id: P34931
gene_symbol: HSPA1L
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  HSPA1L (Heat shock 70 kDa protein 1-like, also known as HSP70-Hom) is a constitutively
  expressed member of the HSP70/HSPA family of molecular chaperones, encoded in the MHC
  class III region on chromosome 6 in close genomic proximity (within approximately 14 kb)
  to the stress-inducible paralogs HSPA1A and HSPA1B
  (DOI:10.62347/cwpe7813). It is approximately 90% identical in sequence to HSPA1A.
  Unlike HSPA1A, HSPA1L is not induced by heat shock (PMID:1700760) and is notably
  enriched in testis/spermatids (PMID:9685725). HSPA1L has the canonical HSP70 domain
  architecture: an N-terminal nucleotide-binding domain (NBD/ATPase) that binds and
  hydrolyzes ATP, a C-terminal substrate-binding domain (SBD) that binds exposed
  hydrophobic peptide segments in client proteins, and an interdomain linker coupling
  nucleotide state to substrate affinity -- ATP binding promotes an open SBD lid
  conformation, ATP hydrolysis promotes lid closure and higher client affinity, and
  nucleotide exchange resets the cycle (DOI:10.14712/fb2024070030152). The ATPase
  domain crystal structure has been solved at 1.80 angstrom resolution (PDB:3GDQ;
  PMID:20072699). HSPA1L has been shown to refold heat-denatured luciferase and to
  suppress polyglutamine aggregation (PMID:21231916). It also functions as a positive
  regulator of PRKN (Parkin) translocation to damaged mitochondria, requiring both its
  ATPase and substrate-binding domains as well as its EEVD co-chaperone interaction
  motif (PMID:24270810). In neuronal heat-stress models, HSPA1L protein was induced
  approximately 2.5-3.5-fold with gene expression peaking at approximately 1 hour
  post-stress and protein at approximately 5-6 hours, indicating context-dependent
  inducibility in some cell types (DOI:10.3390/biology12030416). Recent epitranscriptomic
  studies show that METTL3-mediated m6A modification regulates HSPA1L mRNA levels,
  and METTL3 silencing increases HSPA1L expression while reducing fibrotic markers in
  keratocytes stimulated with TGF-beta1 (DOI:10.1167/iovs.65.13.9). Mendelian
  randomization studies identify circulating HSPA1L as inversely associated with
  ankylosing spondylitis risk (OR=0.089, colocalization PPH4 approximately 0.74;
  DOI:10.3389/fimmu.2024.1394438) and lung squamous cell carcinoma risk (combined
  OR approximately 0.51; DOI:10.1007/s44272-024-00024-w). Additionally, the HSPA1L
  rs2227956 variant is associated with idiopathic male infertility in an Iranian
  population (DOI:10.1016/j.ejogrb.2019.06.014).
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for nuclear localization of HSPA1L based on phylogenetic inference
      across HSP70 family members. Cytosolic HSP70 family members are known to undergo
      nucleocytoplasmic shuttling. While HSPA1L is constitutively expressed rather than
      stress-inducible (PMID:1700760), as an HSP70 family member it retains the same
      domain architecture as HSPA1A enabling nuclear import. The Reactome pathway
      R-HSA-5082356 includes HSPA1L in a nuclear context for HSF1-mediated gene
      expression. The IBA is well-supported phylogenetically with evidence from
      multiple orthologs across species.
    action: ACCEPT
    reason: >-
      Nuclear localization is a well-established property of cytosolic HSP70 family
      members. The phylogenetic inference is sound and additionally supported by
      the Reactome TAS annotation to nucleoplasm (R-HSA-5082356). HSPA1L retains
      the same domain architecture as HSPA1A enabling nuclear import.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for cytoplasmic localization based on phylogenetic inference.
      HSPA1L is a cytosolic HSP70 family member. Hageman et al. (2011) state that
      "most of the corresponding proteins are localized in the cytosol"
      (PMID:21231916). HSPA1L has direct experimental evidence (IDA) for cytosol
      localization from the same study. The cytoplasm annotation is a broader parent
      term that is fully consistent with the more specific cytosol annotation.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is the primary site of action for HSPA1L. This is
      supported by both phylogenetic inference and direct experimental evidence
      from Hageman et al. (2011) (PMID:21231916).
