmed. HSPA1A is released from necrotic cells and detected in extracellular fluids (PMID:17568691). Supporting Evidence: PMID:17568691 HMGB1 and HSP70 were indeed present in the necrotic cell lysate and were responsible for the significant induction of the proinflammatory cytokine expression |
| GO:0048018 receptor ligand activity | IDA PMID:17568691 Endogenous signals released from necrotic cells augment infl... | KEEP AS NON CORE | Summary: El Mezayen et al. (2007) showed extracellular HSP70 acts as a danger signal that stimulates proinflammatory cytokine responses via TREM-1 and TLR4 receptors (PMID:17568691). Reason: Receptor ligand activity is experimentally supported for extracellular Hsp70 (PMID:17568691) but is a non-core extracellular signaling function. Supporting Evidence: PMID:17568691 the newly identified triggering receptor expressed on myeloid cells-1 (TREM-1) was involved in mediating the HMGB1- and HSP70-induced cytokine production. |
| GO:0005615 extracellular space | IDA PMID:26183779 Tag7 (PGLYRP1) in Complex with Hsp70 Induces Alternative Cyt... | ACCEPT | Summary: Yashin et al. (2015) showed the Tag7-Hsp70 complex is released into the extracellular space and induces cytotoxic processes in tumor cells via TNFR1 (PMID:26183779). Reason: Extracellular space localization confirmed by IDA (PMID:26183779). Consistent with known extracellular signaling roles of Hsp70. Supporting Evidence: PMID:26183779 Tag7 (PGLYRP1) in Complex with Hsp70 Induces Alternative Cytotoxic Processes in Tumor Cells via TNFR1 Receptor. |
| GO:0048018 receptor ligand activity | IDA PMID:26183779 Tag7 (PGLYRP1) in Complex with Hsp70 Induces Alternative Cyt... | KEEP AS NON CORE | Summary: Yashin et al. (2015) showed the Tag7-Hsp70 complex acts as a receptor ligand, binding TNFR1 on tumor cells to induce cytotoxicity (PMID:26183779). Reason: Receptor ligand activity via Tag7-Hsp70 complex is experimentally confirmed (PMID:26183779) but is a non-core extracellular function. Supporting Evidence: PMID:26183779 Tag7 (PGLYRP1) in Complex with Hsp70 Induces Alternative Cytotoxic Processes in Tumor Cells via TNFR1 Receptor. |
| GO:0051787 misfolded protein binding | IDA PMID:28842558 HSP70-Hrd1 axis precludes the oncorepressor potential of N-t... | ACCEPT | Summary: Wang et al. (2017) showed HSP70 recognizes and binds N-terminal misfolded Blimp-1 variants, targeting them for Hrd1-mediated degradation in lymphoma cells (PMID:28842558). Misfolded protein binding is a core property of the Hsp70 chaperone system. Reason: Misfolded protein binding is a core molecular function of HSPA1A. Directly demonstrated for misfolded Blimp-1 variants (PMID:28842558) and consistent with its general chaperone role. Supporting Evidence: PMID:28842558 HSP70-Hrd1 axis precludes the oncorepressor potential of N-terminal misfolded Blimp-1s in lymphoma cells. |
| GO:0007041 lysosomal transport | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: HSPA1A has been annotated with lysosomal transport based on sequence similarity (ISS). This may relate to chaperone-mediated autophagy (CMA), where Hsc70/Hsp70 delivers substrates to lysosomes via LAMP2A. However, CMA is primarily attributed to the constitutive HSPA8 (Hsc70) rather than the inducible HSPA1A. Reason: Lysosomal transport via CMA is better attributed to HSPA8 (Hsc70) than HSPA1A. ISS annotation from ortholog transfer; may not be wrong but not a core HSPA1A function. |
| GO:0033120 positive regulation of RNA splicing | IDA PMID:20625543 HSP72 protects cells from ER stress-induced apoptosis via en... | KEEP AS NON CORE | Summary: Gupta et al. (2010) showed Hsp72 enhances XBP1 mRNA splicing by IRE1alpha. Hsp72 forms a stable complex with IRE1alpha and enhances its RNase activity in vitro, promoting the unconventional splicing of XBP1 mRNA (PMID:20625543). Reason: Positive regulation of RNA splicing (specifically XBP1 mRNA splicing via IRE1alpha) is experimentally confirmed (PMID:20625543) but is a specific UPR-related function not a core chaperone role. Supporting Evidence: PMID:20625543 Hsp72 enhances XBP1 mRNA splicing and expression of its target genes, associated with attenuated apoptosis under ER stress conditions. |
| GO:0034620 cellular response to unfolded protein | IMP PMID:20625543 HSP72 protects cells from ER stress-induced apoptosis via en... | ACCEPT | Summary: Gupta et al. (2010) showed Hsp72 enhances cell survival under ER stress conditions by modulating the UPR via IRE1alpha-XBP1 signaling (PMID:20625543). HSPA1A participates in the cellular response to unfolded proteins. Reason: Cellular response to unfolded protein is a core function of HSPA1A as a major stress-inducible chaperone. Confirmed by IMP (PMID:20625543). Supporting Evidence: PMID:20625543 Hsp72 enhances cell survival under ER stress conditions. |
| GO:0045296 cadherin binding | HDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by... | MARK AS OVER ANNOTATED | Summary: HSPA1A was identified in the E-cadherin interactome by quantitative proteomics (PMID:25468996). This may reflect chaperone-mediated interactions with cadherin complexes rather than functional cadherin binding. Reason: HDA-level evidence from proteomics screen (PMID:25468996). Likely reflects chaperone-substrate interactions with cadherin complexes rather than specific cadherin binding activity. |
| GO:0005515 protein binding | IPI PMID:12853476 Cofactor Tpr2 combines two TPR domains and a J domain to reg... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0008180 COP9 signalosome | IDA PMID:18850735 Characterization of the human COP9 signalosome complex using... | MARK AS OVER ANNOTATED | Summary: HSPA1A was identified as associated with the COP9 signalosome by affinity purification and mass spectrometry (PMID:18850735). This may represent a chaperone-client interaction rather than bona fide COP9 signalosome membership. Reason: COP9 signalosome association likely represents chaperone-client interaction detected by mass spectrometry (PMID:18850735) rather than stable complex membership. |
| GO:0005634 nucleus | IDA PMID:17167422 Hsp70 regulates erythropoiesis by preventing caspase-3-media... | ACCEPT | Summary: Ribeil et al. (2007) showed Hsp70 co-localizes and interacts with GATA-1 in the nucleus of erythroid precursors undergoing terminal differentiation (PMID:17167422). Reason: Nuclear localization confirmed by IDA in erythroid precursors (PMID:17167422). Consistent with already-accepted IBA annotation. Supporting Evidence: PMID:17167422 Hsp70 co-localizes and interacts with GATA-1 in the nucleus of erythroid precursors undergoing terminal differentiation. |
| GO:0043066 negative regulation of apoptotic process | IMP PMID:17167422 Hsp70 regulates erythropoiesis by preventing caspase-3-media... | KEEP AS NON CORE | Summary: Ribeil et al. (2007) showed Hsp70 protects GATA-1 from caspase-3-mediated cleavage during erythroid differentiation, preventing apoptosis (PMID:17167422). This demonstrates an anti-apoptotic function. Reason: Negative regulation of apoptosis is experimentally confirmed (PMID:17167422) and also demonstrated via multiple other mechanisms (Apaf-1 binding, Bax translocation inhibition). However, this is a downstream effect of chaperone activity rather than a core function. Supporting Evidence: PMID:17167422 during differentiation, but not during apoptosis, the chaperone protein Hsp70 protects GATA-1 from caspase-mediated proteolysis. |
