id: P17066
gene_symbol: HSPA6
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  HSPA6 (also known as HSP70B') is a strictly stress-inducible member of the HSP70/HSPA
  molecular chaperone family. Unlike the constitutively expressed HSC70 or the basally
  expressed HSPA1A, HSPA6 shows no basal expression and is induced only at higher
  temperatures or under severe stress conditions (PMID:2327978). HSPA6 has the canonical
  HSP70 architecture: an N-terminal ATPase (nucleotide-binding) domain, a substrate-
  binding domain with a lid, and a C-terminal EEVD motif mediating co-chaperone
  interactions (DOI:10.3390/biom13040604). It functions as an ATP-dependent protein
  folding chaperone, cycling through ATP binding, hydrolysis, and ADP release to assist
  in protein folding and refolding, with J-domain proteins (HSP40/DNAJ) delivering
  clients and stimulating hydrolysis, and nucleotide exchange factors (BAG-family,
  HSPBP1, HSP110) promoting ADP release and client recycling
  (DOI:10.3390/biom13040604). In neuronal heat-stress models, HSPA6 is one of the
  most strongly induced HSP70 paralogs, showing approximately 13-14-fold induction
  under extreme heat vs approximately 2-3-fold under mild heat, with gene expression
  peaking at approximately 1 hour and protein at approximately 5-6 hours post-stress
  (DOI:10.3390/biology12030416). HSPA6 is co-expressed with key co-chaperones DNAJB1
  (J-domain), BAG3 (NEF), and HSPH1/HSP110 (NEF) under stress, forming a coordinated
  inducible chaperone module for protein disaggregation and refolding
  (DOI:10.3390/biology12030416). Notably, HSPA6 displays substrate specificity
  distinct from other HSP70 family members; it cannot refold heat-denatured luciferase
  but can assist in reactivation of heat-unfolded p53, suggesting it has evolved to
  maintain specific critical functions under conditions of severe stress (PMID:21231916).
  HSPA6 has also been implicated in RTP1S-dependent trafficking of olfactory receptors,
  where co-expression of HSPA6 partially enhanced surface expression of an olfactory
  receptor by approximately 50-80%, interacting via its C-terminal domain with the
  RTP1S N-terminus (DOI:10.3390/ijms24097829). The HSPA6/HSP70B' promoter has been
  exploited in synthetic biology as a thermal gene switch for remote control of
  mammalian cells via photothermal activation (DOI:10.1021/acssynbio.7b00455).
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation of GO:0005634 (nucleus) based on phylogenetic inference from
      HSP70 family orthologs. Multiple HSP70 family members are known to localize
      to the nucleus, and the phylogenetic evidence is broad, including yeast, worm,
      fly, and mammalian orthologs. CD-CODE database entries for HSPA6 (P17066)
      include nuclear speckle and nucleolus localizations, providing indirect support.
      However, direct experimental evidence for nuclear localization of HSPA6 is
      limited. Khalouei et al. (2014) used YFP-tagged HSPA6 in neuronal cells and
      primarily observed cytoplasmic and centriolar localization after heat stress
      (PMID:24061851). IBA annotations are generally reliable and this is plausible
      for an HSP70 family member.
    action: ACCEPT
    reason: >-
      Nuclear localization is well-established for multiple HSP70 family members and
      the IBA phylogenetic inference is broadly supported. CD-CODE entries for P17066
      list nuclear speckle and nucleolus localizations. While direct experimental
      evidence for HSPA6 nuclear localization is lacking in the available publications,
      the IBA inference is reasonable given the conserved family behavior.
    supported_by:
    - reference_id: PMID:24061851
      supporting_text: >-
        Stable lines of human SH-SY5Y neuronal cells were established that expressed
        YFP-tagged protein products of the human inducible HSP70 genes HSPA6 (HSP70B')
        and HSPA1A (HSP70-1)
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation of GO:0005737 (cytoplasm) based on phylogenetic inference. This
      is strongly supported by direct experimental data: Khalouei et al. (2014)
      showed YFP-tagged HSPA6 localizes in the cytoplasm of human neuronal cells
      (PMID:24061851), and Hageman et al. (2011) showed cytosolic localization
      consistent with cytoplasmic distribution (PMID:21231916). Also supported by
      the IDA annotation from PMID:24061851.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is a core feature of HSP70 family members and is
      directly supported by experimental IDA evidence from PMID:24061851 showing
      HSPA6-YFP in the cytoplasm of neuronal cells. The IBA is consistent with
      multiple lines of evidence.
    supported_by:
    - reference_id: PMID:24061851
      supporting_text: >-
        YFP-tagged HSPA6 and HSPA1A rapidly appeared at centrioles in the cytoplasm
        of human neuronal cells
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation of GO:0005886 (plasma membrane) based on phylogenetic inference.
      Some HSP70 family members have been reported at the plasma membrane,
      particularly HSPA1A in cancer cells. There is no direct experimental evidence
      for HSPA6 at the plasma membrane in available publications. The IBA phylogenetic
      support includes several orthologs. While plasma membrane localization is
      documented for some family members, this may not be a core localization for
      the strictly stress-inducible HSPA6.
    action: KEEP_AS_NON_CORE
    reason: >-
      Plasma membrane localization is documented for some HSP70 family members (e.g.
      HSPA1A in stressed/cancer cells), making the phylogenetic inference plausible.
      However, there is no direct evidence for HSPA6 at the plasma membrane and this
      is unlikely to be a core localization for this strictly stress-inducible member.
      The IBA is retained as non-core because the phylogenetic inference is reasonable
      but this is not experimentally validated for HSPA6.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation of GO:0016887 (ATP hydrolysis activity) based on phylogenetic
      inference across HSP70 family members. This is a core molecular function of
      HSPA6, directly confirmed by Hageman et al. (2011), who demonstrated that
      HSPA6 possesses intrinsic ATPase activity as high as that of canonical HSPA1A
      when stimulated by J-proteins (PMID:21231916). Also supported by IDA evidence
      from the same publication and IEA from InterPro domain mapping.
    action: ACCEPT
    reason: >-
      ATP hydrolysis is the central catalytic activity of HSP70 family chaperones.
