id: P0DMV8
gene_symbol: HSPA1A
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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). It also possesses ATP-dependent protein disaggregase
  activity.
alternative_products:
- name: '1'
  id: P0DMV8-1
- name: '2'
  id: P0DMV8-2
  sequence_note: VSP_044427
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:17167422
      supporting_text: At the onset of caspase activation, Hsp70 co-localizes and interacts with GATA-1
        in the nucleus of erythroid precursors undergoing terminal differentiation.
    - reference_id: PMID:9499401
      supporting_text: the molecular chaperone Hsp70 and the cochaperone Hdj1 interact directly with the
        transactivation domain of HSF1 and repress heat shock gene transcription.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    reason: Cytoplasmic localization is the primary location of HSPA1A, confirmed by numerous independent
      studies and consistent with its core chaperone function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: HSPA1A plasma membrane association is supported by its role as a virus receptor (rotavirus
      A entry, UniProt annotation) and by evidence showing it functions as an extracellular receptor ligand
      via Tag7/PGLYRP1-Hsp70 complexes that interact with TNFR1 on cell surfaces (PMID:26183779). Also
      consistent with its role in extracellular signaling (PMID:17568691). IBA annotation is phylogenetically
      reasonable for the HSP70 family.
    action: ACCEPT
    reason: Plasma membrane association is supported by HSPA1A's roles as a virus receptor and extracellular
      signaling molecule. Phylogenetically consistent for HSP70 family members.
    supported_by:
    - reference_id: PMID:26183779
      supporting_text: Tag7 (PGLYRP1) in Complex with Hsp70 Induces Alternative Cytotoxic Processes in
        Tumor Cells via TNFR1 Receptor
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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. Directly
      demonstrated by IDA evidence (PMID:21231916, PMID:23921388). IBA annotation is phylogenetically
      sound and represents a core function of all HSP70 family members.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: 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
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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. IBA annotation is well-supported and phylogenetically sound.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:22219199
      supporting_text: The C-terminal helices of heat shock protein 70 are essential for J-domain binding
        and ATPase activation
    - reference_id: PMID:23921388
      supporting_text: we identified the methyltransferase METTL21A as the enzyme responsible for trimethylation
        of a conserved lysine residue found in several human Hsp70 (HSPA) proteins.
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    reason: This is the primary molecular function of HSPA1A. Directly demonstrated by multiple independent
      studies (PMID:21231916, PMID:15603737). Conserved across the HSP70 family.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: 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.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    reason: Cytosolic localization is the primary site of HSPA1A chaperone function. Confirmed by direct
      assay and consistent with all known chaperone cycle components.
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: we assessed the effect of overexpression of each of these HSPs on refolding of
        heat-denatured luciferase
    - reference_id: PMID:15603737
      supporting_text: Within this complex, BAG5 inhibits both parkin E3 ubiquitin ligase activity and
        Hsp70-mediated refolding of misfolded proteins.
- term:
    id: GO:0032436
    label: positive regulation of proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:24613385
      supporting_text: over-expressed Hsp70 or inhibition of Hsp90 by geldanamycin (GA) leads to facilitated
        CHIP-induced ubiquitination and degradation of Smad3
- term:
    id: GO:0046718
    label: symbiont entry into host cell
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: HSPA1A serves as a post-attachment receptor for rotavirus A, facilitating virus entry into
      the cell (PMID:16537599). UniProt confirms this function. The IEA annotation via logical inference
      from the virus receptor activity annotation is reasonable.
    action: KEEP_AS_NON_CORE
    reason: HSPA1A functions as a virus receptor for rotavirus A (PMID:16537599), which involves viral
      entry. This is a secondary/non-core function distinct from its primary chaperone role.
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    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). Nucleotide binding is a correct but very broad parent term;
      the more specific GO:0005524 ATP binding is already annotated.
    action: ACCEPT
    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.
- term:
    id: GO:0001618
    label: virus receptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: UniProt directly annotates HSPA1A as a receptor for rotavirus A based on PMID:16537599. The
      peptide-binding and ATPase domains of Hsp70 are required for rotavirus interaction and infectivity
      reduction.
    action: KEEP_AS_NON_CORE
    reason: Virus receptor activity is experimentally supported for rotavirus A entry (PMID:16537599)
      but is a non-core function unrelated to HSPA1A's primary chaperone role.
- term:
    id: GO:0001664
    label: G protein-coupled receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:12150907
      supporting_text: 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.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    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).
    action: ACCEPT
    reason: ATP binding is fundamental to the HSPA1A chaperone cycle and is confirmed by structural and
      biochemical evidence.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    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.
    action: ACCEPT
    reason: Extracellular localization is supported by multiple independent studies showing HSPA1A release
      from cells and its presence in extracellular fluids and exosomes.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    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.
    action: ACCEPT
    reason: IEA annotation consistent with the already-accepted IBA annotation and multiple IDA confirmations.
      Nuclear localization is well-established for HSPA1A.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Duplicate of the IBA-reviewed cytoplasm annotation. Cytoplasm is the primary location of
      HSPA1A under basal conditions. Confirmed by numerous IDA studies.
    action: ACCEPT
    reason: IEA annotation consistent with the already-accepted IBA annotation and multiple IDA confirmations.
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:27137183
      supporting_text: heat shock protein (HSP) 70 considerably accumulates at the mitotic centrosome
        during prometaphase to metaphase and is required for bipolar spindle assembly.
- term:
    id: GO:0005814
    label: centriole
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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).
    action: ACCEPT
    reason: Centriole localization is experimentally confirmed by Khalouei et al. 2014 (PMID:24061851)
      using YFP-tagged HSPA1A in neuronal cells.
    supported_by:
    - reference_id: PMID:24061851
      supporting_text: Following a brief period of thermal stress, YFP-tagged HSPA6 and HSPA1A rapidly
        appeared at centrioles in the cytoplasm of human neuronal cells
- term:
    id: GO:0006402
    label: mRNA catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:10205060
      supporting_text: 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.
- term:
    id: GO:0008285
    label: negative regulation of cell population proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:9553041
      supporting_text: Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires
        association with the inducible chaperone Hsp70.
- term:
    id: GO:0016235
    label: aggresome
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: HSPA1A localizes to aggresomes. PMID:15885686 shows TRIM37 forms ubiquitin- and chaperone-positive
      aggresomes. Confirmed by IDA (PMID:15885686).
    action: ACCEPT
    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.
- term:
    id: GO:0016607
    label: nuclear speck
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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).
    action: ACCEPT
    reason: Nuclear speck localization is confirmed by IDA (PMID:9553041) showing colocalization of Hsp70
      with WT1 in subnuclear clusters.
    supported_by:
    - reference_id: PMID:9553041
      supporting_text: Hsp70 is recruited to the characteristic subnuclear clusters that contain WT1.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Duplicate of the IBA-reviewed ATP hydrolysis annotation. ATP hydrolysis is a core enzymatic
      activity of HSPA1A confirmed by IDA (PMID:21231916).
    action: ACCEPT
    reason: IEA annotation consistent with the already-accepted IBA annotation and confirmed by direct
      assay.
- term:
    id: GO:0030308
    label: negative regulation of cell growth
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: ACCEPT
    reason: IEA annotation consistent with the already-accepted IBA annotation and extensive experimental
      evidence.
- term:
    id: GO:0031397
    label: negative regulation of protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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).
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:12150907
      supporting_text: CHIP promoted the dissociation of Hsp70 from Parkin and Pael-R, thus facilitating
        Parkin-mediated Pael-R ubiquitination.
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0032757
    label: positive regulation of interleukin-8 production
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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).
    action: KEEP_AS_NON_CORE
    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).
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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).
    action: ACCEPT
    reason: IEA annotation consistent with the already-accepted IBA annotation and confirmed by direct
      assay evidence.
- term:
    id: GO:0042826
    label: histone deacetylase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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).
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:27708256
      supporting_text: 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
    - reference_id: PMID:16809764
      supporting_text: 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.
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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).
    action: ACCEPT
    reason: IEA annotation consistent with the already-accepted IBA annotation and confirmed by direct
      assay evidence. Core molecular function of HSPA1A.
- term:
    id: GO:0045648
    label: positive regulation of erythrocyte differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: HSPA1A protects GATA-1 from caspase-3 cleavage during erythroid terminal differentiation,
      enabling proper erythropoiesis (PMID:17167422). Confirmed by IMP (PMID:17167422).