    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:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for plasma membrane localization based on phylogenetic inference
      from multiple HSP70 orthologs. Some HSP70 family members have been detected at
      the plasma membrane, particularly in the context of immune signaling and
      antigen presentation. However, there is no direct experimental evidence for
      HSPA1L specifically at the plasma membrane. The IBA is phylogenetically derived
      and the localization may be more relevant to stress-inducible HSP70 members
      (HSPA1A/B) rather than the constitutively expressed HSPA1L.
    action: KEEP_AS_NON_CORE
    reason: >-
      Plasma membrane localization has been documented for some HSP70 family members,
      particularly in immune and stress contexts. However, HSPA1L is constitutively
      expressed and primarily testis-enriched (PMID:9685725), making plasma membrane
      localization a peripheral rather than core aspect of its function. The
      phylogenetic inference is valid but this is not a primary localization for HSPA1L.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for ATP hydrolysis activity based on phylogenetic inference
      across HSP70 family members. HSPA1L contains a well-characterized N-terminal
      nucleotide-binding domain (NBD, residues 3-388) with defined ATP binding sites
      (UniProt P34931). The crystal structure of the HSPA1L ATPase domain has been
      solved in complex with ADP and phosphate at 1.80 angstrom resolution
      (PDB:3GDQ; PMID:20072699). UniProt describes the function as achieved "through
      cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones"
      (UniProt P34931). The ATPase activity of HSP70 family members is stimulated by
      J-domain proteins (PMID:21231916).
    action: ACCEPT
    reason: >-
      ATP hydrolysis is a core molecular function of HSPA1L. The crystal structure
      of the ATPase domain confirms the structural basis (PDB:3GDQ), and the
      phylogenetic inference is rock-solid across HSP70 family members.
    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:0031072
    label: heat shock protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for heat shock protein binding based on phylogenetic inference.
      HSP70 family members interact with HSP40/DNAJ co-chaperones through J-domain
      interactions. Han et al. (2007) demonstrated that HDJC9 (a J-domain protein)
      "can interact with HSP70s and activate the ATPase activity of HSP70s, both of
      which are dependent on the J domain" (PMID:17182002). UniProt lists interactions
      with BAG4, CCDC28B, DNAJC7, and TRIM38 (UniProt P34931). Taipale et al. (2014)
      characterized the chaperone-cochaperone interaction network and detected HSPA1L
      interactions with cochaperones BAG4 and DNAJC7 (PMID:25036637).
    action: ACCEPT
    reason: >-
      Heat shock protein binding is a core functional property of HSPA1L reflecting
      its interactions with J-domain co-chaperones and other HSP family members.
      This is well-supported by both phylogenetic inference and direct experimental
      evidence (IPI from PMID:17182002 and PMID:25036637).
    supported_by:
      - reference_id: PMID:17182002
        supporting_text: >-
          HDJC9 can interact with HSP70s and activate the ATPase activity of HSP70s,
          both of which are dependent on the J domain.
      - reference_id: PMID:25036637
        supporting_text: >-
          Chaperones are abundant cellular proteins that promote the folding and function
          of their substrate proteins (clients). In vivo, chaperones also associate with a
          large and diverse set of cofactors (cochaperones) that regulate their
          specificity and function.
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for protein folding chaperone activity based on phylogenetic
      inference across HSP70 family members. This is the core molecular function of
      HSPA1L. UniProt describes HSPA1L 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" (UniProt P34931).
      Hageman et al. (2011) directly tested HSPA1L chaperone activity in luciferase
      refolding and polyQ aggregation suppression assays (PMID:21231916).
    action: ACCEPT
    reason: >-
      Protein folding chaperone is the primary molecular function of HSPA1L. This
      is supported by direct experimental evidence (PMID:21231916), UniProt functional
      annotation, and strong phylogenetic inference across HSP70 family members.
    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. To
          test for possible functional differences and/or substrate specificity, 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:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for cytosol localization based on phylogenetic inference. This
      is consistent with the IDA annotation from Hageman et al. (2011) who stated
      that "most of the corresponding proteins are localized in the cytosol"
      (PMID:21231916). HSPA1L is a canonical cytosolic HSP70 family member.
    action: ACCEPT
    reason: >-
      Cytosol is the primary site of action for HSPA1L. The IBA is consistent with
      direct experimental evidence (IDA from PMID:21231916) and is the expected
      localization for a cytosolic HSP70 family member.
    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 for protein refolding based on phylogenetic inference across
      HSP70 family members. HSPA1L has direct experimental support for refolding
      activity from Hageman et al. (2011), who tested its ability to refold
      heat-denatured luciferase (PMID:21231916). UniProt describes HSPA1L function
      as including "re-folding of misfolded proteins" (UniProt P34931).
    action: ACCEPT
    reason: >-
      Protein refolding is a core biological process for HSPA1L. The IBA is
      fully supported by direct experimental evidence from the luciferase
      refolding assay (PMID:21231916) and phylogenetic conservation across
      HSP70 family members.