      HSPA6 ATPase activity is directly demonstrated experimentally (PMID:21231916).
      The IBA annotation is fully consistent with both the biochemical data and the
      conserved HSP70 domain architecture.
    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:0031072
    label: heat shock protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation of GO:0031072 (heat shock protein binding) based on phylogenetic
      inference. This is directly supported by experimental IPI evidence from Hageman
      et al. (2011), who demonstrated physical interactions between HSPA6 and multiple
      J-domain co-chaperones (DNAJA1, DNAJA2, DNAJA4, DNAJB1, DNAJB4, DNAJB6,
      DNAJB2, and others) as well as co-chaperones like BAG1 and HSPBP1
      (PMID:21231916). HSP70-J-protein interactions are central to the HSP70 chaperone
      cycle.
    action: ACCEPT
    reason: >-
      HSP70 proteins functionally depend on interaction with J-domain co-chaperones
      (DNAJ proteins) and nucleotide exchange factors (BAG proteins, HSPBP1). Hageman
      et al. (2011) directly demonstrated these interactions for HSPA6 (PMID:21231916).
      The IBA is well-supported by experimental evidence and reflects a core aspect
      of HSP70 chaperone biology.
    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:0044183
    label: protein folding chaperone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation of GO:0044183 (protein folding chaperone) based on phylogenetic
      inference across HSP70 family members. This is the central molecular function
      of HSPA6. Hageman et al. (2011) demonstrated that purified HSPA6 can assist in
      reactivation of heat-unfolded p53, confirming active chaperone function
      (PMID:21231916). The ATPase activity and substrate-binding domain are functional.
      HSPA6 shows substrate specificity distinct from other HSP70 members (cannot
      refold luciferase but can refold p53), indicating a specialized chaperone role.
    action: ACCEPT
    reason: >-
      Protein folding chaperone activity is the core evolved function of HSPA6 as an
      HSP70 family member. This is directly supported by experimental evidence showing
      HSPA6 can assist in reactivation of heat-unfolded p53 in an ATP-dependent
      manner (PMID:21231916). The IBA annotation correctly captures this core function.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        purified HSPA6 could not chaperone heat-unfolded luciferase but was able to
        assist in reactivation of heat-unfolded p53
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation of GO:0005829 (cytosol) based on phylogenetic inference. This
      is directly supported by IDA evidence from Hageman et al. (2011), who showed
      cytosolic localization of HSPA6 (PMID:21231916). Consistent with the known
      localization of most HSP70 family members.
    action: ACCEPT
    reason: >-
      Cytosol is the primary localization for HSPA6 and most HSP70 family members.
      Directly supported by IDA evidence (PMID:21231916). The IBA annotation is
      consistent with experimental data.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding
        genes and most of the corresponding proteins are localized in the cytosol
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation of GO:0042026 (protein refolding) based on phylogenetic inference.
      Directly supported by experimental IDA evidence from Hageman et al. (2011),
      who showed HSPA6 can assist in reactivation (refolding) of heat-unfolded p53
      (PMID:21231916). However, HSPA6 showed notably limited refolding capability
      compared to other HSP70 members -- it could not refold heat-denatured luciferase
      and could not suppress polyQ aggregation. The refolding function appears to be
      substrate-specific rather than general.
    action: ACCEPT
    reason: >-
      Protein refolding is a core biological process for HSP70 chaperones. HSPA6
      demonstrates refolding activity on at least one substrate (p53), although it
      shows substrate selectivity different from other family members (PMID:21231916).
      The IBA annotation is appropriate even though HSPA6 may have a narrower substrate
      range than other HSP70 members.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        purified HSPA6 could not chaperone heat-unfolded luciferase but was able to
        assist in reactivation of heat-unfolded p53
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation of GO:0000166 (nucleotide binding) based on UniProtKB keyword
      mapping (KW-0547 Nucleotide-binding). This is a broad parent term. HSPA6
      contains a well-characterized nucleotide-binding domain (NBD, residues 3-388)
      that binds ATP and ADP. The crystal structure of the ATPase domain (PDB:3FE1)
      confirms nucleotide binding (PMID:20072699). While correct, this is subsumed
      by the more specific ATP binding annotation.
    action: ACCEPT
    reason: >-
      Nucleotide binding is correct for HSPA6 and is confirmed by crystal structure
      data (PDB:3FE1, PMID:20072699). Although this is a broader term than ATP binding,
      IEA annotations at a broader level than more specific annotations are acceptable.
      The UniProt keyword mapping is accurate.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation of GO:0005524 (ATP binding) from combined automated annotation
      methods including InterPro domain mapping and UniProtKB keyword mapping. HSPA6
      has a well-characterized ATP-binding domain (NBD, residues 3-388) with multiple
      ATP binding sites defined in UniProt (residues 14-17, 73, 204-206, 270-277,
      341-344). The crystal structure of HSPA6 NBD in complex with ADP and phosphate
      (PDB:3FE1) directly confirms nucleotide binding (PMID:20072699). The original
      discovery paper (PMID:2327978) noted that HSP70B' protein bound ATP.
    action: ACCEPT
    reason: >-
      ATP binding is a core biochemical property of HSPA6, confirmed by crystal
      structure (PDB:3FE1), biochemical assays (PMID:21231916), and the original
      characterization showing the protein binds ATP (PMID:2327978). The IEA is
      accurate and well-supported.
    supported_by:
    - reference_id: PMID:2327978
      supporting_text: >-
        a more basic 70 kDa heat-shock protein that both the major stress-inducible
        HSP70 and constitutively expressed HSC70 heat-shock proteins, which in common
        with other heat-shock 70 kDa proteins bound ATP
- term:
    id: GO:0006986
    label: response to unfolded protein
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation of GO:0006986 (response to unfolded protein) generated by ARBA
      machine learning models. HSPA6 is a stress-inducible chaperone that is induced
      under severe stress conditions and participates in refolding of unfolded proteins
      (PMID:21231916). This annotation is consistent with the TAS annotation from
      PMID:2327978 for the same term. While HSPA6 is induced by heat stress rather
      than by unfolded proteins per se, the term is broadly appropriate for a heat
      shock protein that functions in protein quality control.