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:17167422
      supporting_text: during differentiation, but not during apoptosis, the chaperone protein Hsp70 protects
        GATA-1 from caspase-mediated proteolysis.
- term:
    id: GO:0046034
    label: ATP metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: HSPA1A hydrolyzes ATP as part of its chaperone cycle. The ATP metabolic process annotation
      broadly captures the ATPase activity. Confirmed by IDA (PMID:23921388, PMID:21231916).
    action: ACCEPT
    reason: ATP metabolic process is accurate as HSPA1A has intrinsic ATPase activity. Broader than GO:0016887
      (ATP hydrolysis activity) but acceptable.
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:10205060
      supporting_text: Induction of hsp70 by heat shock [...] result in hsp70 sequestration of AUF1 in
        the perinucleus-nucleus
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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).
    action: ACCEPT
    reason: Protein stabilization is a genuine function of HSPA1A chaperone activity, demonstrated for
      multiple substrates including NOD2 (PMID:24790089).
    supported_by:
    - reference_id: PMID:24790089
      supporting_text: 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.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: GO:0051082 "unfolded protein binding" is being obsoleted (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.
    action: MODIFY
    reason: GO:0051082 is being obsoleted. 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_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: 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
- term:
    id: GO:0055131
    label: C3HC4-type RING finger domain binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:15885686
      supporting_text: TRIM37 defective in mulibrey nanism is a novel RING finger ubiquitin E3 ligase.
    - reference_id: PMID:12150907
      supporting_text: CHIP, Hsp70, Parkin, and Pael-R formed a complex in vitro and in vivo.
- term:
    id: GO:0070370
    label: cellular heat acclimation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: whereas overexpression of HSPA1A protected cells from heat-induced cell death,
        overexpression of HSPA6 did not
- term:
    id: GO:0070434
    label: positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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).
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:24790089
      supporting_text: Induced HSP70 expression in cells increased the response of NOD2 to bacterial cell
        wall fragments.
- term:
    id: GO:0071383
    label: cellular response to steroid hormone stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0090063
    label: positive regulation of microtubule nucleation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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).
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:27137183
      supporting_text: Inhibition or depletion of HSP70 impaired the function of mitotic centrosome and
        disrupted MT nucleation and polymerization from the spindle pole
- term:
    id: GO:0090084
    label: negative regulation of inclusion body assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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).
    action: ACCEPT
    reason: Suppression of inclusion body/aggregate formation is a core chaperone function of HSPA1A,
      directly demonstrated by multiple studies (PMID:21231916, PMID:15603737).
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: 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.
- term:
    id: GO:0140545
    label: ATP-dependent protein disaggregase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: HSPA1A has ATP-dependent protein disaggregase activity. Jakobsson et al. (2013) showed METTL21A-mediated
      trimethylation of Hsp70 modulates its chaperone function including effects on alpha-synuclein disaggregation
      (PMID:23921388). Hsp70 disaggregase activity is well-established in the Hsp70/Hsp110/Hsp40 system.
    action: ACCEPT
    reason: ATP-dependent protein disaggregase activity is a core molecular function of HSPA1A, operating
      in concert with Hsp110 and Hsp40 co-chaperones. Confirmed by IDA (PMID:23921388).
    supported_by:
    - reference_id: PMID:23921388
      supporting_text: 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.
- term:
    id: GO:1901673
    label: regulation of mitotic spindle assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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).
    action: KEEP_AS_NON_CORE
    reason: Regulation of mitotic spindle assembly is experimentally supported (PMID:27137183) but represents
      a cell-cycle-specific role, not the core chaperone function.
    supported_by:
    - reference_id: PMID:27137183
      supporting_text: 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.
- term:
    id: GO:1903265
    label: positive regulation of tumor necrosis factor-mediated signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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).
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:26183779
      supporting_text: Tag7 (PGLYRP1) in Complex with Hsp70 Induces Alternative Cytotoxic Processes in
        Tumor Cells via TNFR1 Receptor.
- term:
    id: GO:1904813
    label: ficolin-1-rich granule lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: ACCEPT
    reason: Ficolin-1-rich granule lumen localization is supported by Reactome and consistent with known
      immune cell biology of extracellular Hsp70.
- term:
    id: GO:1990904
    label: ribonucleoprotein complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Ribonucleoprotein complex association is experimentally supported (PMID:17289661) but represents
      a secondary localization rather than a core function.
    supported_by:
    - reference_id: PMID:17289661
      supporting_text: Molecular composition of IMP1 ribonucleoprotein granules.
- term:
    id: GO:2001240
    label: negative regulation of extrinsic apoptotic signaling pathway in absence of ligand
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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).
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:17167422
      supporting_text: during differentiation, but not during apoptosis, the chaperone protein Hsp70 protects
        GATA-1 from caspase-mediated proteolysis.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21044950
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24338975
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24428437
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0043123
    label: positive regulation of canonical NF-kappaB signal transduction
  evidence_type: IMP
  original_reference_id: PMID:24790089
  review:
    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).
    action: KEEP_AS_NON_CORE
    reason: Positive regulation of NF-kappaB is an indirect downstream effect of HSPA1A stabilizing NOD2
      (PMID:24790089). Not a core chaperone function.
    supported_by:
    - reference_id: PMID:24790089
      supporting_text: an HSP70 inhibitor, KNK437, was capable of decreasing NOD2-mediated NF-kappaB activation
        in response to bacterial cell wall stimulation.
- term:
    id: GO:0070434
    label: positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:24790089
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Experimentally confirmed (PMID:24790089) but represents a downstream effect of HSPA1A chaperone-mediated
      NOD2 stabilization, not a core function.
    supported_by:
    - reference_id: PMID:24790089
      supporting_text: Induced HSP70 expression in cells increased the response of NOD2 to bacterial cell
        wall fragments.
- term:
    id: GO:0005814
    label: centriole
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    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).
    action: ACCEPT
    reason: Centriole localization is experimentally confirmed by immunofluorescence (PMID:24061851).
    supported_by:
    - reference_id: PMID:24061851
      supporting_text: Following a brief period of thermal stress, YFP-tagged HSPA6 and HSPA1A rapidly
        appeared at centrioles in the cytoplasm of human neuronal cells
- term:
    id: GO:0071383
    label: cellular response to steroid hormone stimulus
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371497
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: IDA
  original_reference_id: PMID:20625543
  review:
    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).
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:20625543
      supporting_text: binding of Hsp72 to IRE1alpha enhances IRE1alpha/XBP1 signaling at the ER and inhibits
        ER stress-induced apoptosis.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371422
  review:
    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.
    action: ACCEPT
    reason: ATP hydrolysis is a core enzymatic activity of HSPA1A. Consistent with already-accepted IBA
      and IDA annotations. Reactome pathway correctly represents this activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17182002
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21231916
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:9499401
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:9499401
      supporting_text: the molecular chaperone Hsp70 and the cochaperone Hdj1 interact directly with the
        transactivation domain of HSF1 and repress heat shock gene transcription.
- term:
    id: GO:0034605
    label: cellular response to heat
  evidence_type: IDA
  original_reference_id: PMID:9499401
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:9499401
      supporting_text: the repression of heat shock gene transcription, which occurs during attenuation,
        is due to the association of Hsp70 with the HSF1 transactivation domain
- term:
    id: GO:0140416
    label: transcription regulator inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:9499401
  review:
    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).
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:9499401
      supporting_text: Overexpression of either chaperone represses the transcriptional activity of a
        transfected GAL4-HSF1 activation domain fusion protein and endogenous HSF1.