    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. To
          test for possible functional differences and/or substrate specificity, 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:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for nucleotide binding based on UniProtKB keyword mapping
      (KW-0547). HSPA1L has a well-characterized nucleotide-binding domain (NBD,
      residues 3-388) with defined ATP binding sites at positions 14-17, 73,
      204-206, 270-277, and 341-344 (UniProt P34931). The crystal structure
      confirms ADP and phosphate binding (PDB:3GDQ). This is a correct but
      very broad annotation; the more specific GO:0005524 (ATP binding) and
      GO:0016887 (ATP hydrolysis activity) annotations are already present.
    action: ACCEPT
    reason: >-
      Nucleotide binding is correct for HSPA1L. While broad, IEA annotations
      at this level are acceptable. The annotation is consistent with the more
      specific ATP binding and ATP hydrolysis activity annotations and is
      supported by crystal structure data (PDB:3GDQ).
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for ATP binding based on combined automated annotation from
      InterPro and UniProtKB keyword mapping. HSPA1L has extensive ATP binding
      site annotations in UniProt (positions 14-17, 73, 204-206, 270-277, 341-344)
      and the crystal structure of its ATPase domain was solved in complex with
      ADP and phosphate at 1.80 angstrom resolution (PDB:3GDQ; PMID:20072699).
      ATP binding is fundamental to the chaperone cycle.
    action: ACCEPT
    reason: >-
      ATP binding is a core molecular function of HSPA1L, essential for its
      chaperone cycle. The structural evidence from PDB:3GDQ directly confirms
      nucleotide binding in the NBD domain.
- term:
    id: GO:0006950
    label: response to stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation for response to stress based on ARBA machine learning model.
      While HSP70 family members are generally associated with stress response,
      HSPA1L is notable for being constitutively expressed and NOT induced by heat
      shock, unlike HSPA1A/B (PMID:1700760). The annotation is technically not
      wrong since HSPA1L does function in protein quality control which is a
      component of the cellular stress response, but it is misleading for a
      constitutively expressed member. The term is also very broad.
    action: KEEP_AS_NON_CORE
    reason: >-
      HSPA1L participates in protein quality control which broadly relates to
      stress response. However, HSPA1L is specifically NOT heat-shock inducible
      (PMID:1700760) and is constitutively expressed primarily in testis
      (PMID:9685725). The annotation is not wrong but is misleading as it
      suggests stress-inducibility. Keeping as non-core rather than removing
      because HSPA1L does contribute to proteostasis under stress conditions.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation for ATP hydrolysis activity based on InterPro domain mapping
      (IPR013126, HSP70 family). This duplicates the IBA annotation for the same
      GO term (GO_REF:0000033). The annotation is correct; HSPA1L has a
      well-characterized ATPase domain whose crystal structure has been solved
      (PDB:3GDQ; PMID:20072699).
    action: ACCEPT
    reason: >-
      ATP hydrolysis is a core molecular function of HSPA1L. This IEA annotation
      is correctly derived from InterPro domain mapping and is consistent with
      the IBA annotation and structural evidence.
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation for heat shock protein binding from ARBA machine learning
      model. This duplicates the IBA annotation for the same GO term. HSP70
      family members interact with HSP40/DNAJ co-chaperones and other heat shock
      proteins. The annotation is consistent with experimental evidence from
      PMID:17182002 (interaction with HDJC9) and PMID:25036637 (interaction
      with BAG4 and DNAJC7).
    action: ACCEPT
    reason: >-
      Heat shock protein binding is a core function of HSPA1L reflecting its
      co-chaperone interactions. This IEA annotation is consistent with existing
      IBA and IPI annotations for the same term.
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation for ubiquitin protein ligase binding from ARBA machine
      learning model. This is consistent with the IPI annotation from
      PMID:24270810 showing HSPA1L interaction with PRKN (Parkin), an E3
      ubiquitin ligase. Hasson et al. (2013) showed that "HSPA1L (HSP70
      family member) and BAG4 have mutually opposing roles in the regulation
      of parkin translocation" (PMID:24270810).
    action: ACCEPT
    reason: >-
      Ubiquitin protein ligase binding is supported by the experimentally
      validated interaction between HSPA1L and PRKN/Parkin (PMID:24270810).
      This IEA annotation is consistent with the IPI evidence.
    supported_by:
      - reference_id: PMID:24270810
        supporting_text: >-
          We also discovered that HSPA1L (HSP70 family member) and BAG4 have
          mutually opposing roles in the regulation of parkin translocation.
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation for protein refolding from ARBA machine learning model.
      This duplicates the IBA and IDA annotations for the same GO term. Protein
      refolding is directly demonstrated for HSPA1L by Hageman et al. (2011)
      in luciferase refolding assays (PMID:21231916).
    action: ACCEPT
    reason: >-
      Protein refolding is a core biological process for HSPA1L. This IEA
      annotation is consistent with existing IBA and IDA annotations and
      direct experimental evidence from PMID:21231916.