    action: ACCEPT
    reason: >-
      Response to unfolded protein is appropriate for HSPA6 as a stress-inducible
      molecular chaperone that participates in refolding denatured proteins. Consistent
      with the TAS annotation for the same term from PMID:2327978. The IEA prediction
      is reasonable.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation of GO:0016887 (ATP hydrolysis activity) based on InterPro domain
      mapping (IPR013126 HSP70 family). HSPA6 contains the conserved HSP70 domain
      with ATPase activity, directly confirmed by Hageman et al. (2011), who showed
      HSPA6 has intrinsic ATPase activity as high as HSPA1A when stimulated by
      J-proteins (PMID:21231916). Also supported by IBA and IDA annotations for the
      same term.
    action: ACCEPT
    reason: >-
      ATP hydrolysis activity is directly demonstrated for HSPA6 (PMID:21231916) and
      is correctly predicted from the HSP70 InterPro domain. The IEA is consistent
      with both IBA and IDA annotations for the same term.
    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:0019899
    label: enzyme binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation of GO:0019899 (enzyme binding) generated by ARBA machine learning
      models. HSPA6 interacts with METTL21A, a methyltransferase that trimethylates
      HSPA6 at Lys-563 (PMID:23921388). This makes the annotation technically correct.
      However, 'enzyme binding' is a vague term that does not convey informative
      molecular function. The more specific IPI annotation for the same term from
      PMID:23921388 captures the METTL21A interaction. The IEA adds no additional
      information.
    action: ACCEPT
    reason: >-
      The enzyme binding annotation is technically correct as HSPA6 is a substrate of
      the methyltransferase METTL21A (PMID:23921388). While vague, this IEA annotation
      is consistent with the IPI annotation from the same reference. Acceptable as a
      broad IEA that subsumes the more specific experimental annotation.
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation of GO:0042026 (protein refolding) generated by ARBA machine
      learning models. Consistent with IBA and IDA annotations for the same term.
      HSPA6 has been experimentally shown to assist in reactivation of heat-unfolded
      p53 (PMID:21231916), directly supporting this annotation.
    action: ACCEPT
    reason: >-
      Protein refolding is directly demonstrated for HSPA6 (PMID:21231916). The IEA
      prediction is consistent with existing IBA and IDA annotations for the same term.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      This IEA annotation of GO:0051082 (unfolded protein binding) was generated by ARBA
      machine learning models (GO_REF:0000117). GO:0051082 is being obsoleted
      (go-ontology#30962) because it conflates passive binding with active chaperone function.
      HSPA6 is a well-characterized HSP70 family ATP-dependent chaperone. The annotation
      should be replaced with GO:0044183 (protein folding chaperone), which correctly
      represents the active chaperone function demonstrated experimentally for HSPA6
      (PMID:21231916). This IEA annotation will likely be automatically updated when
      GO:0051082 is obsoleted, but should be modified to GO:0044183 regardless.
    action: MODIFY
    reason: >-
      GO:0051082 (unfolded protein binding) is scheduled for obsolescence (go-ontology#30962).
      HSPA6 functions as an ATP-dependent protein folding chaperone, not merely a passive
      binder of unfolded proteins. The ARBA-predicted annotation should be replaced with
      GO:0044183 (protein folding chaperone), consistent with the experimentally validated
      IDA evidence from PMID:21231916 showing HSPA6 assists in reactivation of
      heat-unfolded p53, and with the existing IBA annotation for GO:0044183.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - PMID:21231916
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        purified HSPA6 could not chaperone heat-unfolded luciferase but was able to
        assist in reactivation of heat-unfolded p53
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14743216
  review:
    summary: >-
      IPI annotation of GO:0005515 (protein binding) from Bouwmeester et al. (2004),
      a large-scale TAP-MS study mapping the TNF-alpha/NF-kappa B signaling pathway
      (PMID:14743216). HSPA6 (P17066) was identified as interacting with MAP3K14
      (Q99558/NIK). This is a high-throughput interaction study; the interaction with
      MAP3K14 is recorded in IntAct. However, 'protein binding' is uninformative as
      a molecular function term. HSP70 chaperones interact with many proteins as part
      of their chaperone function, and this interaction likely reflects HSPA6 acting
      as a chaperone or being co-purified rather than a specific functional interaction.
    action: REMOVE
    reason: >-
      GO:0005515 (protein binding) is uninformative and does not convey specific
      molecular function. The interaction with MAP3K14 from a high-throughput TAP-MS
      study (PMID:14743216) likely reflects nonspecific chaperone-client or co-purification
      artifacts rather than a specific functional partnership. HSP70 proteins are
      well-known contaminants in affinity purification experiments. This annotation
      should be removed in favor of more informative terms like heat shock protein
      binding (GO:0031072) or protein folding chaperone (GO:0044183).
    supported_by:
    - reference_id: PMID:14743216
      supporting_text: >-
        mapping of a protein interaction network around 32 known and candidate
        TNF-alpha/NF-kappa B pathway components by using an integrated approach
        comprising tandem affinity purification, liquid-chromatography tandem mass
        spectrometry, network analysis and directed functional perturbation studies
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21044950
  review:
    summary: >-
      IPI annotation of GO:0005515 (protein binding) from Lee et al. (2011), a
      genome-wide YFP fluorescence complementation (BiFC) screen for telomere
      regulators (PMID:21044950). HSPA6 was identified as interacting with TERF1
      (P54274). This is a large-scale high-throughput screen examining ~12,000 human
      proteins. BiFC can trap transient or weak interactions but may also produce
      false positives due to irreversible YFP fragment complementation. The biological
      relevance of an HSPA6-TERF1 interaction is unclear. 'Protein binding' is
      uninformative.
    action: REMOVE
    reason: >-
      GO:0005515 (protein binding) is uninformative. The HSPA6-TERF1 interaction from
      a large-scale BiFC screen (PMID:21044950) is of uncertain biological significance.