- term:
    id: GO:0140545
    label: ATP-dependent protein disaggregase activity
  evidence_type: IDA
  original_reference_id: PMID:23921388
  review:
    summary: Jakobsson et al. (2013) showed METTL21A-mediated trimethylation of Hsp70 modulates its chaperone
      function, altering affinity for monomeric and fibrillar alpha-synuclein (PMID:23921388). The disaggregase
      activity is a core function of the Hsp70/Hsp110/Hsp40 chaperone system.
    action: ACCEPT
    reason: ATP-dependent protein disaggregase activity is a core molecular function of HSPA1A. Confirmed
      by IDA (PMID:23921388).
    supported_by:
    - reference_id: PMID:23921388
      supporting_text: 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.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    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.
    action: ACCEPT
    reason: ATP hydrolysis activity directly demonstrated by Hageman et al. (PMID:21231916). Core enzymatic
      function of HSPA1A.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: 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.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IDA
  original_reference_id: PMID:17568691
  review:
    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).
    action: ACCEPT
    reason: Extracellular space localization is experimentally confirmed. HSPA1A is released from necrotic
      cells and detected in extracellular fluids (PMID:17568691).
    supported_by:
    - reference_id: PMID:17568691
      supporting_text: HMGB1 and HSP70 were indeed present in the necrotic cell lysate and were responsible
        for the significant induction of the proinflammatory cytokine expression
- term:
    id: GO:0048018
    label: receptor ligand activity
  evidence_type: IDA
  original_reference_id: PMID:17568691
  review:
    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).
    action: KEEP_AS_NON_CORE
    reason: Receptor ligand activity is experimentally supported for extracellular Hsp70 (PMID:17568691)
      but is a non-core extracellular signaling function.
    supported_by:
    - reference_id: PMID:17568691
      supporting_text: the newly identified triggering receptor expressed on myeloid cells-1 (TREM-1)
        was involved in mediating the HMGB1- and HSP70-induced cytokine production.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IDA
  original_reference_id: PMID:26183779
  review:
    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).
    action: ACCEPT
    reason: Extracellular space localization confirmed by IDA (PMID:26183779). Consistent with known extracellular
      signaling roles of Hsp70.
    supported_by:
    - reference_id: PMID:26183779
      supporting_text: Tag7 (PGLYRP1) in Complex with Hsp70 Induces Alternative Cytotoxic Processes in
        Tumor Cells via TNFR1 Receptor.
- term:
    id: GO:0048018
    label: receptor ligand activity
  evidence_type: IDA
  original_reference_id: PMID:26183779
  review:
    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).
    action: KEEP_AS_NON_CORE
    reason: Receptor ligand activity via Tag7-Hsp70 complex is experimentally confirmed (PMID:26183779)
      but is a non-core extracellular function.
    supported_by:
    - reference_id: PMID:26183779
      supporting_text: Tag7 (PGLYRP1) in Complex with Hsp70 Induces Alternative Cytotoxic Processes in
        Tumor Cells via TNFR1 Receptor.
- term:
    id: GO:0051787
    label: misfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:28842558
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:28842558
      supporting_text: HSP70-Hrd1 axis precludes the oncorepressor potential of N-terminal misfolded Blimp-1s
        in lymphoma cells.
- term:
    id: GO:0007041
    label: lysosomal transport
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0033120
    label: positive regulation of RNA splicing
  evidence_type: IDA
  original_reference_id: PMID:20625543
  review:
    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).
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:20625543
      supporting_text: Hsp72 enhances XBP1 mRNA splicing and expression of its target genes, associated
        with attenuated apoptosis under ER stress conditions.
- term:
    id: GO:0034620
    label: cellular response to unfolded protein
  evidence_type: IMP
  original_reference_id: PMID:20625543
  review:
    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.
    action: ACCEPT
    reason: Cellular response to unfolded protein is a core function of HSPA1A as a major stress-inducible
      chaperone. Confirmed by IMP (PMID:20625543).
    supported_by:
    - reference_id: PMID:20625543
      supporting_text: Hsp72 enhances cell survival under ER stress conditions.
- term:
    id: GO:0045296
    label: cadherin binding
  evidence_type: HDA
  original_reference_id: PMID:25468996
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: HDA-level evidence from proteomics screen (PMID:25468996). Likely reflects chaperone-substrate
      interactions with cadherin complexes rather than specific cadherin binding activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12853476
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0008180
    label: COP9 signalosome
  evidence_type: IDA
  original_reference_id: PMID:18850735
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: COP9 signalosome association likely represents chaperone-client interaction detected by mass
      spectrometry (PMID:18850735) rather than stable complex membership.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:17167422
  review:
    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).
    action: ACCEPT
    reason: Nuclear localization confirmed by IDA in erythroid precursors (PMID:17167422). Consistent
      with already-accepted IBA annotation.
    supported_by:
    - reference_id: PMID:17167422
      supporting_text: Hsp70 co-localizes and interacts with GATA-1 in the nucleus of erythroid precursors
        undergoing terminal differentiation.
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IMP
  original_reference_id: PMID:17167422
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:17167422
      supporting_text: during differentiation, but not during apoptosis, the chaperone protein Hsp70 protects
        GATA-1 from caspase-mediated proteolysis.
- term:
    id: GO:0045648
    label: positive regulation of erythrocyte differentiation
  evidence_type: IMP
  original_reference_id: PMID:17167422
  review:
    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).
    action: KEEP_AS_NON_CORE
    reason: Positive regulation of erythrocyte differentiation is experimentally confirmed (PMID:17167422)
      but represents a tissue-specific developmental function, not a core chaperone function.
    supported_by:
    - reference_id: PMID:17167422
      supporting_text: during differentiation, but not during apoptosis, the chaperone protein Hsp70 protects
        GATA-1 from caspase-mediated proteolysis.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27133716
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23349634
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:23349634
  review:
    summary: Cloutier et al. (2013) identified HSPA1A in complexes with lysine methyltransferases that
      regulate chaperone activity (PMID:23349634).
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22658674
  review:
    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).
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22681889
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: RNA binding confirmed independently by second HDA study (PMID:22681889). Secondary function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15671022
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18975920
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21081504
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9553041
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:10205060
  review:
    summary: Laroia et al. (1999) showed Hsp70 sequesters AUF1 in the perinucleus-nucleus during heat
      shock (PMID:10205060). This confirms nuclear localization of HSPA1A.
    action: ACCEPT
    reason: Nuclear localization confirmed by IDA (PMID:10205060). Consistent with already-accepted annotations.
    supported_by:
    - reference_id: PMID:10205060
      supporting_text: hsp70 sequestration of AUF1 in the perinucleus-nucleus
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:10859165
  review:
    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).
    action: ACCEPT
    reason: Cytoplasmic localization confirmed by IDA (PMID:10859165). Consistent with already-accepted
      IBA annotation.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: TAS
  original_reference_id: PMID:16130169
  review:
    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.
    action: ACCEPT
    reason: Cytoplasmic localization is well-established for HSPA1A. Consistent with all other evidence.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:24061851
  review:
    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).
    action: ACCEPT
    reason: Cytoplasmic localization confirmed by IDA (PMID:24061851). Consistent with already-accepted
      annotations.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:9553041
  review:
    summary: Maheswaran et al. (1998) showed Hsp70 in the cytoplasm and nucleus of cells expressing WT1
      (PMID:9553041).
    action: ACCEPT
    reason: Cytoplasmic localization confirmed by IDA (PMID:9553041). Consistent with already-accepted
      IBA annotation.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: TAS
  original_reference_id: PMID:16130169
  review:
    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).
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: TAS
  original_reference_id: PMID:16130169
  review:
    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).
    action: KEEP_AS_NON_CORE
    reason: ER association is supported in the context of UPR signaling (PMID:20625543) but is not the
      primary localization of HSPA1A.
- term:
    id: GO:0006402
    label: mRNA catabolic process
  evidence_type: IDA
  original_reference_id: PMID:10205060
  review:
    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).
    action: KEEP_AS_NON_CORE
    reason: mRNA catabolic process involvement is confirmed (PMID:10205060) but is a secondary regulatory
      role of HSPA1A, not a core function.
    supported_by:
    - reference_id: PMID:10205060
      supporting_text: hsp70 sequestration of AUF1 in the perinucleus-nucleus, and all three processes
        block decay of AU-rich mRNAs and AUF1 protein.
- term:
    id: GO:0006986
    label: response to unfolded protein
  evidence_type: IDA
  original_reference_id: PMID:10859165
  review:
    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.
    action: ACCEPT
    reason: Response to unfolded protein is a core biological process for HSPA1A. Confirmed by IDA.
- term:
    id: GO:0008285
    label: negative regulation of cell population proliferation
  evidence_type: IMP
  original_reference_id: PMID:9553041
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:9553041
      supporting_text: Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires
        association with the inducible chaperone Hsp70.