- 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).
      This IEA annotation was generated by the ARBA machine learning model
      (GO_REF:0000117). HSPA1L is a bona fide ATP-dependent protein folding chaperone
      of the HSP70 family. Its function is not merely passive binding to unfolded
      proteins, but rather active, ATP-driven chaperone-mediated protein folding. The
      correct replacement term is GO:0044183 (protein folding chaperone), which is
      already annotated via IBA (GO_REF:0000033). UniProt describes HSPA1L 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" (UniProt P34931). An even more specific term,
      GO:0140662 (ATP-dependent protein folding chaperone), is also annotated via
      IEA from InterPro.
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted. The term conflates passive binding with the
      active chaperone function that HSP70 family members perform. HSPA1L is an
      ATP-dependent foldase that undergoes conformational cycling between ATP-bound
      (low substrate affinity) and ADP-bound (high substrate affinity) states to
      actively fold client proteins (UniProt P34931). The replacement term GO:0044183
      (protein folding chaperone) accurately captures this molecular function. This
      IEA annotation is redundant with existing IBA and IEA annotations to
      GO:0044183 and GO:0140662 respectively.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  review:
    summary: >-
      IPI annotation for protein binding based on Taipale et al. (2014), a
      systematic characterization of the chaperone-cochaperone interaction network
      using mass spectrometry and LUMIER assays. The interacting partners from IntAct
      are BAG4 (O95429) and DNAJC7 (Q99615). BAG4 is a nucleotide exchange factor
      for HSP70, and DNAJC7 is a J-domain co-chaperone. These are functionally
      relevant chaperone-cochaperone interactions. However, GO:0005515 (protein
      binding) is uninformative. The more specific GO:0031072 (heat shock protein
      binding) is already annotated.
    action: MODIFY
    reason: >-
      The interaction data from Taipale et al. (2014) are valid and represent
      functionally meaningful chaperone-cochaperone interactions (HSPA1L with
      BAG4 and DNAJC7). However, GO:0005515 (protein binding) is uninformative
      per curation guidelines. The interactions are better captured by GO:0031072
      (heat shock protein binding), which is already annotated via IBA and IPI.
    proposed_replacement_terms:
      - id: GO:0031072
        label: heat shock protein binding
    supported_by:
      - reference_id: PMID:25036637
        supporting_text: >-
          We combined mass spectrometry and quantitative high-throughput LUMIER assays
          to systematically characterize the chaperone-cochaperone-client interaction
          network in human cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27173435
  review:
    summary: >-
      IPI annotation for protein binding based on Boldt et al. (2016), a large-scale
      organelle-specific protein landscape study. The interacting partner from IntAct
      is CCDC28B (Q9BUN5). CCDC28B is a coiled-coil domain protein associated with
      ciliopathies. The interaction with HSPA1L is from a high-throughput study and
      the functional significance of this specific interaction is unclear. GO:0005515
      (protein binding) is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This annotation derives from a large-scale organelle-specific proteomics study
      (PMID:27173435). The interaction between HSPA1L and CCDC28B has no clear
      functional relevance to HSPA1L chaperone function, and may represent a
      transient or non-specific chaperone-client interaction captured in a
      high-throughput screen. GO:0005515 (protein binding) is uninformative
      per curation guidelines.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: >-
      IPI annotation for protein binding based on Luck et al. (2020), a reference
      map of the human binary protein interactome using yeast two-hybrid and other
      methods. The interacting partners from IntAct are TRIM38 (O00635) and BAG4
      (O95429). BAG4 is a known HSP70 nucleotide exchange factor and this interaction
      is functionally relevant. TRIM38 is an E3 ubiquitin ligase involved in innate
      immunity. UniProt also lists TRIM38 as an interactor (IntAct). GO:0005515
      (protein binding) is uninformative.
    action: MODIFY
    reason: >-
      The BAG4 interaction is well-characterized as a functional cochaperone
      interaction and is better described by GO:0031072 (heat shock protein binding).