      As the authors note, BiFC can trap weak/transient interactions and the
      identified proteins may associate under specific conditions or may be false
      positives. HSP70 chaperones interact broadly with client proteins and this likely
      represents nonspecific chaperone-client binding rather than a telomere-specific
      function.
    supported_by:
    - reference_id: PMID:21044950
      supporting_text: >-
        transient or weak interactions as well as low abundance regulators that may be
        lost during in vitro purification steps, can be "trapped" thanks to the
        cofolding of YFP fragments
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31980649
  review:
    summary: >-
      IPI annotation of GO:0005515 (protein binding) from Kennedy et al. (2020), a
      study on EGFR network rewiring in colorectal cancer cells expressing KRAS(G13D)
      (PMID:31980649). HSPA6 was identified as interacting with MAP3K14 (Q99558) in
      this proteomics study. This is a large-scale interaction study; HSP70 proteins
      are commonly identified as interactors in such studies due to their chaperone
      function. 'Protein binding' is uninformative.
    action: REMOVE
    reason: >-
      GO:0005515 (protein binding) is uninformative. The interaction detected in a
      large-scale network study (PMID:31980649) likely reflects HSPA6 chaperone
      activity on client proteins rather than a specific functional interaction. HSP70
      proteins are frequently detected in interactome studies as nonspecific
      interactors or chaperone-client pairs.
    supported_by:
    - reference_id: PMID:31980649
      supporting_text: >-
        Mapping >6000 PPIs shows that this network is extensively rewired in cells
        expressing transforming levels of KRASG13D (mtKRAS)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: >-
      IPI annotation of GO:0005515 (protein binding) from Luck et al. (2020), the
      Human Reference Interactome (HuRI) systematic yeast two-hybrid binary
      interactome mapping (PMID:32296183). Multiple interactions were detected for
      HSPA6 including with AHCYL1 (O43865), BAG4 (O95429), FLNA (P21333-2), PPIB
      (P23284), RPA1 (P27694), LGALS7B (P47929), COMMD6 (Q7Z4G1), KRT222 (Q8N1A0),
      C22orf15 (Q8WYQ4-2), and PRAP1 (Q96NZ9). The BAG4 interaction is notable as
      BAG proteins are known nucleotide exchange factors for HSP70 chaperones and
      this interaction is biologically meaningful. However, 'protein binding' is
      uninformative. The BAG4 interaction would be better annotated under heat shock
      protein binding (GO:0031072).
    action: REMOVE
    reason: >-
      GO:0005515 (protein binding) is uninformative. While some interactions from HuRI
      may be biologically relevant (e.g., BAG4 as a nucleotide exchange factor), the
      generic 'protein binding' term does not capture this specificity. HSP70 proteins
      interact broadly with many partners through their chaperone function. The BAG4
      interaction is already better captured by the heat shock protein binding
      annotation (GO:0031072). The remaining interactions are likely chaperone-client
      interactions or Y2H artifacts.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        HuRI is a systematic proteome-wide reference that links genomic variation to
        phenotypic outcomes
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      IDA annotation of GO:0016887 (ATP hydrolysis activity) from Hageman et al.
      (2011). This study directly demonstrated that HSPA6 possesses intrinsic ATPase
      activity that is as high as that of the canonical HSPA1A when stimulated by
      J-proteins (PMID:21231916). This is high-quality direct experimental evidence
      for a core molecular function of HSPA6.
    action: ACCEPT
    reason: >-
      This is well-supported IDA evidence for a core molecular function. Hageman et
      al. (2011) directly measured HSPA6 ATPase activity and showed it is comparable
      to HSPA1A when stimulated by J-proteins (PMID:21231916). ATP hydrolysis is
      central to the HSP70 chaperone cycle and represents a core function of HSPA6.
    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:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798748
  review:
    summary: >-
      TAS annotation of GO:0005576 (extracellular region) from Reactome pathway
      R-HSA-6798748 (Exocytosis of secretory granule lumen proteins). This annotation
      indicates HSPA6 is found in the extracellular space, presumably after release
      from neutrophil secretory granules. HSP70 proteins can be released extracellularly,
      particularly from immune cells. This is a plausible but non-core localization
      for HSPA6, which primarily functions as an intracellular chaperone.
    action: KEEP_AS_NON_CORE
    reason: >-
      Extracellular release of HSP70 family members from neutrophil granules is
      documented. However, this is not a core localization for HSPA6, which primarily
      functions as an intracellular stress-inducible chaperone. The Reactome pathway
      annotation is retained as non-core.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800434
  review:
    summary: >-
      TAS annotation of GO:0005576 (extracellular region) from Reactome pathway
      R-HSA-6800434 (Exocytosis of ficolin-rich granule lumen proteins). Same
      rationale as the R-HSA-6798748 annotation above -- HSPA6 may be released
      extracellularly from neutrophil granules, but this is not a core localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Duplicate extracellular region annotation from a different Reactome pathway
      (ficolin-rich granule exocytosis). Same rationale as R-HSA-6798748: extracellular
      release is plausible but not a core localization for this intracellular chaperone.
- term:
    id: GO:0034774
    label: secretory granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798748
  review:
    summary: >-
      TAS annotation of GO:0034774 (secretory granule lumen) from Reactome pathway
      R-HSA-6798748 (Exocytosis of secretory granule lumen proteins). This indicates
      HSPA6 is found in neutrophil secretory granule lumens. HSP70 proteins have been
      detected in neutrophil granules. This is a specialized localization for an immune
      cell context, not a core localization for HSPA6.
    action: KEEP_AS_NON_CORE
    reason: >-
      Localization to neutrophil secretory granule lumen is plausible based on Reactome
      curation of neutrophil degranulation pathways. However, this is a specialized
      immune cell context and not a core localization for HSPA6, which primarily
      functions as a cytosolic stress-inducible chaperone.
- term:
    id: GO:1904813
    label: ficolin-1-rich granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800434
  review:
    summary: >-
      TAS annotation of GO:1904813 (ficolin-1-rich granule lumen) from Reactome
      pathway R-HSA-6800434 (Exocytosis of ficolin-rich granule lumen proteins). This
      is a specific sub-type of neutrophil granule. Similar rationale to the secretory
      granule lumen annotation -- this is a specialized immune cell localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Ficolin-1-rich granule lumen is a specific neutrophil granule compartment. While
      plausible based on Reactome curation, this represents a specialized immune cell
      context rather than a core localization for the stress-inducible cytosolic
      chaperone HSPA6.