- term:
    id: GO:0016235
    label: aggresome
  evidence_type: IDA
  original_reference_id: PMID:15885686
  review:
    summary: HSPA1A localizes to aggresomes, confirmed by IDA (PMID:15885686). Consistent with its role
      in protein quality control.
    action: ACCEPT
    reason: Aggresome localization confirmed by IDA (PMID:15885686). Consistent with already-accepted
      IEA annotation.
- term:
    id: GO:0016607
    label: nuclear speck
  evidence_type: IDA
  original_reference_id: PMID:9553041
  review:
    summary: Maheswaran et al. (1998) showed Hsp70 is recruited to subnuclear clusters containing WT1
      (PMID:9553041).
    action: ACCEPT
    reason: Nuclear speck localization confirmed by IDA (PMID:9553041). Consistent with already-accepted
      IEA annotation.
- term:
    id: GO:0030308
    label: negative regulation of cell growth
  evidence_type: IMP
  original_reference_id: PMID:9553041
  review:
    summary: Similar to GO:0008285, the cell growth inhibition requires WT1 with Hsp70 as a cofactor (PMID:9553041).
    action: MARK_AS_OVER_ANNOTATED
    reason: Cell growth effect mediated by WT1, not directly by Hsp70. Chaperone client effect.
    supported_by:
    - reference_id: PMID:9553041
      supporting_text: Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires
        association with the inducible chaperone Hsp70.
- term:
    id: GO:0031982
    label: vesicle
  evidence_type: HDA
  original_reference_id: PMID:19190083
  review:
    summary: HSPA1A detected in exosome-like vesicles from human tracheobronchial epithelium (PMID:19190083).
      Consistent with known exosomal/vesicular localization of Hsp70.
    action: ACCEPT
    reason: Vesicle localization confirmed by HDA proteomics (PMID:19190083). Consistent with known extracellular
      vesicle biology of Hsp70.
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: TAS
  original_reference_id: PMID:16130169
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Anti-apoptotic function is well-supported but represents a downstream pleiotropic effect of
      HSPA1A chaperone activity, not a core molecular function.
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:10205060
  review:
    summary: Laroia et al. (1999) showed Hsp70 sequesters AUF1 in the perinucleus-nucleus (PMID:10205060).
      Confirmed by IDA.
    action: ACCEPT
    reason: Perinuclear localization confirmed by IDA (PMID:10205060). Consistent with already-accepted
      IEA annotation.
    supported_by:
    - reference_id: PMID:10205060
      supporting_text: hsp70 sequestration of AUF1 in the perinucleus-nucleus
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: TAS
  original_reference_id: PMID:16130169
  review:
    summary: GO:0051082 "unfolded protein binding" is being obsoleted (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.
    action: MODIFY
    reason: GO:0051082 is being obsoleted. 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_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - PMID:21231916
    supported_by:
    - reference_id: PMID:16130169
      supporting_text: 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.
    - reference_id: PMID:21231916
      supporting_text: 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
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19199708
  review:
    summary: HSPA1A detected in exosomes from human parotid gland by MudPIT proteomics (PMID:19199708).
      Hsp70 is a well-established exosomal marker.
    action: ACCEPT
    reason: Extracellular exosome localization confirmed by proteomics (PMID:19199708). Hsp70 is a well-known
      exosomal protein.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  review:
    summary: HSPA1A detected in B-cell exosomes by proteomics (PMID:20458337). Independent confirmation
      of exosomal localization.
    action: ACCEPT
    reason: Extracellular exosome localization confirmed by independent proteomics study (PMID:20458337).
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  review:
    summary: HSPA1A detected in exosomes from expressed prostatic secretions (PMID:23533145). Third independent
      confirmation of exosomal localization.
    action: ACCEPT
    reason: Extracellular exosome localization confirmed by third independent proteomics study (PMID:23533145).
- term:
    id: GO:1990904
    label: ribonucleoprotein complex
  evidence_type: IDA
  original_reference_id: PMID:17289661
  review:
    summary: Jonson et al. (2007) identified HSPA1A as a component of IMP1 ribonucleoprotein granules
      by mass spectrometry (PMID:17289661).
    action: KEEP_AS_NON_CORE
    reason: RNP complex association confirmed by IDA (PMID:17289661) but is a secondary localization related
      to HSPA1A's role in mRNA metabolism.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24318877
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27137183
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27708256
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IDA
  original_reference_id: PMID:27137183
  review:
    summary: Fang et al. (2016) showed HSP70 accumulates at mitotic centrosomes during prometaphase to
      metaphase (PMID:27137183).
    action: ACCEPT
    reason: Centrosome localization confirmed by IDA (PMID:27137183). Consistent with already-accepted
      IEA annotation.
    supported_by:
    - reference_id: PMID:27137183
      supporting_text: heat shock protein (HSP) 70 considerably accumulates at the mitotic centrosome
        during prometaphase to metaphase
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IMP
  original_reference_id: PMID:27708256
  review:
    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).
    action: ACCEPT
    reason: Protein refolding confirmed by IMP (PMID:27708256). Core function of HSPA1A. Consistent with
      already-accepted IBA and IDA annotations.
    supported_by:
    - reference_id: PMID:27708256
      supporting_text: Hsp70 preferentially facilitates protein refolding after stress, gradually switching
        to protein degradation via a mechanism dependent on ARD1-mediated Hsp70 acetylation
- term:
    id: GO:0090063
    label: positive regulation of microtubule nucleation
  evidence_type: IMP
  original_reference_id: PMID:27137183
  review:
    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).
    action: KEEP_AS_NON_CORE
    reason: Positive regulation of microtubule nucleation experimentally confirmed (PMID:27137183) but
      is a cell-cycle-specific function, not core chaperone activity.
    supported_by:
    - reference_id: PMID:27137183
      supporting_text: Inhibition or depletion of HSP70 impaired the function of mitotic centrosome and
        disrupted MT nucleation and polymerization from the spindle pole
- term:
    id: GO:1901673
    label: regulation of mitotic spindle assembly
  evidence_type: IMP
  original_reference_id: PMID:27137183
  review:
    summary: Fang et al. (2016) showed HSP70 is required for bipolar spindle assembly and maintenance
      of a functional mitotic centrosome (PMID:27137183).
    action: KEEP_AS_NON_CORE
    reason: Regulation of mitotic spindle assembly experimentally confirmed (PMID:27137183) but is a cell-cycle-specific
      function.
    supported_by:
    - reference_id: PMID:27137183
      supporting_text: HSP70 is required for the maintenance of a functional mitotic centrosome that supports
        the assembly of a bipolar mitotic spindle.
- term:
    id: GO:0051131
    label: chaperone-mediated protein complex assembly
  evidence_type: IDA
  original_reference_id: PMID:10811660
  review:
    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).
    action: ACCEPT
    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).
- term:
    id: GO:0003714
    label: transcription corepressor activity
  evidence_type: IDA
  original_reference_id: PMID:9499401
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Transcription corepressor activity toward HSF1 is experimentally confirmed (PMID:9499401).
      Part of the autoregulatory heat shock response, not a core chaperone function.
    supported_by:
    - reference_id: PMID:9499401
      supporting_text: the molecular chaperone Hsp70 and the cochaperone Hdj1 interact directly with the
        transactivation domain of HSF1 and repress heat shock gene transcription.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9499401
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9222587
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22219199
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24613385
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0030512
    label: negative regulation of transforming growth factor beta receptor signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:24613385
  review:
    summary: Shang et al. (2014) showed Hsp70 promotes CHIP-mediated Smad3 ubiquitination and degradation,
      thereby negatively regulating TGF-beta signaling (PMID:24613385).
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:24613385
      supporting_text: over-expressed Hsp70 or inhibition of Hsp90 by geldanamycin (GA) leads to facilitated
        CHIP-induced ubiquitination and degradation of Smad3
- term:
    id: GO:0032436
    label: positive regulation of proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:24613385
  review:
    summary: Shang et al. (2014) showed Hsp70 facilitates CHIP-induced ubiquitination and degradation
      of Smad3 (PMID:24613385). Core triage function.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:24613385
      supporting_text: over-expressed Hsp70 or inhibition of Hsp90 by geldanamycin (GA) leads to facilitated
        CHIP-induced ubiquitination and degradation of Smad3
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:11785981
  review:
    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).
    action: ACCEPT
    reason: Cytoplasmic localization confirmed by IDA (PMID:11785981). Consistent with already-accepted
      annotations.