      The TRIM38 interaction is validated in two independent studies but GO:0005515
      does not inform us about function. More specific terms for E3 ligase or
      cochaperone binding are preferred.
    proposed_replacement_terms:
      - id: GO:0031072
        label: heat shock protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  review:
    summary: >-
      IPI annotation for protein binding from Schaffer et al. (2025), a multimodal
      cell map study. The interacting partner from IntAct is DNAJC7 (Q99615), a
      J-domain co-chaperone that is a known functional partner of HSP70 family
      members. This duplicates information already captured by the PMID:25036637
      annotation. GO:0005515 (protein binding) is uninformative.
    action: MODIFY
    reason: >-
      The DNAJC7 interaction is functionally meaningful as a J-domain co-chaperone
      partner but GO:0005515 is uninformative. This interaction is better captured
      by GO:0031072 (heat shock protein binding) which is already annotated.
    proposed_replacement_terms:
      - id: GO:0031072
        label: heat shock protein binding
- term:
    id: GO:0002199
    label: zona pellucida receptor complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation for zona pellucida receptor complex transferred from mouse
      ortholog Hspa1l (UniProtKB:P16627) via Ensembl Compara. In mouse, HSP70
      family members have been implicated in sperm-zona pellucida interactions
      during fertilization. Given that HSPA1L is specifically expressed in
      spermatids (PMID:9685725) and the mouse ortholog Hsc70t shares the same
      spermatid-specific expression pattern, this annotation is biologically
      plausible for a role in fertilization.
    action: KEEP_AS_NON_CORE
    reason: >-
      The annotation is transferred from the mouse ortholog and is biologically
      plausible given HSPA1L spermatid-specific expression (PMID:9685725).
      However, direct experimental evidence for HSPA1L in the zona pellucida
      receptor complex in human is lacking. This is a specialized reproductive
      function rather than the core chaperone function.
    supported_by:
      - reference_id: PMID:9685725
        supporting_text: >-
          The Hsc70t gene is a Hsp70 homolog gene expressed constitutively in
          spermatids in mice.
- term:
    id: GO:0044297
    label: cell body
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation for cell body localization transferred from mouse ortholog
      Hspa1l (UniProtKB:P16627) via Ensembl Compara. The term GO:0044297 (cell
      body) refers to the neuronal cell body (soma). While some HSP70 family
      members are expressed in neurons, HSPA1L is primarily testis-enriched
      (PMID:9685725). The transfer from mouse ortholog may reflect neuronal
      expression of Hsc70t in mouse but this is not well-established for human
      HSPA1L.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Cell body (neuronal soma) localization is likely an over-annotation for
      HSPA1L. While transferred from the mouse ortholog, HSPA1L is primarily
      enriched in testis/spermatids (PMID:9685725) and there is no specific
      evidence for neuronal cell body localization in human. The ortholog
      transfer may not be appropriate for this specific localization.
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IPI
  original_reference_id: PMID:17182002
  review:
    summary: >-
      IPI annotation for heat shock protein binding based on Han et al. (2007),
      who characterized HDJC9 (DNAJC9, Q8WXX5), a novel J-domain protein. The
      study demonstrated that "HDJC9 can interact with HSP70s and activate the
      ATPase activity of HSP70s, both of which are dependent on the J domain"
      (PMID:17182002). The J-domain-dependent interaction between DNAJC9 and
      HSP70 (including HSPA1L) is a core functional interaction in the HSP70
      chaperone machine.
    action: ACCEPT
    reason: >-
      This is a well-characterized functional interaction between HSPA1L and
      a J-domain co-chaperone (DNAJC9/HDJC9). The J-domain-dependent interaction
      is fundamental to HSP70 chaperone function, as J-domain proteins stimulate
      the ATPase cycle. Heat shock protein binding accurately captures this
      co-chaperone interaction.
    supported_by:
      - reference_id: PMID:17182002
        supporting_text: >-
          HDJC9 can interact with HSP70s and activate the ATPase activity of HSP70s,
          both of which are dependent on the J domain.
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:24270810
  review:
    summary: >-
      IPI annotation for ubiquitin protein ligase binding based on Hasson et al.
      (2013), who identified HSPA1L as a positive regulator of PRKN (Parkin)
      translocation to damaged mitochondria. The interacting partner is PRKN/Parkin
      (O60260), an E3 ubiquitin ligase. The abstract states "HSPA1L (HSP70 family
      member) and BAG4 have mutually opposing roles in the regulation of parkin
      translocation" (PMID:24270810). UniProt confirms the interaction and notes
      mutagenesis data: K73E (ATPase domain), L396D (substrate-binding domain),
      and deletion of the C-terminal EEVD motif (residues 638-641) all abolish
      rescue of PRKN translocation (UniProt P34931).
    action: ACCEPT
    reason: >-
      The interaction between HSPA1L and PRKN/Parkin is well-characterized with
      supporting mutagenesis data. The binding to this E3 ubiquitin ligase is
      functionally significant in regulating mitochondrial quality control. This
      annotation is accurate and represents a validated non-chaperone interaction
      of HSPA1L.
    supported_by:
      - reference_id: PMID:24270810
        supporting_text: >-
          We also discovered that HSPA1L (HSP70 family member) and BAG4 have
          mutually opposing roles in the regulation of parkin translocation.