- term:
    id: GO:0005814
    label: centriole
  evidence_type: IDA
  original_reference_id: PMID:24061851
  review:
    summary: >-
      IDA annotation of GO:0005814 (centriole) from Khalouei et al. (2014), who
      demonstrated that YFP-tagged HSPA6 rapidly localizes to centrioles in human
      SH-SY5Y neuronal cells following thermal stress (PMID:24061851). HSPA6 showed
      more prolonged centriolar localization than HSPA1A and specifically targeted
      the proximal end of centrioles (identified by gamma-tubulin marker). The authors
      suggest this indicates the proximal end of centrioles may be a stress-sensitive
      site in neurons.
    action: ACCEPT
    reason: >-
      This is well-supported IDA evidence showing stress-induced centriolar
      localization in neuronal cells (PMID:24061851). The localization was confirmed
      using YFP-tagged HSPA6 and co-localization with centrosome markers. The prolonged
      localization at centrioles compared to HSPA1A suggests a specific stress-
      protective role at this structure.
    supported_by:
    - reference_id: PMID:24061851
      supporting_text: >-
        YFP-tagged HSPA6 and HSPA1A rapidly appeared at centrioles in the cytoplasm
        of human neuronal cells, with HSPA6 demonstrating a more prolonged signal
        compared to HSPA1A
    - reference_id: PMID:24061851
      supporting_text: >-
        The YFP-tagged HSP70 proteins targeted the proximal end of centrioles
        (identified by gamma-tubulin marker) rather than the distal end (centrin marker)
- term:
    id: GO:0034605
    label: cellular response to heat
  evidence_type: IMP
  original_reference_id: PMID:21597468
  review:
    summary: >-
      IMP annotation of GO:0034605 (cellular response to heat) from Kaitsuka et al.
      (2011) (PMID:21597468). This paper is about eEF1Bdelta (a translation elongation
      factor), not directly about HSPA6. The paper describes how eEF1BdeltaL induces
      HSE-containing genes including HSP70 genes in cooperation with HSF1. HSPA6 as
      a heat-inducible gene is expected to be among the targets induced. The connection
      to HSPA6 in this IMP annotation may derive from HSPA6 being used as a reporter
      or marker of the heat shock response. As an HSP70 gene strictly induced by heat
      stress, HSPA6 is clearly involved in cellular response to heat.
    action: ACCEPT
    reason: >-
      HSPA6 is a strictly heat-inducible gene that shows no basal expression and is
      only expressed under severe thermal stress (PMID:2327978). Cellular response to
      heat is a core biological process for HSPA6. While PMID:21597468 focuses on
      eEF1BdeltaL, HSPA6 involvement in the heat shock response is well-established
      and supported by multiple references.
    additional_reference_ids:
    - PMID:2327978
    supported_by:
    - reference_id: PMID:2327978
      supporting_text: >-
        HSP70B' mRNA was induced only at higher temperature and showed no basal
        expression
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:23921388
  review:
    summary: >-
      IPI annotation of GO:0019899 (enzyme binding) from Jakobsson et al. (2013),
      who identified METTL21A (Q8WXB1) as the methyltransferase responsible for
      trimethylation of HSPA6 at Lys-563 (PMID:23921388). HSPA6 is a substrate of
      METTL21A, so this interaction is well-characterized. However, the term 'enzyme
      binding' is somewhat vague. In this case, HSPA6 is the substrate of the
      methyltransferase, so the interaction is real and specific, but it reflects HSPA6
      being modified rather than performing enzyme binding as a molecular function.
    action: ACCEPT
    reason: >-
      The interaction between HSPA6 and METTL21A is directly demonstrated with
      biochemical evidence showing METTL21A trimethylates HSPA6 at Lys-563
      (PMID:23921388). While 'enzyme binding' is vague, the annotation correctly
      reflects a validated physical interaction with the methyltransferase. HSPA6 is
      a substrate in this context. The annotation is acceptable as it captures a real
      interaction.
    supported_by:
    - 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:0031072
    label: heat shock protein binding
  evidence_type: IPI
  original_reference_id: PMID:21231916
  review:
    summary: >-
      IPI annotation of GO:0031072 (heat shock protein binding) from Hageman et al.
      (2011) (PMID:21231916). The GOA data shows interactions with multiple co-chaperones
      including DNAJA2 (O60884), DNAJB1 (P25685), DNAJB4 (Q9UDY4), DNAJB6 (O75190),
      DNAJB2 (P25686), DNAJA1 (P31689), DNAJA4 (Q8WW22), and others (Q7Z6W7/DNAJB12,
      Q8NHS0/DNAJB14). These are J-domain proteins (HSP40 family) that function as
      co-chaperones essential for the HSP70 chaperone cycle. This is a core molecular
      function for HSPA6.
    action: ACCEPT
    reason: >-
      HSP70-J-protein (HSP40/DNAJ) interactions are essential for the HSP70 chaperone
      cycle. Hageman et al. (2011) directly demonstrated HSPA6 interactions with
      multiple J-domain co-chaperones including DNAJA1, DNAJA2, DNAJA4, DNAJB1,
      DNAJB2, DNAJB4, DNAJB6, and others (PMID:21231916). These interactions stimulate
      HSPA6 ATPase activity, confirming functional relevance. This is a core function
      annotation.
    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:0042026
    label: protein refolding
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      IDA annotation of GO:0042026 (protein refolding) from Hageman et al. (2011).