| GO:0045648 positive regulation of erythrocyte differentiation | IMP PMID:17167422 Hsp70 regulates erythropoiesis by preventing caspase-3-media... | KEEP AS NON CORE | Summary: Ribeil et al. (2007) showed Hsp70 enables erythroid terminal differentiation by protecting GATA-1 from caspase-3 cleavage. Depletion of Hsp70 leads to GATA-1 cleavage and apoptosis (PMID:17167422). Reason: Positive regulation of erythrocyte differentiation is experimentally confirmed (PMID:17167422) but represents a tissue-specific developmental function, not a core chaperone function. Supporting Evidence: PMID:17167422 during differentiation, but not during apoptosis, the chaperone protein Hsp70 protects GATA-1 from caspase-mediated proteolysis. |
| GO:0005515 protein binding | IPI PMID:27133716 A novel nuclear DnaJ protein, DNAJC8, can suppress the forma... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0005515 protein binding | IPI PMID:23349634 A newly uncovered group of distantly related lysine methyltr... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0032991 protein-containing complex | IDA PMID:23349634 A newly uncovered group of distantly related lysine methyltr... | MARK AS OVER ANNOTATED | Summary: Cloutier et al. (2013) identified HSPA1A in complexes with lysine methyltransferases that regulate chaperone activity (PMID:23349634). Reason: GO:0032991 'protein-containing complex' is very generic. HSPA1A forms many complexes as part of its chaperone function. This annotation is too broad to be informative. |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | KEEP AS NON CORE | Summary: Castello et al. (2012) identified HSPA1A in a global mRNA-binding protein atlas (PMID:22658674). HSPA1A associates with mRNA, consistent with its role in mRNA metabolism via AUF1 (PMID:10205060) and IMP1 RNP granules (PMID:17289661). Reason: RNA binding is supported by HDA proteomics (PMID:22658674) and consistent with known roles in mRNA metabolism. However, this is a secondary function not a core MF. |
| GO:0003723 RNA binding | HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ... | KEEP AS NON CORE | Summary: Baltz et al. (2012) identified HSPA1A among mRNA-bound proteins by global UV crosslinking and mass spectrometry (PMID:22681889). Consistent with its association with RNP complexes. Reason: RNA binding confirmed independently by second HDA study (PMID:22681889). Secondary function. |
| GO:0005515 protein binding | IPI PMID:15671022 Heat shock protein 70 inhibits alpha-synuclein fibril format... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0005515 protein binding | IPI PMID:18975920 Interactions between Hsp70 and the hydrophobic core of alpha... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0005515 protein binding | IPI PMID:21081504 ChChd3, an inner mitochondrial membrane protein, is essentia... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0005515 protein binding | IPI PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor supp... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0005634 nucleus | IDA PMID:10205060 Control of mRNA decay by heat shock-ubiquitin-proteasome pat... | ACCEPT | Summary: Laroia et al. (1999) showed Hsp70 sequesters AUF1 in the perinucleus-nucleus during heat shock (PMID:10205060). This confirms nuclear localization of HSPA1A. Reason: Nuclear localization confirmed by IDA (PMID:10205060). Consistent with already-accepted annotations. Supporting Evidence: PMID:10205060 hsp70 sequestration of AUF1 in the perinucleus-nucleus |
| GO:0005737 cytoplasm | IDA PMID:10859165 Chaperone hsp27 inhibits translation during heat shock by bi... | ACCEPT | Summary: Cuesta et al. (2000) showed Hsp27 inhibits translation during heat shock by interacting with eIF4G, and Hsp70 was detected in the cytoplasm (PMID:10859165). Reason: Cytoplasmic localization confirmed by IDA (PMID:10859165). Consistent with already-accepted IBA annotation. |
| GO:0005737 cytoplasm | TAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied... | ACCEPT | Summary: Bruneel et al. (2005) identified HSPA1A among 162 proteins in a proteomics study of human endothelial cells (PMID:16130169). Cytoplasmic localization is well-established. Reason: Cytoplasmic localization is well-established for HSPA1A. Consistent with all other evidence. |
| GO:0005737 cytoplasm | IDA PMID:24061851 Stress-induced localization of HSPA6 (HSP70B') and HSPA1A (H... | ACCEPT | Summary: Khalouei et al. (2014) showed YFP-tagged HSPA1A in the cytoplasm of human neuronal cells, with stress-induced localization to centrioles in the cytoplasm (PMID:24061851). Reason: Cytoplasmic localization confirmed by IDA (PMID:24061851). Consistent with already-accepted annotations. |
| GO:0005737 cytoplasm | IDA PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor supp... | ACCEPT | Summary: Maheswaran et al. (1998) showed Hsp70 in the cytoplasm and nucleus of cells expressing WT1 (PMID:9553041). Reason: Cytoplasmic localization confirmed by IDA (PMID:9553041). Consistent with already-accepted IBA annotation. |
| GO:0005739 mitochondrion | TAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied... | KEEP AS NON CORE | Summary: Mitochondrial localization of HSPA1A is annotated via TAS from Bruneel et al. (2005) (PMID:16130169). HSPA1A can associate with mitochondria, particularly in the context of preventing Bax translocation and cytochrome c release during stress (PMID:20625543). Reason: Mitochondrial association is supported but is not the primary localization of HSPA1A. It occurs in the context of anti-apoptotic function rather than constitutive localization. |
| GO:0005783 endoplasmic reticulum | TAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied... | KEEP AS NON CORE | Summary: ER localization is annotated via TAS from Bruneel et al. (2005) (PMID:16130169). HSPA1A can associate with the ER in the context of its interaction with IRE1alpha cytosolic domain during ER stress (PMID:20625543). Reason: ER association is supported in the context of UPR signaling (PMID:20625543) but is not the primary localization of HSPA1A. |
| GO:0006402 mRNA catabolic process | IDA PMID:10205060 Control of mRNA decay by heat shock-ubiquitin-proteasome pat... | KEEP AS NON CORE | Summary: Laroia et al. (1999) showed Hsp70 modulates AU-rich element-mediated mRNA decay through AUF1 sequestration. Heat shock-induced Hsp70 sequesters AUF1, blocking decay of AU-rich mRNAs (PMID:10205060). Reason: mRNA catabolic process involvement is confirmed (PMID:10205060) but is a secondary regulatory role of HSPA1A, not a core function. Supporting Evidence: PMID:10205060 hsp70 sequestration of AUF1 in the perinucleus-nucleus, and all three processes block decay of AU-rich mRNAs and AUF1 protein. |
| GO:0006986 response to unfolded protein | IDA PMID:10859165 Chaperone hsp27 inhibits translation during heat shock by bi... | ACCEPT | Summary: HSPA1A is induced by unfolded proteins and serves as a primary effector of the response to unfolded protein. PMID:10859165 provides IDA evidence. Core process. Reason: Response to unfolded protein is a core biological process for HSPA1A. Confirmed by IDA. |
| GO:0008285 negative regulation of cell population proliferation | IMP PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor supp... | MARK AS OVER ANNOTATED | Summary: Maheswaran et al. (1998) showed Hsp70 is required for WT1-mediated growth suppression (PMID:9553041). The antiproliferative effect is mediated by WT1, not Hsp70 directly. Reason: Negative regulation of cell proliferation requires WT1 as the effector. Hsp70 acts as a cofactor/chaperone. This is a chaperone client effect, not a direct HSPA1A function. Supporting Evidence: PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires association with the inducible chaperone Hsp70. |