- term:
    id: GO:0097718
    label: disordered domain specific binding
  evidence_type: IPI
  original_reference_id: PMID:11785981
  review:
    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.
    action: ACCEPT
    reason: Disordered domain binding is consistent with HSPA1A's substrate recognition of exposed hydrophobic
      segments in unfolded/disordered regions. Confirmed by IPI (PMID:11785981).
- term:
    id: GO:0031249
    label: denatured protein binding
  evidence_type: IPI
  original_reference_id: PMID:21909508
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IDA
  original_reference_id: PMID:21909508
  review:
    summary: Arhar et al. (2011) showed Hsp70 stabilizes intrinsically disordered proteins, acting as
      a molecular shield (PMID:21909508).
    action: ACCEPT
    reason: Protein stabilization confirmed by IDA (PMID:21909508). Consistent with already-accepted IEA
      annotation.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800434
  review:
    summary: Reactome annotates HSPA1A in the extracellular region via pathway R-HSA-6800434 (neutrophil
      degranulation). Consistent with known extracellular Hsp70.
    action: ACCEPT
    reason: Extracellular region localization consistent with known biology. Supported by Reactome pathway.
- term:
    id: GO:1904813
    label: ficolin-1-rich granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800434
  review:
    summary: Reactome pathway R-HSA-6800434 places HSPA1A in ficolin-1-rich granule lumen as part of neutrophil
      degranulation.
    action: ACCEPT
    reason: Ficolin-1-rich granule lumen localization supported by Reactome. Consistent with already-accepted
      IEA annotation.
- term:
    id: GO:0032757
    label: positive regulation of interleukin-8 production
  evidence_type: IMP
  original_reference_id: PMID:24790089
  review:
    summary: Mohanan & Grimes (2014) showed HSP70 stabilizes NOD2, which activates NF-kappaB signaling
      and downstream IL-8 production (PMID:24790089).
    action: KEEP_AS_NON_CORE
    reason: IL-8 production regulation is an indirect downstream effect of HSPA1A-mediated NOD2 stabilization
      (PMID:24790089). Consistent with already-accepted IEA annotation.
- term:
    id: GO:0031396
    label: regulation of protein ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:16809764
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:16809764
      supporting_text: 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.
- term:
    id: GO:0042826
    label: histone deacetylase binding
  evidence_type: IPI
  original_reference_id: PMID:16809764
  review:
    summary: Lee et al. (2006) showed HDAC8 recruits Hsp70 to a protein complex (PMID:16809764). Confirmed
      by IPI evidence.
    action: ACCEPT
    reason: Histone deacetylase binding confirmed by IPI (PMID:16809764). Consistent with already-accepted
      IEA annotation.
- term:
    id: GO:1902236
    label: negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:12150907
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Anti-apoptotic role in ER stress is experimentally supported (PMID:12150907) but is a downstream
      effect of chaperone-ubiquitin quality control.
    supported_by:
    - reference_id: PMID:12150907
      supporting_text: CHIP enhanced the ability of Parkin to inhibit cell death induced by Pael-R.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371467
  review:
    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.
    action: ACCEPT
    reason: Nucleoplasm localization consistent with known nuclear translocation of HSPA1A during stress.
      Supported by Reactome pathway annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371518
  review:
    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.
    action: ACCEPT
    reason: Nucleoplasm localization consistent with known nuclear translocation of HSPA1A during stress.
      Supported by Reactome pathway annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371554
  review:
    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.
    action: ACCEPT
    reason: Nucleoplasm localization consistent with known nuclear translocation of HSPA1A during stress.
      Supported by Reactome pathway annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5082356
  review:
    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.
    action: ACCEPT
    reason: Nucleoplasm localization consistent with known nuclear translocation of HSPA1A during stress.
      Supported by Reactome pathway annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5082369
  review:
    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.
    action: ACCEPT
    reason: Nucleoplasm localization consistent with known nuclear translocation of HSPA1A during stress.
      Supported by Reactome pathway annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5082384
  review:
    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.
    action: ACCEPT
    reason: Nucleoplasm localization consistent with known nuclear translocation of HSPA1A during stress.
      Supported by Reactome pathway annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5251955
  review:
    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.
    action: ACCEPT
    reason: Nucleoplasm localization consistent with known nuclear translocation of HSPA1A during stress.
      Supported by Reactome pathway annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5252041
  review:
    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.
    action: ACCEPT
    reason: Nucleoplasm localization consistent with known nuclear translocation of HSPA1A during stress.
      Supported by Reactome pathway annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371422
  review:
    summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-3371422). Cytosol is the primary
      site of HSPA1A chaperone function.
    action: ACCEPT
    reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway
      and confirmed by IBA and IDA evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371503
  review:
    summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-3371503). Cytosol is the primary
      site of HSPA1A chaperone function.
    action: ACCEPT
    reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway
      and confirmed by IBA and IDA evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371590
  review:
    summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-3371590). Cytosol is the primary
      site of HSPA1A chaperone function.
    action: ACCEPT
    reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway
      and confirmed by IBA and IDA evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-450551
  review:
    summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-450551). Cytosol is the primary
      site of HSPA1A chaperone function.
    action: ACCEPT
    reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway
      and confirmed by IBA and IDA evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-450580
  review:
    summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-450580). Cytosol is the primary
      site of HSPA1A chaperone function.
    action: ACCEPT
    reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway
      and confirmed by IBA and IDA evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5251942
  review:
    summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-5251942). Cytosol is the primary
      site of HSPA1A chaperone function.
    action: ACCEPT
    reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway
      and confirmed by IBA and IDA evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5251959
  review:
    summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-5251959). Cytosol is the primary
      site of HSPA1A chaperone function.
    action: ACCEPT
    reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway
      and confirmed by IBA and IDA evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5252041
  review:
    summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-5252041). Cytosol is the primary
      site of HSPA1A chaperone function.
    action: ACCEPT
    reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway
      and confirmed by IBA and IDA evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5252079
  review:
    summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-5252079). Cytosol is the primary
      site of HSPA1A chaperone function.
    action: ACCEPT
    reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway
      and confirmed by IBA and IDA evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618085
  review:
    summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-5618085). Cytosol is the primary
      site of HSPA1A chaperone function.
    action: ACCEPT
    reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway
      and confirmed by IBA and IDA evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618098
  review:
    summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-5618098). Cytosol is the primary
      site of HSPA1A chaperone function.
    action: ACCEPT
    reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway
      and confirmed by IBA and IDA evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618105
  review:
    summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-5618105). Cytosol is the primary
      site of HSPA1A chaperone function.
    action: ACCEPT
    reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway
      and confirmed by IBA and IDA evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618107
  review:
    summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-5618107). Cytosol is the primary
      site of HSPA1A chaperone function.
    action: ACCEPT
    reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway
      and confirmed by IBA and IDA evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618110
  review:
    summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-5618110). Cytosol is the primary
      site of HSPA1A chaperone function.
    action: ACCEPT
    reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway
      and confirmed by IBA and IDA evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9835411
  review:
    summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-9835411). Cytosol is the primary
      site of HSPA1A chaperone function.
    action: ACCEPT
    reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway
      and confirmed by IBA and IDA evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9857076
  review:
    summary: Cytosol localization from Reactome pathway (Reactome:R-HSA-9857076). Cytosol is the primary
      site of HSPA1A chaperone function.
    action: ACCEPT
    reason: Cytosol localization consistent with primary HSPA1A function. Supported by Reactome pathway
      and confirmed by IBA and IDA evidence.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22528486
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0055131
    label: C3HC4-type RING finger domain binding
  evidence_type: IPI
  original_reference_id: PMID:25281747
  review:
    summary: Roder et al. (2014) showed RNF207 interacts with Hsp70 (PMID:25281747). RNF207 is a C3HC4-type
      RING finger protein involved in cardiac excitation.
    action: ACCEPT
    reason: RING finger domain binding confirmed by IPI (PMID:25281747). Consistent with HSPA1A interactions
      with RING E3 ligases in the chaperone-ubiquitin triage system.
- term:
    id: GO:0001664
    label: G protein-coupled receptor binding
  evidence_type: IDA
  original_reference_id: PMID:12150907
  review:
    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).