      The authors directly demonstrated that purified HSPA6 can assist in reactivation
      of heat-unfolded p53 in vitro (PMID:21231916). Notably, HSPA6 showed restricted
      substrate specificity -- it could not refold heat-denatured luciferase and could
      not suppress polyQ aggregation, unlike HSPA1A. This IDA evidence directly
      supports protein refolding activity with specific substrate selectivity.
    action: ACCEPT
    reason: >-
      Direct experimental evidence from in vitro refolding assays demonstrates HSPA6
      can refold heat-unfolded p53 (PMID:21231916). This is high-quality IDA evidence
      for a core biological process of HSPA6. The substrate specificity (p53 but not
      luciferase) highlights that HSPA6 has evolved specialized refolding function.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        purified HSPA6 could not chaperone heat-unfolded luciferase but was able to
        assist in reactivation of heat-unfolded p53
- 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). HSPA6
      is an HSP70 family member that functions as an ATP-dependent foldase chaperone, not
      merely a passive binder of unfolded proteins. Hageman et al. (2011) demonstrated that
      HSPA6 has a functional substrate-binding domain and intrinsic ATPase activity, and that
      purified HSPA6 could assist in reactivation of heat-unfolded p53 (PMID:21231916).
      These data support annotation to GO:0044183 (protein folding chaperone), which captures
      the active chaperone mechanism. The IBA annotation for GO:0044183 already exists for
      HSPA6 via phylogenetic inference, consistent with this replacement.
    action: MODIFY
    reason: >-
      GO:0051082 (unfolded protein binding) is scheduled for obsolescence (go-ontology#30962)
      because it conflates passive binding of unfolded proteins with active chaperone function.
      HSPA6 is a bona fide ATP-dependent molecular chaperone of the HSP70 family. The original
      IDA evidence from PMID:21231916 demonstrates that HSPA6 possesses intrinsic ATPase
      activity stimulated by J-proteins and can assist in reactivation of heat-unfolded p53,
      which constitutes active chaperone function rather than mere unfolded protein binding.
      The correct replacement term is GO:0044183 (protein folding chaperone), defined as
      "Binding to a protein or a protein-containing complex to assist the protein folding
      process." This term is already applied to HSPA6 via IBA (GO_REF:0000033).
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - GO_REF:0000033
    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
    - reference_id: PMID:21231916
      supporting_text: >-
        purified HSPA6 could not chaperone heat-unfolded luciferase but was able to
        assist in reactivation of heat-unfolded p53
- term:
    id: GO:0070370
    label: cellular heat acclimation
  evidence_type: IMP
  original_reference_id: PMID:21231916
  negated: true
  review:
    summary: >-
      NOT annotation for GO:0070370 (cellular heat acclimation) from Hageman et al.
      (2011) (PMID:21231916). The authors showed that siRNA-mediated blocking of
      HSPA6 did not impair the development of heat-induced thermotolerance, and that
      overexpression of HSPA6 did not protect cells from heat-induced cell death
      (unlike HSPA1A). This negative result is informative and demonstrates that
      despite being heat-inducible, HSPA6 does not contribute to acquired
      thermotolerance, distinguishing it functionally from HSPA1A.
    action: ACCEPT
    reason: >-
      This is a well-supported NOT annotation based on direct experimental evidence.
      Hageman et al. (2011) demonstrated via both loss-of-function (siRNA knockdown)
      and gain-of-function (overexpression) experiments that HSPA6 does not contribute
      to cellular heat acclimation/thermotolerance (PMID:21231916). This negative
      annotation is informative and functionally distinguishes HSPA6 from HSPA1A.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        whereas overexpression of HSPA1A protected cells from heat-induced cell death,
        overexpression of HSPA6 did not
    - reference_id: PMID:21231916
      supporting_text: >-
        siRNA (small interfering RNA)-mediated blocking of HSPA6 did not impair the
        development of heat-induced thermotolerance
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:24061851
  review:
    summary: >-
      IDA annotation of GO:0005737 (cytoplasm) from Khalouei et al. (2014). Using
      YFP-tagged HSPA6 in stable human SH-SY5Y neuronal cell lines, the authors
      observed HSPA6 in the cytoplasm following thermal stress (PMID:24061851). This
      is consistent with the IBA annotation for the same term and with the known
      cytoplasmic localization of HSP70 family members.
    action: ACCEPT
    reason: >-
      Direct experimental evidence using YFP-tagged HSPA6 confirms cytoplasmic
      localization in human neuronal cells (PMID:24061851). Cytoplasm is a core
      localization for HSPA6. Consistent with IBA annotation.
    supported_by:
    - reference_id: PMID:24061851
      supporting_text: >-
        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: >-
      IDA annotation of GO:0005829 (cytosol) from Hageman et al. (2011). The study
      establishes HSPA6 as a cytosolic HSP70 family member (PMID:21231916). Most
      HSP70/HSPA family members are cytosolic, and HSPA6 is described as such in this
      study. Consistent with the IBA annotation for the same term.
    action: ACCEPT
    reason: >-
      Cytosol is the primary localization for HSPA6 as established in PMID:21231916.
      This is consistent with the general cytosolic localization of HSP70 family
      members and with the IBA annotation. Core localization for HSPA6.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding
        genes and most of the corresponding proteins are localized in the cytosol
- term:
    id: GO:0034605
    label: cellular response to heat
  evidence_type: IDA
  original_reference_id: PMID:24061851
  review:
    summary: >-
      IDA annotation of GO:0034605 (cellular response to heat) from Khalouei et al.
      (2014). The authors showed that HSPA6 rapidly localizes to centrioles in human
      neuronal cells following thermal stress (PMID:24061851). HSPA6 is a strictly
      heat-inducible gene with no basal expression (PMID:2327978), and its rapid
      stress-induced relocalization to centrioles is a direct cellular response to
      heat.
    action: ACCEPT
    reason: >-
      HSPA6 is a strictly heat-inducible chaperone and its stress-induced localization
      to centrioles directly demonstrates cellular response to heat (PMID:24061851).
      Combined with the original characterization showing no basal expression and
      induction only at higher temperatures (PMID:2327978), cellular response to heat
      is a core process for HSPA6.
    additional_reference_ids:
    - PMID:2327978
    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
    - reference_id: PMID:2327978
      supporting_text: >-
        HSP70B' mRNA was induced only at higher temperature and showed no basal
        expression
- term:
    id: GO:0072562
    label: blood microparticle
  evidence_type: HDA
  original_reference_id: PMID:22516433
  review:
    summary: >-
      HDA annotation of GO:0072562 (blood microparticle) from Bastos-Amador et al.