| GO:0016235 aggresome | IDA PMID:15885686 TRIM37 defective in mulibrey nanism is a novel RING finger u... | ACCEPT | Summary: HSPA1A localizes to aggresomes, confirmed by IDA (PMID:15885686). Consistent with its role in protein quality control. Reason: Aggresome localization confirmed by IDA (PMID:15885686). Consistent with already-accepted IEA annotation. |
| GO:0016607 nuclear speck | IDA PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor supp... | ACCEPT | Summary: Maheswaran et al. (1998) showed Hsp70 is recruited to subnuclear clusters containing WT1 (PMID:9553041). Reason: Nuclear speck localization confirmed by IDA (PMID:9553041). Consistent with already-accepted IEA annotation. |
| GO:0030308 negative regulation of cell growth | IMP PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor supp... | MARK AS OVER ANNOTATED | Summary: Similar to GO:0008285, the cell growth inhibition requires WT1 with Hsp70 as a cofactor (PMID:9553041). Reason: Cell growth effect mediated by WT1, not directly by Hsp70. Chaperone client effect. Supporting Evidence: PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires association with the inducible chaperone Hsp70. |
| GO:0031982 vesicle | HDA PMID:19190083 Characterization of exosome-like vesicles released from huma... | ACCEPT | Summary: HSPA1A detected in exosome-like vesicles from human tracheobronchial epithelium (PMID:19190083). Consistent with known exosomal/vesicular localization of Hsp70. Reason: Vesicle localization confirmed by HDA proteomics (PMID:19190083). Consistent with known extracellular vesicle biology of Hsp70. |
| GO:0043066 negative regulation of apoptotic process | TAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied... | KEEP AS NON CORE | Summary: Anti-apoptotic function of HSPA1A is well-established by multiple mechanisms including Apaf-1 binding, Bax translocation inhibition, JNK suppression, and AIF sequestration (PMID:20625543). TAS annotation from PMID:16130169. Reason: Anti-apoptotic function is well-supported but represents a downstream pleiotropic effect of HSPA1A chaperone activity, not a core molecular function. |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:10205060 Control of mRNA decay by heat shock-ubiquitin-proteasome pat... | ACCEPT | Summary: Laroia et al. (1999) showed Hsp70 sequesters AUF1 in the perinucleus-nucleus (PMID:10205060). Confirmed by IDA. Reason: Perinuclear localization confirmed by IDA (PMID:10205060). Consistent with already-accepted IEA annotation. Supporting Evidence: PMID:10205060 hsp70 sequestration of AUF1 in the perinucleus-nucleus |
| GO:0051082 unfolded protein binding | TAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied... | MODIFY | Summary: GO:0051082 "unfolded protein binding" is now formally obsolete (go-ontology#30962). The TAS reference (PMID:16130169) is a proteomics study of endothelial cells that identified HSPA1A among 162 proteins and mentions "protein folding" among characterized functional categories, but does not specifically assay unfolded protein binding or chaperone activity of HSPA1A. Regardless, the broader literature clearly demonstrates HSPA1A has active protein folding chaperone activity (PMID:21231916), so the annotation should be modified to GO:0044183. Reason: GO:0051082 is now formally obsolete. The TAS reference (PMID:16130169, Bruneel et al. 2005) is a proteomics study that identified HSPA1A among endothelial cell proteins related to "protein folding" but did not specifically characterize HSPA1A chaperone activity. Nevertheless, HSPA1A is well-established as a protein folding chaperone with genuine foldase activity (PMID:21231916), so the annotation should be replaced with GO:0044183 "protein folding chaperone" which is already supported by IBA and IDA evidence on this gene. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:16130169 The overall functional characterization of the 162 identified proteins from primary cultures of HUVECs confirms the metabolic capabilities of endothelium and illustrates various cellular functions more related to cell motility and angiogenesis, protein folding, anti-oxidant defenses, signal transduction, proteasome pathway and resistance to apoptosis. PMID:21231916 Overexpressed chaperones that suppressed polyQ aggregation were found not to be able to stimulate luciferase refolding. Inversely, chaperones that supported luciferase refolding were poor suppressors of polyQ aggregation. [...] overexpression of HSPA1A protected cells from heat-induced cell death |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | ACCEPT | Summary: HSPA1A detected in exosomes from human parotid gland by MudPIT proteomics (PMID:19199708). Hsp70 is a well-established exosomal marker. Reason: Extracellular exosome localization confirmed by proteomics (PMID:19199708). Hsp70 is a well-known exosomal protein. |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | ACCEPT | Summary: HSPA1A detected in B-cell exosomes by proteomics (PMID:20458337). Independent confirmation of exosomal localization. Reason: Extracellular exosome localization confirmed by independent proteomics study (PMID:20458337). |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | ACCEPT | Summary: HSPA1A detected in exosomes from expressed prostatic secretions (PMID:23533145). Third independent confirmation of exosomal localization. Reason: Extracellular exosome localization confirmed by third independent proteomics study (PMID:23533145). |
| GO:1990904 ribonucleoprotein complex | IDA PMID:17289661 Molecular composition of IMP1 ribonucleoprotein granules. | KEEP AS NON CORE | Summary: Jonson et al. (2007) identified HSPA1A as a component of IMP1 ribonucleoprotein granules by mass spectrometry (PMID:17289661). Reason: RNP complex association confirmed by IDA (PMID:17289661) but is a secondary localization related to HSPA1A's role in mRNA metabolism. |
| GO:0005515 protein binding | IPI PMID:24318877 Binding of human nucleotide exchange factors to heat shock p... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0005515 protein binding | IPI PMID:27137183 HSP70 regulates the function of mitotic centrosomes. | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0005515 protein binding | IPI PMID:27708256 ARD1-mediated Hsp70 acetylation balances stress-induced prot... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0005813 centrosome | IDA PMID:27137183 HSP70 regulates the function of mitotic centrosomes. | ACCEPT | Summary: Fang et al. (2016) showed HSP70 accumulates at mitotic centrosomes during prometaphase to metaphase (PMID:27137183). Reason: Centrosome localization confirmed by IDA (PMID:27137183). Consistent with already-accepted IEA annotation. Supporting Evidence: PMID:27137183 heat shock protein (HSP) 70 considerably accumulates at the mitotic centrosome during prometaphase to metaphase |
| GO:0042026 protein refolding | IMP PMID:27708256 ARD1-mediated Hsp70 acetylation balances stress-induced prot... | ACCEPT | Summary: Seo et al. (2016) showed Hsp70 acetylation by ARD1/NAA10 determines whether it functions in protein refolding (via HOPX co-chaperone) or protein degradation (via CHIP ubiquitin ligase) (PMID:27708256). Reason: Protein refolding confirmed by IMP (PMID:27708256). Core function of HSPA1A. Consistent with already-accepted IBA and IDA annotations. Supporting Evidence: PMID:27708256 Hsp70 preferentially facilitates protein refolding after stress, gradually switching to protein degradation via a mechanism dependent on ARD1-mediated Hsp70 acetylation |