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:12150907
      supporting_text: CHIP, Hsp70, Parkin, and Pael-R formed a complex in vitro and in vivo.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17616579
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20625543
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0031397
    label: negative regulation of protein ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:12150907
  review:
    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).
    action: ACCEPT
    reason: Negative regulation of ubiquitination confirmed by IDA (PMID:12150907). Core chaperone triage
      function. Consistent with already-accepted IEA annotation.
    supported_by:
    - reference_id: PMID:12150907
      supporting_text: CHIP promoted the dissociation of Hsp70 from Parkin and Pael-R, thus facilitating
        Parkin-mediated Pael-R ubiquitination.
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:12150907
  review:
    summary: Imai et al. (2002) showed Hsp70 forms complexes with CHIP (E3 ligase) and Parkin (E3 ligase)
      (PMID:12150907).
    action: ACCEPT
    reason: Ubiquitin protein ligase binding confirmed by IPI (PMID:12150907). Consistent with already-accepted
      IEA annotation.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: TAS
  original_reference_id: PMID:24252804
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Cellular response to oxidative stress is a secondary cytoprotective role. Consistent with
      already-accepted IEA annotation.
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: TAS
  original_reference_id: PMID:24252804
  review:
    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.
    action: ACCEPT
    reason: Protein stabilization is a core chaperone function. Consistent with already-accepted IEA annotation.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: NAS
  original_reference_id: PMID:12150907
  review:
    summary: GO:0051082 "unfolded protein binding" is being obsoleted (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.
    action: MODIFY
    reason: GO:0051082 is being obsoleted. 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_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - PMID:21231916
    supported_by:
    - reference_id: PMID:12150907
      supporting_text: 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.
    - reference_id: PMID:21231916
      supporting_text: 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.
- term:
    id: GO:1901029
    label: negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic
      signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:20625543
  review:
    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).
    action: KEEP_AS_NON_CORE
    reason: Inhibition of mitochondrial outer membrane permeabilization is experimentally supported (PMID:20625543)
      but is a downstream anti-apoptotic function.
    supported_by:
    - reference_id: PMID:20625543
      supporting_text: Hsp72 functions upstream of the caspase cascade by inhibiting the release of cytochrome
        c from the mitochondria
- term:
    id: GO:1902236
    label: negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:20625543
  review:
    summary: Gupta et al. (2010) showed Hsp72 protects cells from ER stress-induced apoptosis by enhancing
      IRE1alpha-XBP1 signaling (PMID:20625543).
    action: KEEP_AS_NON_CORE
    reason: Anti-apoptotic function in ER stress confirmed (PMID:20625543) but is a secondary cytoprotective
      function.
    supported_by:
    - reference_id: PMID:20625543
      supporting_text: binding of Hsp72 to IRE1alpha enhances IRE1alpha/XBP1 signaling at the ER and inhibits
        ER stress-induced apoptosis.
- term:
    id: GO:0005814
    label: centriole
  evidence_type: IDA
  original_reference_id: PMID:24061851
  review:
    summary: Khalouei et al. (2014) showed YFP-tagged HSPA1A localizes to centrioles upon thermal stress
      in human neuronal cells (PMID:24061851).
    action: ACCEPT
    reason: Centriole localization confirmed by IDA (PMID:24061851). Consistent with already-accepted
      IEA annotation.
    supported_by:
    - reference_id: PMID:24061851
      supporting_text: Following a brief period of thermal stress, YFP-tagged HSPA6 and HSPA1A rapidly
        appeared at centrioles in the cytoplasm of human neuronal cells
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: Hageman et al. (2011) performed chaperone assays with cytosolic HSPA1A (PMID:21231916). Cytosol
      is the primary location of HSPA1A function.
    action: ACCEPT
    reason: Cytosol localization confirmed by IDA (PMID:21231916). Consistent with already-accepted IBA
      annotation.
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: HDA
  original_reference_id: PMID:21423176
  review:
    summary: HSPA1A detected in focal adhesion proteome by mass spectrometry (PMID:21423176). This may
      reflect chaperone interactions with adhesion complex proteins.
    action: MARK_AS_OVER_ANNOTATED
    reason: Focal adhesion localization from HDA proteomics (PMID:21423176) likely reflects chaperone-client
      interactions rather than specific focal adhesion targeting.
- term:
    id: GO:0034605
    label: cellular response to heat
  evidence_type: IDA
  original_reference_id: PMID:24061851
  review:
    summary: Khalouei et al. (2014) showed HSPA1A rapidly localizes to centrioles following thermal stress,
      demonstrating a cellular response to heat (PMID:24061851).
    action: ACCEPT
    reason: Cellular response to heat confirmed by IDA (PMID:24061851). Core biological process.
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: Hageman et al. (2011) directly demonstrated HSPA1A refolds heat-denatured luciferase (PMID:21231916).
      Core function.
    action: ACCEPT
    reason: Protein refolding confirmed by direct luciferase refolding assay (PMID:21231916). Core function
      of HSPA1A.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: we assessed the effect of overexpression of each of these HSPs on refolding of
        heat-denatured luciferase
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: GO:0051082 "unfolded protein binding" is being obsoleted (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.
    action: MODIFY
    reason: 'GO:0051082 is being obsoleted. 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_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: 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.
    - reference_id: PMID:21231916
      supporting_text: whereas overexpression of HSPA1A protected cells from heat-induced cell death,
        overexpression of HSPA6 did not
- term:
    id: GO:0070370
    label: cellular heat acclimation
  evidence_type: IMP
  original_reference_id: PMID:21231916
  review:
    summary: Hageman et al. (2011) showed HSPA1A overexpression protects cells from heat-induced cell
      death (PMID:21231916). Core thermotolerance function.
    action: ACCEPT
    reason: Cellular heat acclimation confirmed by IMP (PMID:21231916). Core function.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: whereas overexpression of HSPA1A protected cells from heat-induced cell death,
        overexpression of HSPA6 did not
- term:
    id: GO:0072562
    label: blood microparticle
  evidence_type: HDA
  original_reference_id: PMID:22516433
  review:
    summary: HSPA1A detected in blood microparticles by proteomics (PMID:22516433). Consistent with known
      extracellular presence of Hsp70.
    action: ACCEPT
    reason: Blood microparticle localization confirmed by HDA proteomics (PMID:22516433). Consistent with
      known extracellular Hsp70 biology.
- term:
    id: GO:0090084
    label: negative regulation of inclusion body assembly
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: Hageman et al. (2011) showed HSPA1A suppresses polyQ aggregation/inclusion body formation
      (PMID:21231916). Core aggregation suppression function.
    action: ACCEPT
    reason: Negative regulation of inclusion body assembly confirmed by IDA (PMID:21231916). Core chaperone
      function.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: 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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15603737
  review:
    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.
    action: REMOVE
    reason: GO:0005515 'protein binding' is uninformative and should be replaced by more specific molecular
      function terms. HSPA1A already has appropriate specific MF annotations.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IDA
  original_reference_id: PMID:23921388
  review:
    summary: Jakobsson et al. (2013) showed METTL21A-mediated methylation of Hsp70 is stimulated by ATP,
      confirming ATP binding (PMID:23921388). Core molecular function.
    action: ACCEPT
    reason: ATP binding confirmed by IDA (PMID:23921388). Core molecular function of HSPA1A.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:25281747
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: Positive regulation of gene expression in the context of RNF207-Hsp70 interaction (PMID:25281747)
      is likely an indirect effect of chaperone-client relationship.
- term:
    id: GO:0016234
    label: inclusion body
  evidence_type: IDA
  original_reference_id: PMID:15603737
  review:
    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).
    action: ACCEPT
    reason: Inclusion body localization confirmed by IDA (PMID:15603737). Consistent with HSPA1A's role
      in protein quality control at aggregation sites.
    supported_by:
    - reference_id: PMID:15603737
      supporting_text: BAG5 enhances parkin sequestration within protein aggregates
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:23921388
  review:
    summary: Jakobsson et al. (2013) showed HSPA1A interacts with the methyltransferase METTL21A (PMID:23921388).
      Enzyme binding is accurate but broad.
    action: ACCEPT
    reason: Enzyme binding confirmed by IPI with METTL21A methyltransferase (PMID:23921388). Accurate
      but broad term.