- term:
    id: GO:1903749
    label: positive regulation of protein localization to mitochondrion
  evidence_type: IMP
  original_reference_id: PMID:24270810
  review:
    summary: >-
      IMP annotation for positive regulation of establishment of protein
      localization to mitochondrion based on Hasson et al. (2013). The study used
      genome-wide RNAi screens and found that HSPA1L promotes PRKN translocation
      to damaged mitochondria. The abstract states that "HSPA1L (HSP70 family
      member) and BAG4 have mutually opposing roles in the regulation of parkin
      translocation" (PMID:24270810). UniProt mutagenesis data confirm that the
      ATPase domain (K73E), substrate-binding domain (L396D), and EEVD motif
      (deletion of 638-641) are all required for this function (UniProt P34931).
      This represents a specific biological role for HSPA1L in mitochondrial
      quality control.
    action: ACCEPT
    reason: >-
      This annotation is well-supported by the genome-wide RNAi screen and
      subsequent validation in Hasson et al. (2013). HSPA1L positively regulates
      PRKN/Parkin translocation to damaged mitochondria, requiring functional
      ATPase, substrate-binding, and co-chaperone interaction domains. This is a
      validated biological role distinct from the general chaperone function.
    supported_by:
      - reference_id: PMID:24270810
        supporting_text: >-
          We also discovered that HSPA1L (HSP70 family member) and BAG4 have
          mutually opposing roles in the regulation of parkin translocation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      IDA annotation for cytosol localization based on Hageman et al. (2011), who
      systematically characterized HSP70 family members. The study states that
      "most of the corresponding proteins are localized in the cytosol"
      (PMID:21231916). This is the primary subcellular localization for HSPA1L
      and is consistent with its function as a cytosolic chaperone.
    action: ACCEPT
    reason: >-
      Cytosol is the primary localization for HSPA1L function. The IDA evidence
      from Hageman et al. (2011) directly supports this annotation and is
      consistent with the IBA annotation for the same term.
    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: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      IDA annotation for protein refolding based on Hageman et al. (2011), who
      directly tested HSPA1L in luciferase refolding and polyQ aggregation
      suppression assays. The study "assessed the effect of overexpression of
      each of these HSPs on refolding of heat-denatured luciferase and on the
      suppression of aggregation of a non-foldable polyQ (polyglutamine)-expanded
      Huntingtin fragment" (PMID:21231916). This is direct experimental evidence
      for HSPA1L protein refolding activity.
    action: ACCEPT
    reason: >-
      Protein refolding is directly demonstrated for HSPA1L by functional assays
      in Hageman et al. (2011). This is a core biological process annotation with
      strong direct experimental support.
    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. To
          test for possible functional differences and/or substrate specificity, 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: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).
      This IDA annotation is based on Hageman et al. (2011), which systematically
      compared the chaperone activities of mammalian HSP70 family members. The study
      tested HSPA1L and other HSP70 members for their ability to refold heat-denatured
      luciferase and suppress polyglutamine aggregation. As stated in the abstract,
      the authors "assessed the effect of overexpression of each of these HSPs on
      refolding of heat-denatured luciferase and on the suppression of aggregation
      of a non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment"
      (PMID:21231916). These assays measure active protein folding chaperone function,
      not merely passive binding to unfolded substrates. HSPA1L, like other cytosolic
      HSP70 members, functions as an ATP-dependent foldase with a substrate-binding
      domain (residues 396-511) that binds client proteins and a nucleotide-binding
      domain (residues 3-388) that drives conformational cycling. The correct
      replacement is GO:0044183 (protein folding chaperone).
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted. The original annotation was made based on data
      from Hageman et al. (2011), who tested HSP70 family members in functional
      chaperone assays including luciferase refolding and polyQ aggregation suppression.
      These are active chaperone assays, not passive binding assays. The abstract
      states that "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" and describes their role in "refolding of heat-denatured
      luciferase" (PMID:21231916). UniProt further describes HSPA1L function as
      achieved "through cycles of ATP binding, ATP hydrolysis and ADP release,
      mediated by co-chaperones" where "the affinity for polypeptides is regulated
      by its nucleotide bound state" (UniProt P34931). This is protein folding
      chaperone activity, not passive unfolded protein binding. GO:0044183 (protein
      folding chaperone) is the correct replacement term and already has IBA support.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
    additional_reference_ids:
      - UniProt:P34931
    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. To
          test for possible functional differences and/or substrate specificity, 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.