| GO:0090063 positive regulation of microtubule nucleation | IMP PMID:27137183 HSP70 regulates the function of mitotic centrosomes. | KEEP AS NON CORE | Summary: Fang et al. (2016) showed HSP70 is required for microtubule nucleation from the mitotic centrosome. Inhibition or depletion of HSP70 impaired MT nucleation and polymerization (PMID:27137183). Reason: Positive regulation of microtubule nucleation experimentally confirmed (PMID:27137183) but is a cell-cycle-specific function, not core chaperone activity. Supporting Evidence: PMID:27137183 Inhibition or depletion of HSP70 impaired the function of mitotic centrosome and disrupted MT nucleation and polymerization from the spindle pole |
| GO:1901673 regulation of mitotic spindle assembly | IMP PMID:27137183 HSP70 regulates the function of mitotic centrosomes. | KEEP AS NON CORE | Summary: Fang et al. (2016) showed HSP70 is required for bipolar spindle assembly and maintenance of a functional mitotic centrosome (PMID:27137183). Reason: Regulation of mitotic spindle assembly experimentally confirmed (PMID:27137183) but is a cell-cycle-specific function. Supporting Evidence: PMID:27137183 HSP70 is required for the maintenance of a functional mitotic centrosome that supports the assembly of a bipolar mitotic spindle. |
| GO:0051131 chaperone-mediated protein complex assembly | IDA PMID:10811660 Crystal structure and activity of human p23, a heat shock pr... | ACCEPT | Summary: Weaver et al. (2000) studied p23 and the HSP90 co-chaperone system for steroid receptor assembly. HSPA1A participates in chaperone-mediated assembly of steroid hormone receptor complexes by handing off substrates to HSP90 (PMID:10811660). Reason: Chaperone-mediated protein complex assembly is a genuine function of HSPA1A, particularly in the HSP70-HOP-HSP90 pathway for steroid receptor maturation. Confirmed by IDA (PMID:10811660). |
| GO:0003714 transcription corepressor activity | IDA PMID:9499401 Molecular chaperones as HSF1-specific transcriptional repres... | KEEP AS NON CORE | Summary: Shi et al. (1998) showed Hsp70 represses HSF1 transcriptional activity by directly interacting with its transactivation domain (PMID:9499401). This constitutes transcription corepressor activity specifically toward HSF1. Reason: Transcription corepressor activity toward HSF1 is experimentally confirmed (PMID:9499401). Part of the autoregulatory heat shock response, not a core chaperone function. Supporting Evidence: PMID:9499401 the molecular chaperone Hsp70 and the cochaperone Hdj1 interact directly with the transactivation domain of HSF1 and repress heat shock gene transcription. |
| GO:0005515 protein binding | IPI PMID:9499401 Molecular chaperones as HSF1-specific transcriptional repres... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0005515 protein binding | IPI PMID:9222587 Evidence for a role of Hsp70 in the regulation of the heat s... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0005515 protein binding | IPI PMID:22219199 The C-terminal helices of heat shock protein 70 are essentia... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0005515 protein binding | IPI PMID:24613385 Hsp70 and Hsp90 oppositely regulate TGF-Ξ² signaling through ... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0030512 negative regulation of transforming growth factor beta receptor signaling pathway | IMP PMID:24613385 Hsp70 and Hsp90 oppositely regulate TGF-Ξ² signaling through ... | KEEP AS NON CORE | Summary: Shang et al. (2014) showed Hsp70 promotes CHIP-mediated Smad3 ubiquitination and degradation, thereby negatively regulating TGF-beta signaling (PMID:24613385). Reason: Negative regulation of TGF-beta signaling is experimentally confirmed (PMID:24613385) but is a downstream effect of HSPA1A-CHIP chaperone-ubiquitin triage, not a core function. Supporting Evidence: PMID:24613385 over-expressed Hsp70 or inhibition of Hsp90 by geldanamycin (GA) leads to facilitated CHIP-induced ubiquitination and degradation of Smad3 |
| GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process | IDA PMID:24613385 Hsp70 and Hsp90 oppositely regulate TGF-Ξ² signaling through ... | ACCEPT | Summary: Shang et al. (2014) showed Hsp70 facilitates CHIP-induced ubiquitination and degradation of Smad3 (PMID:24613385). Core triage function. Reason: Positive regulation of proteasomal degradation is a core chaperone triage function of HSPA1A. Confirmed by IDA (PMID:24613385). Consistent with already-accepted IBA annotation. Supporting Evidence: PMID:24613385 over-expressed Hsp70 or inhibition of Hsp90 by geldanamycin (GA) leads to facilitated CHIP-induced ubiquitination and degradation of Smad3 |
| GO:0005737 cytoplasm | IDA PMID:11785981 HSP90, HSP70, and GAPDH directly interact with the cytoplasm... | ACCEPT | Summary: Nakamura et al. (2002) showed HSP90, HSP70, and GAPDH directly interact with the cytoplasmic domain of macrophage scavenger receptors in the cytoplasm (PMID:11785981). Reason: Cytoplasmic localization confirmed by IDA (PMID:11785981). Consistent with already-accepted annotations. |
| GO:0097718 disordered domain specific binding | IPI PMID:11785981 HSP90, HSP70, and GAPDH directly interact with the cytoplasm... | ACCEPT | Summary: Nakamura et al. (2002) showed HSP70 binds the cytoplasmic domain of macrophage scavenger receptors, which may contain disordered regions (PMID:11785981). This is consistent with HSPA1A's preference for hydrophobic peptide segments. Reason: Disordered domain binding is consistent with HSPA1A's substrate recognition of exposed hydrophobic segments in unfolded/disordered regions. Confirmed by IPI (PMID:11785981). |
| GO:0031249 denatured protein binding | IPI PMID:21909508 Intrinsically disordered proteins as molecular shields. | MODIFY | Summary: GO:0031249 is under the same obsoletion discussion as GO:0051082 (go-ontology#30962). The PMID:21909508 data support HSPA1A recognition of non-native/disordered protein states, but the mechanistically informative molecular function for HSPA1A is ATP-dependent protein folding chaperone activity rather than a generic denatured-protein binding label. Reason: For HSPA1A, denatured-protein recognition is part of the broader Hsp70 chaperone cycle. The annotation is better represented by GO:0044183 (protein folding chaperone), which captures active substrate handling and folding support rather than passive binding alone. Proposed replacements: protein folding chaperone |
| GO:0050821 protein stabilization | IDA PMID:21909508 Intrinsically disordered proteins as molecular shields. | ACCEPT | Summary: Arhar et al. (2011) showed Hsp70 stabilizes intrinsically disordered proteins, acting as a molecular shield (PMID:21909508). Reason: Protein stabilization confirmed by IDA (PMID:21909508). Consistent with already-accepted IEA annotation. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6800434 | ACCEPT | Summary: Reactome annotates HSPA1A in the extracellular region via pathway R-HSA-6800434 (neutrophil degranulation). Consistent with known extracellular Hsp70. Reason: Extracellular region localization consistent with known biology. Supported by Reactome pathway. |
| GO:1904813 ficolin-1-rich granule lumen | TAS Reactome:R-HSA-6800434 | ACCEPT | Summary: Reactome pathway R-HSA-6800434 places HSPA1A in ficolin-1-rich granule lumen as part of neutrophil degranulation. Reason: Ficolin-1-rich granule lumen localization supported by Reactome. Consistent with already-accepted IEA annotation. |