      (2012), a proteomic analysis of microvesicles from plasma of healthy donors
      (PMID:22516433). HSPA6 was detected in blood microparticles by mass spectrometry.
      This is a high-throughput proteomics identification. HSP70 proteins are commonly
      found in extracellular vesicles, but this is not a core localization for HSPA6,
      which is primarily an intracellular stress-inducible chaperone.
    action: KEEP_AS_NON_CORE
    reason: >-
      Detection of HSPA6 in blood microparticles by HDA proteomics (PMID:22516433)
      is plausible given that HSP70 proteins are commonly found in extracellular
      vesicles. However, this is not a core localization for HSPA6. The annotation
      is retained as non-core. Note that HSP70 proteins are common contaminants in
      proteomic studies.
    supported_by:
    - reference_id: PMID:22516433
      supporting_text: >-
        We have detected 161 microvesicle-associated proteins, including many
        associated with the complement and coagulation signal-transduction cascades
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19199708
  review:
    summary: >-
      HDA annotation of GO:0070062 (extracellular exosome) from Gonzalez-Begne et al.
      (2009), a proteomic analysis of human parotid gland exosomes by MudPIT mass
      spectrometry (PMID:19199708). HSPA6 was identified among 491 exosomal proteins.
      HSP70 family proteins (including HSC70/HSPA8) are well-established exosome
      markers, so detection of HSPA6 is not surprising. However, this may reflect
      co-purification with other more abundant HSP70 family members, especially since
      HSPA6 has no basal expression and would not be expected in normal parotid
      exosomes unless the cells were stressed.
    action: KEEP_AS_NON_CORE
    reason: >-
      HSPA6 detection in exosomes (PMID:19199708) is plausible but raises questions
      given that HSPA6 has no basal expression (PMID:2327978). This may reflect
      cross-identification with other HSP70 family members given high sequence
      similarity, or the cells may have been under stress. HSP70 family members are
      common exosome cargo. Retained as non-core since extracellular exosome is not
      a core localization for HSPA6.
    supported_by:
    - reference_id: PMID:19199708
      supporting_text: >-
        we catalogued 491 proteins in the exosome fraction of human parotid saliva
- term:
    id: GO:0008180
    label: COP9 signalosome
  evidence_type: IDA
  original_reference_id: PMID:18850735
  review:
    summary: >-
      IDA annotation of GO:0008180 (COP9 signalosome) from Fang et al. (2008), who
      performed proteomic characterization of the human COP9 signalosome using affinity
      purification and mass spectrometry (PMID:18850735). The GOA data shows this
      annotation uses the qualifier 'colocalizes_with' rather than 'is_active_in',
      indicating HSPA6 was found co-localizing with the COP9 signalosome rather than
      being a core component. HSPA6 was likely identified as one of 52 putative CSN
      interacting proteins. HSP70 proteins are commonly identified in affinity
      purification experiments as chaperone-client interactions or co-purification
      artifacts.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      HSPA6 was identified as co-localizing with the COP9 signalosome in a
      high-throughput AP-MS study (PMID:18850735). HSP70 chaperones are well-known
      co-purification contaminants in affinity purification experiments. The
      colocalizes_with qualifier is appropriate (not a core CSN component), but this
      likely represents a transient chaperone-client interaction rather than meaningful
      co-localization with the COP9 signalosome. This is an over-annotation of what
      is probably a non-specific interaction.
    supported_by:
    - reference_id: PMID:18850735
      supporting_text: >-
        A total of 52 putative human CSN interacting proteins were identified, most
        of which are reported for the first time
- term:
    id: GO:0006986
    label: response to unfolded protein
  evidence_type: TAS
  original_reference_id: PMID:2327978
  review:
    summary: >-
      TAS annotation of GO:0006986 (response to unfolded protein) from Leung et al.
      (1990), the original paper characterizing HSPA6/HSP70B' (PMID:2327978). The
      paper showed that HSPA6 is a heat-inducible HSP70 family member with no basal
      expression, induced only at higher temperatures. As a stress-inducible molecular
      chaperone of the HSP70 family, HSPA6 participates in the cellular response to
      unfolded/denatured proteins generated by heat stress. The annotation is
      appropriate, though the direct connection to unfolded protein specifically
      (rather than heat stress generally) requires inference from the HSP70 function.
    action: ACCEPT
    reason: >-
      HSPA6 is a heat-inducible HSP70 molecular chaperone (PMID:2327978) that
      functions in refolding denatured proteins (PMID:21231916). The response to
      unfolded protein annotation is appropriate because HSPA6 is induced under
      conditions that generate unfolded proteins (heat stress) and directly participates
      in their refolding. The TAS evidence from the original characterization paper is
      reasonable.
    supported_by:
    - reference_id: PMID:2327978
      supporting_text: >-
        HSP70B' mRNA was induced only at higher temperature and showed no basal
        expression
core_functions:
- description: >-
    Strictly stress-inducible ATP-dependent protein folding chaperone with
    substrate selectivity distinct from other HSP70 family members. HSPA6
    shows no basal expression and is induced only under severe thermal stress,
    with approximately 13-14-fold induction under extreme heat vs approximately
    2-3-fold under mild heat in neuronal models (DOI:10.3390/biology12030416).