      - 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:0072562
    label: blood microparticle
  evidence_type: HDA
  original_reference_id: PMID:22516433
  review:
    summary: >-
      HDA annotation for blood microparticle localization based on Bastos-Amador
      et al. (2012), a proteomic analysis of microvesicles from plasma of healthy
      donors. The study "purified microvesicles smaller than 220nm from plasma of
      healthy donors and performed proteomic, ultra-structural, biochemical and
      functional analyses" and "detected 161 microvesicle-associated proteins"
      (PMID:22516433). HSPA1L was identified among these proteins. This is a
      high-throughput proteomic detection that likely reflects the general
      abundance of HSP70 proteins in extracellular vesicles.
    action: KEEP_AS_NON_CORE
    reason: >-
      Detection in blood microparticles is from a high-throughput proteomics study
      and likely reflects general HSP70 family presence in extracellular vesicles
      rather than a specific function of HSPA1L. The study noted "remarkably high
      variability in the protein content of plasma from different donors"
      (PMID:22516433), suggesting this may not be a consistent localization.
      Not a core localization for HSPA1L function.
    supported_by:
      - reference_id: PMID:22516433
        supporting_text: >-
          In this study, we have purified microvesicles smaller than 220nm from plasma
          of healthy donors and performed proteomic, ultra-structural, biochemical and
          functional analyses. We have detected 161 microvesicle-associated proteins
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5082356
  review:
    summary: >-
      TAS annotation for nucleoplasm localization based on Reactome pathway
      R-HSA-5082356 (HSF1-mediated gene expression). The Reactome pathway describes
      HSF1-driven upregulation of heat shock genes and places HSP70 family members
      in the nucleoplasm in the context of heat shock response regulation. HSF1 is
      "best known for rapid stress-induced upregulation of certain genes related to
      protein folding, such as HSPA1A/HSP70" (Reactome:R-HSA-5082356). While HSPA1L
      is not itself heat-inducible, it is included in this Reactome pathway as an
      HSP70 family member. Nuclear/nucleoplasmic localization is consistent with
      the IBA annotation for nucleus.
    action: KEEP_AS_NON_CORE
    reason: >-
      Nucleoplasm localization is plausible for HSP70 family members that shuttle
      between cytoplasm and nucleus. However, the Reactome pathway context (HSF1-mediated
      heat shock response) is somewhat misleading for HSPA1L since it is not
      heat-inducible (PMID:1700760). The nucleoplasm localization is likely a
      secondary site rather than the primary cytosolic localization.
- term:
    id: GO:0008180
    label: COP9 signalosome
  evidence_type: IDA
  original_reference_id: PMID:18850735
  review:
    summary: >-
      IDA annotation for COP9 signalosome colocalization based on Fang et al.
      (2008), who characterized the human CSN complex using affinity purification
      and mass spectrometry. HSPA1L was identified among "52 putative human CSN
      interacting proteins" (PMID:18850735). Note that the GOA qualifier is
      "colocalizes_with" rather than "part_of", indicating HSPA1L was detected
      in proximity to the CSN but is not a core subunit. HSP70 chaperones
      commonly co-purify with multi-protein complexes as transient interactors
      assisting in complex assembly or quality control.
    action: KEEP_AS_NON_CORE
    reason: >-
      HSPA1L colocalization with the COP9 signalosome likely reflects its role
      as a chaperone transiently interacting with the complex during assembly or
      quality control, rather than being a functional component of the CSN. The
      study identified HSPA1L among 52 putative interactors using mass spectrometry
      (PMID:18850735). This is a peripheral observation rather than a core
      localization for HSPA1L.
    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:9685725
  review:
    summary: >-
      TAS annotation for response to unfolded protein based on Ito et al. (1998),
      who characterized the genomic structure of HSPA1L and its mouse ortholog
      Hsc70t. The paper describes HSPA1L as a "spermatid-specific hsp70 homolog
      gene" and establishes its "constitutive" expression in spermatids
      (PMID:9685725). While HSPA1L is an HSP70 family member that functions in
      protein quality control, the term "response to unfolded protein" specifically
      implies a response to proteotoxic stress. HSPA1L is constitutively expressed,
      not stress-inducible, and the cited paper does not provide evidence for
      induction by unfolded protein stress.
    action: KEEP_AS_NON_CORE
    reason: >-
      HSPA1L does function in protein quality control as an HSP70 chaperone, which
      is part of the broader unfolded protein response system. However, the
      annotation is somewhat misleading because HSPA1L is constitutively expressed
      rather than induced by proteotoxic stress (PMID:1700760, PMID:9685725). The
      cited reference (PMID:9685725) characterizes genomic structure and tissue
      specificity rather than stress response per se. Keeping as non-core because
      HSPA1L does participate in protein quality control but is not a stress-responsive
      component.