| GO:0032757 positive regulation of interleukin-8 production | IMP PMID:24790089 The molecular chaperone HSP70 binds to and stabilizes NOD2, ... | KEEP AS NON CORE | Summary: Mohanan & Grimes (2014) showed HSP70 stabilizes NOD2, which activates NF-kappaB signaling and downstream IL-8 production (PMID:24790089). Reason: IL-8 production regulation is an indirect downstream effect of HSPA1A-mediated NOD2 stabilization (PMID:24790089). Consistent with already-accepted IEA annotation. |
| GO:0031396 regulation of protein ubiquitination | IDA PMID:16809764 Histone deacetylase 8 safeguards the human ever-shorter telo... | ACCEPT | Summary: Lee et al. (2006) showed phosphorylated HDAC8 recruits Hsp70 to a complex that inhibits CHIP E3 ligase-mediated degradation of hEST1B (PMID:16809764). Hsp70 participates in regulating protein ubiquitination. Reason: Regulation of protein ubiquitination is a genuine function of HSPA1A through its interactions with CHIP and other E3 ligases. Confirmed by IDA (PMID:16809764). Supporting Evidence: PMID:16809764 Phosphorylated HDAC8 preferentially recruits Hsp70 to a complex that inhibits the CHIP (C-terminal heat shock protein interacting protein) E3 ligase-mediated degradation of hEST1B. |
| GO:0042826 histone deacetylase binding | IPI PMID:16809764 Histone deacetylase 8 safeguards the human ever-shorter telo... | ACCEPT | Summary: Lee et al. (2006) showed HDAC8 recruits Hsp70 to a protein complex (PMID:16809764). Confirmed by IPI evidence. Reason: Histone deacetylase binding confirmed by IPI (PMID:16809764). Consistent with already-accepted IEA annotation. |
| GO:1902236 negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway | IDA PMID:12150907 CHIP is associated with Parkin, a gene responsible for famil... | KEEP AS NON CORE | Summary: Imai et al. (2002) showed the CHIP-Hsp70-Parkin complex promotes ubiquitination of Pael-R, preventing ER stress-induced neurodegeneration (PMID:12150907). Hsp70 is part of the protective mechanism against ER stress-induced apoptosis. Reason: Anti-apoptotic role in ER stress is experimentally supported (PMID:12150907) but is a downstream effect of chaperone-ubiquitin quality control. Supporting Evidence: PMID:12150907 CHIP enhanced the ability of Parkin to inhibit cell death induced by Pael-R. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-3371467 | ACCEPT | Summary: Nucleoplasm localization from Reactome pathway (Reactome:R-HSA-3371467). HSPA1A is known to translocate to the nucleus during heat stress and participates in nuclear HSF1 regulation and HSP90 chaperone cycles. Reason: Nucleoplasm localization consistent with known nuclear translocation of HSPA1A during stress. Supported by Reactome pathway annotation. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-3371518 | ACCEPT | Summary: Nucleoplasm localization from Reactome pathway (Reactome:R-HSA-3371518). HSPA1A is known to translocate to the nucleus during heat stress and participates in nuclear HSF1 regulation and HSP90 chaperone cycles. Reason: Nucleoplasm localization consistent with known nuclear translocation of HSPA1A during stress. Supported by Reactome pathway annotation. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-3371554 | ACCEPT | Summary: Nucleoplasm localization from Reactome pathway (Reactome:R-HSA-3371554). HSPA1A is known to translocate to the nucleus during heat stress and participates in nuclear HSF1 regulation and HSP90 chaperone cycles. Reason: Nucleoplasm localization consistent with known nuclear translocation of HSPA1A during stress. Supported by Reactome pathway annotation. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5082356 | ACCEPT | Summary: Nucleoplasm localization from Reactome pathway (Reactome:R-HSA-5082356). HSPA1A is known to translocate to the nucleus during heat stress and participates in nuclear HSF1 regulation and HSP90 chaperone cycles. Reason: Nucleoplasm localization consistent with known nuclear translocation of HSPA1A during stress. Supported by Reactome pathway annotation. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5082369 | ACCEPT | Summary: Nucleoplasm localization from Reactome pathway (Reactome:R-HSA-5082369). HSPA1A is known to translocate to the nucleus during heat stress and participates in nuclear HSF1 regulation and HSP90 chaperone cycles. Reason: Nucleoplasm localization consistent with known nuclear translocation of HSPA1A during stress. Supported by Reactome pathway annotation. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5082384 | ACCEPT | Summary: Nucleoplasm localization from Reactome pathway (Reactome:R-HSA-5082384). HSPA1A is known to translocate to the nucleus during heat stress and participates in nuclear HSF1 regulation and HSP90 chaperone cycles. Reason: Nucleoplasm localization consistent with known nuclear translocation of HSPA1A during stress. Supported by Reactome pathway annotation. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5251955 | ACCEPT | Summary: Nucleoplasm localization from Reactome pathway (Reactome:R-HSA-5251955). HSPA1A is known to translocate to the nucleus during heat stress and participates in nuclear HSF1 regulation and HSP90 chaperone cycles. Reason: Nucleoplasm localization consistent with known nuclear translocation of HSPA1A during stress. Supported by Reactome pathway annotation. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5252041 | ACCEPT | Summary: Nucleoplasm localization from Reactome pathway (Reactome:R-HSA-5252041). HSPA1A is known to translocate to the nucleus during heat stress and participates in nuclear HSF1 regulation and HSP90 chaperone cycles. Reason: Nucleoplasm localization consistent with known nuclear translocation of HSPA1A during stress. Supported by Reactome pathway annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3371422 | ACCEPT | Summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-3371422). Cytosol is the primary site of HSPA1A chaperone function. Reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway and confirmed by IBA and IDA evidence. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3371503 | ACCEPT | Summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-3371503). Cytosol is the primary site of HSPA1A chaperone function. Reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway and confirmed by IBA and IDA evidence. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3371590 | ACCEPT | Summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-3371590). Cytosol is the primary site of HSPA1A chaperone function. Reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway and confirmed by IBA and IDA evidence. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-450551 | ACCEPT | Summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-450551). Cytosol is the primary site of HSPA1A chaperone function. Reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway and confirmed by IBA and IDA evidence. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-450580 | ACCEPT | Summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-450580). Cytosol is the primary site of HSPA1A chaperone function. Reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway and confirmed by IBA and IDA evidence. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5251942 | ACCEPT | Summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-5251942). Cytosol is the primary site of HSPA1A chaperone function. Reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway and confirmed by IBA and IDA evidence. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5251959 | ACCEPT | Summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-5251959). Cytosol is the primary site of HSPA1A chaperone function. Reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway and confirmed by IBA and IDA evidence. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5252041 | ACCEPT | Summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-5252041). Cytosol is the primary site of HSPA1A chaperone function. Reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway and confirmed by IBA and IDA evidence. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5252079 | ACCEPT | Summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-5252079). Cytosol is the primary site of HSPA1A chaperone function. Reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway and confirmed by IBA and IDA evidence. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5618085 | ACCEPT | Summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-5618085). Cytosol is the primary site of HSPA1A chaperone function. Reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway and confirmed by IBA and IDA evidence. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5618098 | ACCEPT | Summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-5618098). Cytosol is the primary site of HSPA1A chaperone function. Reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway and confirmed by IBA and IDA evidence. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5618105 | ACCEPT | Summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-5618105). Cytosol is the primary site of HSPA1A chaperone function. Reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway and confirmed by IBA and IDA evidence. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5618107 | ACCEPT | Summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-5618107). Cytosol is the primary site of HSPA1A chaperone function. Reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway and confirmed by IBA and IDA evidence. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5618110 | ACCEPT | Summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-5618110). Cytosol is the primary site of HSPA1A chaperone function. Reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway and confirmed by IBA and IDA evidence. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9835411 | ACCEPT | Summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-9835411). Cytosol is the primary site of HSPA1A chaperone function. Reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway and confirmed by IBA and IDA evidence. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9857076 | ACCEPT | Summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-9857076). Cytosol is the primary site of HSPA1A chaperone function. Reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway and confirmed by IBA and IDA evidence. |
| GO:0005515 protein binding | IPI PMID:22528486 Nucleophosmin (NPM1/B23) interacts with activating transcrip... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0055131 C3HC4-type RING finger domain binding | IPI PMID:25281747 RING finger protein RNF207, a novel regulator of cardiac exc... | ACCEPT | Summary: Roder et al. (2014) showed RNF207 interacts with Hsp70 (PMID:25281747). RNF207 is a C3HC4-type RING finger protein involved in cardiac excitation. Reason: RING finger domain binding confirmed by IPI (PMID:25281747). Consistent with HSPA1A interactions with RING E3 ligases in the chaperone-ubiquitin triage system. |
| GO:0001664 G protein-coupled receptor binding | IDA PMID:12150907 CHIP is associated with Parkin, a gene responsible for famil... | MARK AS OVER ANNOTATED | Summary: Imai et al. (2002) showed Hsp70 binds unfolded Pael-R (GPR37), a GPCR. However, this binding is in the context of chaperone-mediated quality control of a misfolded GPCR substrate, not functional GPCR binding in a signaling context (PMID:12150907). Reason: Hsp70 binds unfolded Pael-R as a chaperone substrate, not as a GPCR binding partner in the signaling sense. Consistent with already-reviewed IEA annotation. Over-annotation. Supporting Evidence: PMID:12150907 CHIP, Hsp70, Parkin, and Pael-R formed a complex in vitro and in vivo. |
| GO:0005515 protein binding | IPI PMID:17616579 Cellular cofactors affecting hepatitis C virus infection and... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0005515 protein binding | IPI PMID:20625543 HSP72 protects cells from ER stress-induced apoptosis via en... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0031397 negative regulation of protein ubiquitination | IDA PMID:12150907 CHIP is associated with Parkin, a gene responsible for famil... | ACCEPT | Summary: Imai et al. (2002) showed Hsp70 binding to Pael-R prevents its ubiquitination. CHIP promotes the dissociation of Hsp70 to facilitate ubiquitination (PMID:12150907). Reason: Negative regulation of ubiquitination confirmed by IDA (PMID:12150907). Core chaperone triage function. Consistent with already-accepted IEA annotation. Supporting Evidence: PMID:12150907 CHIP promoted the dissociation of Hsp70 from Parkin and Pael-R, thus facilitating Parkin-mediated Pael-R ubiquitination. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:12150907 CHIP is associated with Parkin, a gene responsible for famil... | ACCEPT | Summary: Imai et al. (2002) showed Hsp70 forms complexes with CHIP (E3 ligase) and Parkin (E3 ligase) (PMID:12150907). Reason: Ubiquitin protein ligase binding confirmed by IPI (PMID:12150907). Consistent with already-accepted IEA annotation. |
| GO:0034599 cellular response to oxidative stress | TAS PMID:24252804 The role of oxidative stress in Parkinson's disease. | KEEP AS NON CORE | Summary: PMID:24252804 is a review on oxidative stress in Parkinson's disease that discusses the role of chaperones including Hsp70 in response to oxidative damage. Reason: Cellular response to oxidative stress is a secondary cytoprotective role. Consistent with already-accepted IEA annotation. |
| GO:0050821 protein stabilization | TAS PMID:24252804 The role of oxidative stress in Parkinson's disease. | ACCEPT | Summary: PMID:24252804 discusses Hsp70's role in stabilizing proteins in the context of Parkinson's disease. Protein stabilization is a well-established chaperone function. Reason: Protein stabilization is a core chaperone function. Consistent with already-accepted IEA annotation. |
| GO:0051082 unfolded protein binding | NAS PMID:12150907 CHIP is associated with Parkin, a gene responsible for famil... | MODIFY | Summary: GO:0051082 "unfolded protein binding" is now formally obsolete (go-ontology#30962). The NAS reference (PMID:12150907, Imai et al. 2002) describes CHIP-Hsp70-Parkin complex formation with unfolded Pael receptor as substrate, showing Hsp70 binds unfolded Pael-R in the context of ER stress and Parkin-mediated ubiquitination. While this demonstrates Hsp70 interacts with an unfolded substrate, the functional context is chaperone-mediated quality control, not merely binding. HSPA1A has well-characterized protein folding chaperone activity (PMID:21231916), so the annotation should be modified to GO:0044183. Reason: GO:0051082 is now formally obsolete. PMID:12150907 (Imai et al. 2002) demonstrates that Hsp70 forms a complex with CHIP, Parkin, and unfolded Pael-R, and that CHIP promotes dissociation of Hsp70 from the complex to facilitate ubiquitination. This is a chaperone triage function, not passive binding of unfolded proteins. HSPA1A is a genuine protein folding chaperone with foldase activity (PMID:21231916), so the annotation should be replaced with GO:0044183 which accurately captures its molecular function. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:12150907 CHIP, Hsp70, Parkin, and Pael-R formed a complex in vitro and in vivo. The amount of CHIP in the complex was increased during ER stress. CHIP promoted the dissociation of Hsp70 from Parkin and Pael-R, thus facilitating Parkin-mediated Pael-R ubiquitination. PMID:21231916 Overexpressed chaperones that suppressed polyQ aggregation were found not to be able to stimulate luciferase refolding. Inversely, chaperones that supported luciferase refolding were poor suppressors of polyQ aggregation. |