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IPI
  original_reference_id: PMID:23921388
  review:
    summary: Jakobsson et al. (2013) showed METTL21A specifically methylates Hsp70 family proteins (PMID:23921388).
      Heat shock protein binding is core.
    action: ACCEPT
    reason: Heat shock protein binding confirmed by IPI (PMID:23921388). Consistent with already-accepted
      IBA annotation.
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:15603737
  review:
    summary: Kalia et al. (2004) showed BAG5 directly interacts with parkin and Hsp70 in a complex. Hsp70
      binds parkin (E3 ubiquitin ligase) (PMID:15603737).
    action: ACCEPT
    reason: Ubiquitin protein ligase binding confirmed by IPI (PMID:15603737). Consistent with already-accepted
      IEA annotation.
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IDA
  original_reference_id: PMID:15603737
  review:
    summary: Kalia et al. (2004) showed BAG5 inhibits Hsp70-mediated refolding of misfolded proteins (PMID:15603737).
      Confirms protein refolding activity.
    action: ACCEPT
    reason: Protein refolding confirmed by IDA (PMID:15603737). Core function.
    supported_by:
    - reference_id: PMID:15603737
      supporting_text: BAG5 inhibits both parkin E3 ubiquitin ligase activity and Hsp70-mediated refolding
        of misfolded proteins.
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IDA
  original_reference_id: PMID:15603737
  review:
    summary: Kalia et al. (2004) demonstrated Hsp70 chaperone activity inhibited by BAG5 (PMID:15603737).
      Confirms protein folding chaperone as core MF.
    action: ACCEPT
    reason: Protein folding chaperone confirmed by IDA (PMID:15603737). Core molecular function.
- term:
    id: GO:0046034
    label: ATP metabolic process
  evidence_type: IDA
  original_reference_id: PMID:23921388
  review:
    summary: Jakobsson et al. (2013) showed METTL21A-mediated methylation is stimulated by ATP, confirming
      Hsp70 ATPase function (PMID:23921388).
    action: ACCEPT
    reason: ATP metabolic process confirmed by IDA (PMID:23921388). Consistent with already-accepted IEA
      annotation.
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:15603737
  review:
    summary: Kalia et al. (2004) showed BAG5-Hsp70 complex localizes to the perinuclear region (PMID:15603737).
    action: ACCEPT
    reason: Perinuclear localization confirmed by IDA (PMID:15603737). Consistent with already-accepted
      IEA annotation.
- term:
    id: GO:0090084
    label: negative regulation of inclusion body assembly
  evidence_type: IDA
  original_reference_id: PMID:15603737
  review:
    summary: Kalia et al. (2004) showed Hsp70 suppresses protein aggregation, which is inhibited by BAG5
      (PMID:15603737).
    action: ACCEPT
    reason: Negative regulation of inclusion body assembly confirmed by IDA (PMID:15603737). Core function.
- term:
    id: GO:2001240
    label: negative regulation of extrinsic apoptotic signaling pathway in absence of ligand
  evidence_type: IMP
  original_reference_id: PMID:17167422
  review:
    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).
    action: KEEP_AS_NON_CORE
    reason: Anti-apoptotic function in the absence of survival signaling is experimentally supported (PMID:17167422)
      but is a downstream effect.
    supported_by:
    - reference_id: PMID:17167422
      supporting_text: erythropoietin starvation induces the nuclear export of Hsp70 and the cleavage
        of GATA-1.
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IPI
  original_reference_id: PMID:24790089
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Signaling receptor binding is confirmed for NOD2 (PMID:24790089) but represents a chaperone-client
      interaction rather than a core signaling function.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:24790089
  review:
    summary: Mohanan & Grimes (2014) showed HSP70 and NOD2 interact in the cytoplasm (PMID:24790089).
    action: ACCEPT
    reason: Cytoplasmic localization confirmed by IDA (PMID:24790089). Consistent with already-accepted
      IBA annotation.
- term:
    id: GO:1903265
    label: positive regulation of tumor necrosis factor-mediated signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:24790089
  review:
    summary: Mohanan & Grimes (2014) showed HSP70-mediated NOD2 stabilization enhances downstream signaling
      including TNF-mediated pathways (PMID:24790089).
    action: KEEP_AS_NON_CORE
    reason: Positive regulation of TNF signaling is an indirect downstream effect of NOD2 stabilization
      by HSPA1A (PMID:24790089). Not a core function.
core_functions:
- molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  description: >-
    HSPA1A is the major stress-inducible HSP70 chaperone. It functions as an ATP-dependent
    foldase that assists folding of newly synthesized polypeptides and refolding of
    stress-denatured proteins. HSPA1A binds unfolded/misfolded substrates via its C-terminal
    substrate-binding domain and undergoes iterative ATP hydrolysis-driven conformational
    cycles regulated by J-domain co-chaperones (DNAJB1, DNAJA1/2) and nucleotide exchange
    factors (BAG1/2/3, HSPH1). It triages substrates between refolding and proteasomal
    degradation via STUB1/CHIP E3 ubiquitin ligase. HSPA1A protected cells from heat-induced
    cell death and supported luciferase refolding in functional assays.
  directly_involved_in:
  - id: GO:0042026
    label: protein refolding
  - id: GO:0032436
    label: positive regulation of proteasomal ubiquitin-dependent protein catabolic
      process
  - id: GO:0070370
    label: cellular heat acclimation
  - id: GO:0006986
    label: response to unfolded protein
  - id: GO:0090084
    label: negative regulation of inclusion body assembly
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:21231916
    supporting_text: >-
      overexpression of HSPA1A protected cells from heat-induced cell death
  - reference_id: PMID:21231916
    supporting_text: >-
      chaperones that supported luciferase refolding were poor suppressors of polyQ
      aggregation
- molecular_function:
    id: GO:0140545
    label: ATP-dependent protein disaggregase activity
  description: >-
    HSPA1A works with DNAJ co-chaperones and HSPH1 nucleotide exchange factor to
    solubilize and disaggregate protein aggregates. This disaggregase activity uses
    the same ATP hydrolysis cycle as the foldase function but is directed toward
    pre-formed aggregates rather than nascent or stress-denatured monomers. This
    function is important for preventing accumulation of toxic protein aggregates
    and inclusion bodies under stress conditions.
  directly_involved_in:
  - id: GO:0090084
    label: negative regulation of inclusion body assembly
  locations:
  - id: GO:0005829
    label: cytosol
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator
    judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping,
    accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10205060
  title: Control of mRNA decay by heat shock-ubiquitin-proteasome pathway.
  findings: []
- id: PMID:10811660
  title: Crystal structure and activity of human p23, a heat shock protein 90 co-chaperone.
  findings: []
- id: PMID:10859165
  title: Chaperone hsp27 inhibits translation during heat shock by binding eIF4G and facilitating dissociation
    of cap-initiation complexes.
  findings: []
- id: PMID:11785981
  title: HSP90, HSP70, and GAPDH directly interact with the cytoplasmic domain of macrophage scavenger
    receptors.
  findings: []
- id: PMID:12150907
  title: CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances
    its ubiquitin ligase activity.
  findings: []
- id: PMID:12853476
  title: Cofactor Tpr2 combines two TPR domains and a J domain to regulate the Hsp70/Hsp90 chaperone system.
  findings: []
- id: PMID:15603737
  title: BAG5 inhibits parkin and enhances dopaminergic neuron degeneration.
  findings: []
- id: PMID:15671022
  title: Heat shock protein 70 inhibits alpha-synuclein fibril formation via preferential binding to prefibrillar
    species.
  findings: []
- id: PMID:15885686
  title: TRIM37 defective in mulibrey nanism is a novel RING finger ubiquitin E3 ligase.
  findings: []
- id: PMID:16130169
  title: Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis.
  findings: []
- id: PMID:16809764
  title: Histone deacetylase 8 safeguards the human ever-shorter telomeres 1B (hEST1B) protein from ubiquitin-mediated
    degradation.
  findings: []
- id: PMID:17167422
  title: Hsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage of GATA-1.
  findings: []
- id: PMID:17182002
  title: HDJC9, a novel human type C DnaJ/HSP40 member interacts with and cochaperones HSP70 through the
    J domain.
  findings: []
- id: PMID:17289661
  title: Molecular composition of IMP1 ribonucleoprotein granules.