    It possesses intrinsic ATPase activity comparable to HSPA1A when
    stimulated by J-domain co-chaperones, but displays restricted substrate
    specificity: it can refold heat-unfolded p53 but not heat-denatured
    luciferase, and does not suppress polyQ aggregation or confer
    thermotolerance. Under thermal stress, HSPA6 rapidly localizes to
    centrioles, suggesting a specific stress-protective role at this
    structure. HSPA6 operates as part of a coordinated inducible chaperone
    module with DNAJB1, BAG3, and HSPH1/HSP110 that expands folding and
    disaggregation capacity under proteotoxic stress
    (DOI:10.3390/biology12030416). The HSP70 chaperone cycle involves J-domain
    protein delivery of clients and stimulation of ATP hydrolysis, followed by
    nucleotide exchange factor-mediated ADP release and client recycling;
    HSP110 proteins cooperate with HSP70 and HSP40 to disaggregate and refold
    denatured proteins (DOI:10.3390/biom13040604). HSPA6 has also been
    implicated in RTP1S-dependent membrane protein trafficking, partially
    enhancing olfactory receptor surface expression by approximately 50-80%
    (DOI:10.3390/ijms24097829).
  molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  directly_involved_in:
  - id: GO:0042026
    label: protein refolding
  - id: GO:0034605
    label: cellular response to heat
  - id: GO:0006986
    label: response to unfolded protein
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005814
    label: centriole
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:21231916
    supporting_text: >-
      purified HSPA6 could not chaperone heat-unfolded luciferase but was able to
      assist in reactivation of heat-unfolded p53
  - 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
  - reference_id: PMID:2327978
    supporting_text: >-
      HSP70B' mRNA was induced only at higher temperature and showed no basal
      expression
  - reference_id: PMID:24061851
    supporting_text: >-
      YFP-tagged HSPA6 and HSPA1A rapidly appeared at centrioles in the cytoplasm
      of human neuronal cells, with HSPA6 demonstrating a more prolonged signal
      compared to HSPA1A
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  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: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:14743216
  title: A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction
    pathway.
  findings: []
- id: PMID:18850735
  title: Characterization of the human COP9 signalosome complex using affinity purification
    and mass spectrometry.
  findings: []
- id: PMID:19199708
  title: Proteomic analysis of human parotid gland exosomes by multidimensional protein
    identification technology (MudPIT).
  findings: []
- id: PMID:20072699
  title: Crystal structures of the ATPase domains of four human Hsp70 isoforms.
  findings: []
- id: PMID:21044950
  title: Genome-wide YFP fluorescence complementation screen identifies new regulators
    for telomere signaling in human cells.
  findings: []
- id: PMID:21231916
  title: The diverse members of the mammalian HSP70 machine show distinct chaperone-like
    activities.
  findings: []
- id: PMID:21597468
  title: "Transformation of eEF1B\u03B4 into heat-shock response transcription factor\
    \ by alternative splicing."
  findings: []
- id: PMID:22516433
  title: Proteomic analysis of microvesicles from plasma of healthy donors reveals
    high individual variability.
  findings: []
- id: PMID:2327978
  title: The human heat-shock protein family. Expression of a novel heat-inducible
    HSP70 (HSP70B') and isolation of its cDNA and genomic DNA.
  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:31980649
  title: Extensive rewiring of the EGFR network in colorectal cancer cells expressing
    transforming levels of KRAS(G13D).
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: Reactome:R-HSA-6798748
  title: Exocytosis of secretory granule lumen proteins
  findings: []
- id: Reactome:R-HSA-6800434
  title: Exocytosis of ficolin-rich granule lumen proteins
  findings: []
- id: DOI:10.3390/biology12030416
  title: Profiling the Hsp70 Chaperone Network in Heat-Induced Proteotoxic Stress
    Models of Human Neurons
  findings:
  - statement: >-
      HSPA6 was among the most strongly induced HSP70 paralogs in neuronal heat-stress
      models, with approximately 13-14-fold induction under extreme heat vs approximately
      2-3-fold under mild heat. Gene expression peaked at approximately 1 hour and
      protein at approximately 5-6 hours post-stress. Co-expressed with DNAJB1, BAG3,
      and HSPH1/HSP110 as a coordinated inducible chaperone module.
- id: DOI:10.3390/biom13040604
  title: Is It Still Possible to Think about HSP70 as a Therapeutic Target in Onco-Hematological
    Diseases?
  findings:
  - statement: >-
      Describes canonical HSP70 architecture including N-terminal ATPase domain,
      substrate-binding domain with lid, and C-terminal EEVD motif. J-domain proteins
      deliver clients and stimulate hydrolysis; NEFs (BAG-family, HSPBP1) promote
      ADP release. HSP110 proteins cooperate with HSP70 and HSP40 for disaggregation.
      HSP70 inhibitors have not reached the clinic despite extensive preclinical work.
- id: DOI:10.3390/ijms24097829
  title: Identification and characterization of proteins that are involved in RTP1S-dependent
    transport of olfactory receptors
  findings:
  - statement: >-
      HSPA6 was biotinylated by RTP1S-AirID (proximity-labeling), indicating physical
      proximity. Co-expression of HSPA6 partially enhanced surface expression of
      olfactory receptor Olfr544 by approximately 50-80%. RTP1S N-terminus interacts
      with HSPA6 C-terminal domain; the olfactory receptor itself did not significantly
      interact with HSPA6, suggesting indirect trafficking role via RTP1S.
- id: DOI:10.3390/cancers16030638
  title: The Interplay between Heat Shock Proteins and Cancer Pathogenesis
  findings:
  - statement: >-
      Updated 2024 review of HSP70 family in cancer biology. Summarizes co-chaperone
      regulation (DNAJ/HSP40, BAG proteins, HSP110, CHIP) and HSF1-driven transcriptional
      control. Supports consensus that inducible HSP70 family members like HSPA6
      contribute to tumor phenotypes when dysregulated.
- id: DOI:10.1021/acssynbio.7b00455
  title: Remote Control of Mammalian Cells with Heat-Triggered Gene Switches and Photothermal
    Pulse Trains
  findings:
  - statement: >-
      Uses the HSPA6/HSP70B' promoter as a thermal gene switch for remote control
      of mammalian cells. In vivo photothermal activation demonstrated with gold
      nanorods and near-infrared laser. Demonstrates HSPA6 promoter as a clinically
      relevant interface for spatially restricted transgene expression in cell
      therapies.
- id: DOI:10.1186/s13018-023-03690-z
  title: BARX1 promotes osteosarcoma cell proliferation and invasion by regulating
    HSPA6 expression
  findings:
  - statement: >-
      BARX1 overexpression increases HSPA6 expression (RNA-seq, qPCR, Western blot).
      Dual-luciferase reporter supports direct regulation at HSPA6 promoter. Silencing
      HSPA6 attenuates BARX1-driven osteosarcoma proliferation and migration/invasion
      in vitro.