| GO:1901029 negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway | IDA PMID:20625543 HSP72 protects cells from ER stress-induced apoptosis via en... | KEEP AS NON CORE | Summary: Gupta et al. (2010) showed Hsp72 inhibits several features of the intrinsic apoptotic pathway including inhibiting cytochrome c release from mitochondria (preventing Bax translocation) (PMID:20625543). Reason: Inhibition of mitochondrial outer membrane permeabilization is experimentally supported (PMID:20625543) but is a downstream anti-apoptotic function. Supporting Evidence: PMID:20625543 Hsp72 functions upstream of the caspase cascade by inhibiting the release of cytochrome c from the mitochondria |
| GO:1902236 negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway | IDA PMID:20625543 HSP72 protects cells from ER stress-induced apoptosis via en... | KEEP AS NON CORE | Summary: Gupta et al. (2010) showed Hsp72 protects cells from ER stress-induced apoptosis by enhancing IRE1alpha-XBP1 signaling (PMID:20625543). Reason: Anti-apoptotic function in ER stress confirmed (PMID:20625543) but is a secondary cytoprotective function. Supporting Evidence: PMID:20625543 binding of Hsp72 to IRE1alpha enhances IRE1alpha/XBP1 signaling at the ER and inhibits ER stress-induced apoptosis. |
| GO:0005814 centriole | IDA PMID:24061851 Stress-induced localization of HSPA6 (HSP70B') and HSPA1A (H... | ACCEPT | Summary: Khalouei et al. (2014) showed YFP-tagged HSPA1A localizes to centrioles upon thermal stress in human neuronal cells (PMID:24061851). Reason: Centriole localization confirmed by IDA (PMID:24061851). Consistent with already-accepted IEA annotation. Supporting Evidence: PMID:24061851 Following a brief period of thermal stress, YFP-tagged HSPA6 and HSPA1A rapidly appeared at centrioles in the cytoplasm of human neuronal cells |
| GO:0005829 cytosol | IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist... | ACCEPT | Summary: Hageman et al. (2011) performed chaperone assays with cytosolic HSPA1A (PMID:21231916). Cytosol is the primary location of HSPA1A function. Reason: Cytosol localization confirmed by IDA (PMID:21231916). Consistent with already-accepted IBA annotation. |
| GO:0005925 focal adhesion | HDA PMID:21423176 Analysis of the myosin-II-responsive focal adhesion proteome... | MARK AS OVER ANNOTATED | Summary: HSPA1A detected in focal adhesion proteome by mass spectrometry (PMID:21423176). This may reflect chaperone interactions with adhesion complex proteins. Reason: Focal adhesion localization from HDA proteomics (PMID:21423176) likely reflects chaperone-client interactions rather than specific focal adhesion targeting. |
| GO:0034605 cellular response to heat | IDA PMID:24061851 Stress-induced localization of HSPA6 (HSP70B') and HSPA1A (H... | ACCEPT | Summary: Khalouei et al. (2014) showed HSPA1A rapidly localizes to centrioles following thermal stress, demonstrating a cellular response to heat (PMID:24061851). Reason: Cellular response to heat confirmed by IDA (PMID:24061851). Core biological process. |
| GO:0042026 protein refolding | IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist... | ACCEPT | Summary: Hageman et al. (2011) directly demonstrated HSPA1A refolds heat-denatured luciferase (PMID:21231916). Core function. Reason: Protein refolding confirmed by direct luciferase refolding assay (PMID:21231916). Core function of HSPA1A. Supporting Evidence: PMID:21231916 we assessed the effect of overexpression of each of these HSPs on refolding of heat-denatured luciferase |
| GO:0051082 unfolded protein binding | IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist... | MODIFY | Summary: GO:0051082 "unfolded protein binding" is now formally obsolete (go-ontology#30962). The IDA reference (PMID:21231916, Hageman et al. 2011) is the key study that directly assayed HSPA1A chaperone activities. It demonstrated that HSPA1A has genuine foldase activity via luciferase refolding assays, can suppress polyQ aggregation, and protected cells from heat-induced cell death. The study also showed HSPA1A possesses intrinsic ATPase activity stimulated by J-domain co-chaperones. These are hallmarks of protein folding chaperone activity, not merely unfolded protein binding. The annotation should be modified to GO:0044183 "protein folding chaperone", which is already annotated to this gene by both IBA (GO_REF:0000033) and IDA (PMID:15603737) evidence. Reason: GO:0051082 is now formally obsolete. PMID:21231916 (Hageman et al. 2011) directly demonstrates HSPA1A has active protein folding chaperone function: it refolds heat-denatured luciferase, suppresses aggregation, and protects cells from heat-induced death, all in an ATP-dependent manner with J-protein co-chaperones. This is clearly protein folding chaperone activity (GO:0044183), not passive unfolded protein binding. UniProt also describes HSPA1A as a "molecular chaperone implicated in a wide variety of cellular processes, including protection of the proteome from stress, folding and transport of newly synthesized polypeptides, activation of proteolysis of misfolded proteins". The annotation should be replaced with GO:0044183. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:21231916 we assessed the effect of overexpression of each of these HSPs on refolding of heat-denatured luciferase and on the suppression of aggregation of a non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment. Overexpressed chaperones that suppressed polyQ aggregation were found not to be able to stimulate luciferase refolding. Inversely, chaperones that supported luciferase refolding were poor suppressors of polyQ aggregation. PMID:21231916 whereas overexpression of HSPA1A protected cells from heat-induced cell death, overexpression of HSPA6 did not |
| GO:0070370 cellular heat acclimation | IMP PMID:21231916 The diverse members of the mammalian HSP70 machine show dist... | ACCEPT | Summary: Hageman et al. (2011) showed HSPA1A overexpression protects cells from heat-induced cell death (PMID:21231916). Core thermotolerance function. Reason: Cellular heat acclimation confirmed by IMP (PMID:21231916). Core function. Supporting Evidence: PMID:21231916 whereas overexpression of HSPA1A protected cells from heat-induced cell death, overexpression of HSPA6 did not |
| GO:0072562 blood microparticle | HDA PMID:22516433 Proteomic analysis of microvesicles from plasma of healthy d... | ACCEPT | Summary: HSPA1A detected in blood microparticles by proteomics (PMID:22516433). Consistent with known extracellular presence of Hsp70. Reason: Blood microparticle localization confirmed by HDA proteomics (PMID:22516433). Consistent with known extracellular Hsp70 biology. |
| GO:0090084 negative regulation of inclusion body assembly | IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist... | ACCEPT | Summary: Hageman et al. (2011) showed HSPA1A suppresses polyQ aggregation/inclusion body formation (PMID:21231916). Core aggregation suppression function. Reason: Negative regulation of inclusion body assembly confirmed by IDA (PMID:21231916). Core chaperone function. Supporting Evidence: PMID:21231916 we assessed the effect of overexpression of each of these HSPs on refolding of heat-denatured luciferase and on the suppression of aggregation of a non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment. |