  findings: []
- id: PMID:17568691
  title: Endogenous signals released from necrotic cells augment inflammatory responses to bacterial endotoxin.
  findings: []
- id: PMID:17616579
  title: Cellular cofactors affecting hepatitis C virus infection and replication.
  findings: []
- id: PMID:18850735
  title: Characterization of the human COP9 signalosome complex using affinity purification and mass spectrometry.
  findings: []
- id: PMID:18975920
  title: Interactions between Hsp70 and the hydrophobic core of alpha-synuclein inhibit fibril assembly.
  findings: []
- id: PMID:19190083
  title: 'Characterization of exosome-like vesicles released from human tracheobronchial ciliated epithelium:
    a possible role in innate defense.'
  findings: []
- id: PMID:19199708
  title: Proteomic analysis of human parotid gland exosomes by multidimensional protein identification
    technology (MudPIT).
  findings: []
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional implications for
    exosome biogenesis.
  findings: []
- id: PMID:20625543
  title: HSP72 protects cells from ER stress-induced apoptosis via enhancement of IRE1alpha-XBP1 signaling
    through a physical interaction.
  findings: []
- id: PMID:21044950
  title: Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling
    in human cells.
  findings: []
- id: PMID:21081504
  title: ChChd3, an inner mitochondrial membrane protein, is essential for maintaining crista integrity
    and mitochondrial function.
  findings: []
- id: PMID:21231916
  title: The diverse members of the mammalian HSP70 machine show distinct chaperone-like activities.
  findings: []
- id: PMID:21423176
  title: Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative
    regulation of focal adhesion maturation.
  findings: []
- id: PMID:21909508
  title: Intrinsically disordered proteins as molecular shields.
  findings: []
- id: PMID:22219199
  title: The C-terminal helices of heat shock protein 70 are essential for J-domain binding and ATPase
    activation.
  findings: []
- id: PMID:22516433
  title: Proteomic analysis of microvesicles from plasma of healthy donors reveals high individual variability.
  findings: []
- id: PMID:22528486
  title: Nucleophosmin (NPM1/B23) interacts with activating transcription factor 5 (ATF5) protein and
    promotes proteasome- and caspase-dependent ATF5 degradation in hepatocellular carcinoma cells.
  findings: []
- id: PMID:22658674
  title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
  findings: []
- id: PMID:22681889
  title: The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.
  findings: []
- id: PMID:23349634
  title: A newly uncovered group of distantly related lysine methyltransferases preferentially interact
    with molecular chaperones to regulate their activity.
  findings: []
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
  findings: []
- id: PMID:23921388
  title: Identification and characterization of a novel human methyltransferase modulating Hsp70 protein
    function through lysine methylation.
  findings: []
- id: PMID:24061851
  title: Stress-induced localization of HSPA6 (HSP70B') and HSPA1A (HSP70-1) proteins to centrioles in
    human neuronal cells.
  findings: []
- id: PMID:24252804
  title: The role of oxidative stress in Parkinson's disease.
  findings: []
- id: PMID:24318877
  title: Binding of human nucleotide exchange factors to heat shock protein 70 (Hsp70) generates functionally
    distinct complexes in vitro.
  findings: []
- id: PMID:24338975
  title: Discovery of multiple interacting partners of gankyrin, a proteasomal chaperone and an oncoprotein--evidence
    for a common hot spot site at the interface and its functional relevance.
  findings: []
- id: PMID:24428437
  title: Mutations in the substrate binding site of human heat-shock protein 70 indicate specific interaction
    with HLA-DR outside the peptide binding groove.
  findings: []
- id: PMID:24613385
  title: Hsp70 and Hsp90 oppositely regulate TGF-β signaling through CHIP/Stub1.
  findings: []
- id: PMID:24790089
  title: The molecular chaperone HSP70 binds to and stabilizes NOD2, an important protein involved in
    Crohn disease.
  findings: []
- id: PMID:25281747
  title: RING finger protein RNF207, a novel regulator of cardiac excitation.
  findings: []
- id: PMID:25468996
  title: E-cadherin interactome complexity and robustness resolved by quantitative proteomics.
  findings: []
- id: PMID:26183779
  title: Tag7 (PGLYRP1) in Complex with Hsp70 Induces Alternative Cytotoxic Processes in Tumor Cells via
    TNFR1 Receptor.
  findings: []
- id: PMID:27133716
  title: A novel nuclear DnaJ protein, DNAJC8, can suppress the formation of spinocerebellar ataxia 3
    polyglutamine aggregation in a J-domain independent manner.
  findings: []
- id: PMID:27137183
  title: HSP70 regulates the function of mitotic centrosomes.
  findings: []
- id: PMID:27708256
  title: ARD1-mediated Hsp70 acetylation balances stress-induced protein refolding and degradation.
  findings: []
- id: PMID:28842558
  title: HSP70-Hrd1 axis precludes the oncorepressor potential of N-terminal misfolded Blimp-1s in lymphoma
    cells.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread
    Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:9222587
  title: Evidence for a role of Hsp70 in the regulation of the heat shock response in mammalian cells.
  findings: []
- id: PMID:9499401
  title: Molecular chaperones as HSF1-specific transcriptional repressors.
  findings: []
- id: PMID:9553041
  title: Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires association with
    the inducible chaperone Hsp70.
  findings: []
- id: Reactome:R-HSA-3371422
  title: ATP hydrolysis by HSP70
  findings: []
- id: Reactome:R-HSA-3371467
  title: SIRT1 deacetylates HSF1
  findings: []
- id: Reactome:R-HSA-3371497
  title: HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand
  findings: []
- id: Reactome:R-HSA-3371503
  title: STIP1(HOP) binds HSP90 and HSP70:HSP40:nascent protein
  findings: []
- id: Reactome:R-HSA-3371518
  title: SIRT1 binds to HSF1
  findings: []
- id: Reactome:R-HSA-3371554
  title: HSF1 acetylation at Lys80
  findings: []
- id: Reactome:R-HSA-3371590
  title: HSP70 binds to HSP40:nascent protein
  findings: []
- id: Reactome:R-HSA-450551
  title: AUF1 binds translation and heat shock proteins
  findings: []
- id: Reactome:R-HSA-450580
  title: AUF1 (hnRNP D0) is ubiquitinylated
  findings: []
- id: Reactome:R-HSA-5082356
  title: HSF1-mediated gene expression
  findings: []
- id: Reactome:R-HSA-5082369
  title: Acetylated HSF1 dissociates from DNA
  findings: []
- id: Reactome:R-HSA-5082384
  title: HSP70:DNAJB1 binds HSF1
  findings: []
- id: Reactome:R-HSA-5251942
  title: Hikeshi binds HSP70s:ATP
  findings: []
- id: Reactome:R-HSA-5251955
  title: HSP40s activate intrinsic ATPase activity of HSP70s in the nucleoplasm
  findings: []
- id: Reactome:R-HSA-5251959
  title: HSP40s activate intrinsic ATPase activity of HSP70s in the cytosol
  findings: []
- id: Reactome:R-HSA-5252041
  title: NPC transports Hikeshi:HSP70s:ATP from cytosol to nucleoplasm
  findings: []
- id: Reactome:R-HSA-5252079
  title: HSP110s exchange ATP for ADP on HSP70s:ADP
  findings: []
- id: Reactome:R-HSA-5618085
  title: FKBP4 binds HSP90:ATP:STIP1:HSP70:nascent protein
  findings: []
- id: Reactome:R-HSA-5618098
  title: p23 (PTGES3) binds HSP90:ATP:FKBP5:nascent protein
  findings: []
- id: Reactome:R-HSA-5618105
  title: FKBP5 binds HSP90:ATP:STIP1:HSP70:nascent protein
  findings: []
- id: Reactome:R-HSA-5618107
  title: ATP binding to HSP90 triggers conformation change
  findings: []
- id: Reactome:R-HSA-5618110
  title: p23 (PTGES3) binds HSP90:ATP:FKBP4:nascent protein
  findings: []
- id: Reactome:R-HSA-6800434
  title: Exocytosis of ficolin-rich granule lumen proteins
  findings: []
- id: Reactome:R-HSA-9835411
  title: FA core complex:HSP70s binds PKR
  findings: []
- id: Reactome:R-HSA-9857076
  title: Oxidized DNAJA1 binds HSPA1A,B (HSP70) displacing HSF1
  findings: []