| GO:0005515 protein binding | IPI PMID:15603737 BAG5 inhibits parkin and enhances dopaminergic neuron degene... | REMOVE | Summary: GO:0005515 'protein binding' is uninformative per GO curation guidelines. HSPA1A interacts with many proteins as part of its chaperone function, but the generic 'protein binding' term does not convey meaningful functional information. More specific MF terms (e.g., GO:0044183 protein folding chaperone, GO:0031072 heat shock protein binding, GO:0031625 ubiquitin protein ligase binding) already capture the biologically meaningful interactions. Reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular function terms. HSPA1A already has appropriate specific MF annotations. |
| GO:0005524 ATP binding | IDA PMID:23921388 Identification and characterization of a novel human methylt... | ACCEPT | Summary: Jakobsson et al. (2013) showed METTL21A-mediated methylation of Hsp70 is stimulated by ATP, confirming ATP binding (PMID:23921388). Core molecular function. Reason: ATP binding confirmed by IDA (PMID:23921388). Core molecular function of HSPA1A. |
| GO:0010628 positive regulation of gene expression | IMP PMID:25281747 RING finger protein RNF207, a novel regulator of cardiac exc... | MARK AS OVER ANNOTATED | Summary: Roder et al. (2014) showed RNF207 interacts with Hsp70 and this interaction regulates cardiac excitation (PMID:25281747). The gene expression regulation may be indirect. Reason: Positive regulation of gene expression in the context of RNF207-Hsp70 interaction (PMID:25281747) is likely an indirect effect of chaperone-client relationship. |
| GO:0016234 inclusion body | IDA PMID:15603737 BAG5 inhibits parkin and enhances dopaminergic neuron degene... | ACCEPT | Summary: Kalia et al. (2004) showed BAG5 enhances parkin sequestration within protein aggregates/inclusion bodies. Hsp70 localizes to inclusion bodies as part of quality control (PMID:15603737). Reason: Inclusion body localization confirmed by IDA (PMID:15603737). Consistent with HSPA1A's role in protein quality control at aggregation sites. Supporting Evidence: PMID:15603737 BAG5 enhances parkin sequestration within protein aggregates |
| GO:0019899 enzyme binding | IPI PMID:23921388 Identification and characterization of a novel human methylt... | ACCEPT | Summary: Jakobsson et al. (2013) showed HSPA1A interacts with the methyltransferase METTL21A (PMID:23921388). Enzyme binding is accurate but broad. Reason: Enzyme binding confirmed by IPI with METTL21A methyltransferase (PMID:23921388). Accurate but broad term. |
| GO:0031072 heat shock protein binding | IPI PMID:23921388 Identification and characterization of a novel human methylt... | ACCEPT | Summary: Jakobsson et al. (2013) showed METTL21A specifically methylates Hsp70 family proteins (PMID:23921388). Heat shock protein binding is core. Reason: Heat shock protein binding confirmed by IPI (PMID:23921388). Consistent with already-accepted IBA annotation. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:15603737 BAG5 inhibits parkin and enhances dopaminergic neuron degene... | ACCEPT | Summary: Kalia et al. (2004) showed BAG5 directly interacts with parkin and Hsp70 in a complex. Hsp70 binds parkin (E3 ubiquitin ligase) (PMID:15603737). Reason: Ubiquitin protein ligase binding confirmed by IPI (PMID:15603737). Consistent with already-accepted IEA annotation. |
| GO:0042026 protein refolding | IDA PMID:15603737 BAG5 inhibits parkin and enhances dopaminergic neuron degene... | ACCEPT | Summary: Kalia et al. (2004) showed BAG5 inhibits Hsp70-mediated refolding of misfolded proteins (PMID:15603737). Confirms protein refolding activity. Reason: Protein refolding confirmed by IDA (PMID:15603737). Core function. Supporting Evidence: PMID:15603737 BAG5 inhibits both parkin E3 ubiquitin ligase activity and Hsp70-mediated refolding of misfolded proteins. |
| GO:0044183 protein folding chaperone | IDA PMID:15603737 BAG5 inhibits parkin and enhances dopaminergic neuron degene... | ACCEPT | Summary: Kalia et al. (2004) demonstrated Hsp70 chaperone activity inhibited by BAG5 (PMID:15603737). Confirms protein folding chaperone as core MF. Reason: Protein folding chaperone confirmed by IDA (PMID:15603737). Core molecular function. |
| GO:0046034 ATP metabolic process | IDA PMID:23921388 Identification and characterization of a novel human methylt... | REMOVE | Summary: PMID:23921388 describes METTL21A methylation assays and HSPA8/Hsc70 functional effects, not HSPA1A-specific ATP metabolic process. Reason: The cited IDA evidence does not support a broad HSPA1A ATP metabolic process annotation; ATP use is better captured by ATPase/chaperone molecular-function annotations. |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:15603737 BAG5 inhibits parkin and enhances dopaminergic neuron degene... | ACCEPT | Summary: Kalia et al. (2004) showed BAG5-Hsp70 complex localizes to the perinuclear region (PMID:15603737). Reason: Perinuclear localization confirmed by IDA (PMID:15603737). Consistent with already-accepted IEA annotation. |
| GO:0090084 negative regulation of inclusion body assembly | IDA PMID:15603737 BAG5 inhibits parkin and enhances dopaminergic neuron degene... | ACCEPT | Summary: Kalia et al. (2004) showed Hsp70 suppresses protein aggregation, which is inhibited by BAG5 (PMID:15603737). Reason: Negative regulation of inclusion body assembly confirmed by IDA (PMID:15603737). Core function. |
| GO:2001240 negative regulation of extrinsic apoptotic signaling pathway in absence of ligand | IMP PMID:17167422 Hsp70 regulates erythropoiesis by preventing caspase-3-media... | KEEP AS NON CORE | Summary: Ribeil et al. (2007) showed Hsp70 protects GATA-1 from caspase-3 cleavage, preventing apoptosis during erythroid differentiation. Erythropoietin starvation (absence of ligand) leads to Hsp70 nuclear export and GATA-1 cleavage (PMID:17167422). Reason: Anti-apoptotic function in the absence of survival signaling is experimentally supported (PMID:17167422) but is a downstream effect. Supporting Evidence: PMID:17167422 erythropoietin starvation induces the nuclear export of Hsp70 and the cleavage of GATA-1. |
| GO:0005102 signaling receptor binding | IPI PMID:24790089 The molecular chaperone HSP70 binds to and stabilizes NOD2, ... | KEEP AS NON CORE | Summary: Mohanan & Grimes (2014) showed HSP70 binds NOD2, an intracellular pattern recognition receptor (PMID:24790089). This is a chaperone-client interaction with a signaling receptor. Reason: Signaling receptor binding is confirmed for NOD2 (PMID:24790089) but represents a chaperone-client interaction rather than a core signaling function. |
| GO:0005737 cytoplasm | IDA PMID:24790089 The molecular chaperone HSP70 binds to and stabilizes NOD2, ... | ACCEPT | Summary: Mohanan & Grimes (2014) showed HSP70 and NOD2 interact in the cytoplasm (PMID:24790089). Reason: Cytoplasmic localization confirmed by IDA (PMID:24790089). Consistent with already-accepted IBA annotation. |
| GO:1903265 positive regulation of tumor necrosis factor-mediated signaling pathway | IMP PMID:24790089 The molecular chaperone HSP70 binds to and stabilizes NOD2, ... | KEEP AS NON CORE | Summary: Mohanan & Grimes (2014) showed HSP70-mediated NOD2 stabilization enhances downstream signaling including TNF-mediated pathways (PMID:24790089). Reason: Positive regulation of TNF signaling is an indirect downstream effect of NOD2 stabilization by HSPA1A (PMID:24790089). Not a core function. |
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