    supported_by:
      - reference_id: PMID:9685725
        supporting_text: >-
          The Hsc70t gene is a Hsp70 homolog gene expressed constitutively in
          spermatids in mice.
core_functions:
- description: >-
    Constitutively expressed ATP-dependent protein folding chaperone enriched
    in testis/spermatids. Functions as a foldase that refolds heat-denatured
    proteins and suppresses polyglutamine aggregation in the cytosol, through
    the canonical HSP70 ATPase-driven allosteric cycle: ATP binding promotes
    an open SBD lid conformation permissive for substrate binding, ATP
    hydrolysis promotes lid closure and higher client affinity, and nucleotide
    exchange (mediated by BAG-family and HSP110-type NEFs) resets the cycle
    (DOI:10.14712/fb2024070030152). J-domain proteins (DNAJC7, DNAJC9)
    stimulate ATP hydrolysis and deliver substrates. The crystal structure of
    the HSPA1L ATPase domain has been solved at 1.80 angstrom resolution
    (PDB:3GDQ; PMID:20072699). Unlike the closely related HSPA1A, HSPA1L is
    generally not induced by heat shock, though context-dependent induction
    (approximately 2.5-3.5-fold) has been observed in neuronal heat-stress
    models (DOI:10.3390/biology12030416). HSPA1L expression is also regulated
    by the METTL3-m6A epitranscriptomic axis in keratocyte fibrosis models
    (DOI:10.1167/iovs.65.13.9).
  molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  directly_involved_in:
  - id: GO:0042026
    label: protein refolding
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005634
    label: nucleus
  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
  - reference_id: PMID:9685725
    supporting_text: >-
      The Hsc70t gene is a Hsp70 homolog gene expressed constitutively in
      spermatids in mice.
- description: >-
    Positive regulator of PRKN (Parkin) translocation to damaged
    mitochondria, functioning as a chaperone that facilitates the
    mitochondrial quality control pathway. This activity requires
    the ATPase domain, substrate-binding domain, and the C-terminal
    EEVD co-chaperone interaction motif. BAG4 acts as an antagonist
    of this HSPA1L-mediated function. Co-expression/network analysis
    in neuronal proteotoxic stress models links HSPA1L with PRKN and
    STUB1 (an E3 ubiquitin ligase/co-chaperone), connecting HSPA1L to
    protein quality control pathways that interface with ubiquitination
    and mitophagy (DOI:10.3390/biology12030416).
  molecular_function:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  directly_involved_in:
  - id: GO:1903749
    label: positive regulation of protein localization to mitochondrion
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:24270810
    supporting_text: >-
      We also discovered that HSPA1L (HSP70 family member) and BAG4 have
      mutually opposing roles in the regulation of parkin translocation.
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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  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:17182002
  title: HDJC9, a novel human type C DnaJ/HSP40 member interacts with and cochaperones
    HSP70 through the J domain.
  findings: []
- id: PMID:18850735
  title: Characterization of the human COP9 signalosome complex using affinity purification
    and mass spectrometry.
  findings: []
- id: PMID:21231916
  title: The diverse members of the mammalian HSP70 machine show distinct chaperone-like
    activities.
  findings: []
- id: PMID:22516433
  title: Proteomic analysis of microvesicles from plasma of healthy donors reveals
    high individual variability.
  findings: []
- id: PMID:24270810
  title: High-content genome-wide RNAi screens identify regulators of parkin upstream
    of mitophagy.
  findings: []
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of
    cellular protein homeostasis pathways.
  findings: []
- id: PMID:27173435
  title: An organelle-specific protein landscape identifies novel diseases and molecular
    mechanisms.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:9685725
  title: Genomic structure of the spermatid-specific hsp70 homolog gene located in
    the class III region of the major histocompatibility complex of mouse and man.
  findings: []
- id: Reactome:R-HSA-5082356
  title: HSF1-mediated gene expression
  findings: []
- id: DOI:10.14712/fb2024070030152
  title: Heat Shock Protein Network - the Mode of Action, the Role in Protein Folding
    and Human Pathologies
  findings:
  - statement: >-
      Describes the canonical HSP70 ATPase-driven allosteric cycle in detail:
      ATP binding promotes open SBD lid, hydrolysis promotes closure and higher
      client affinity, nucleotide exchange resets cycle. J-domain proteins deliver
      substrates and stimulate hydrolysis; NEFs (BAG proteins, HSP110) accelerate
      ADP-to-ATP exchange. HSPA1L function cannot be fully interpreted from sequence
      alone; context-specific co-chaperone availability drives functional
      specialization among paralogs.
- id: DOI:10.3390/biology12030416
  title: Profiling the Hsp70 Chaperone Network in Heat-Induced Proteotoxic Stress
    Models of Human Neurons
  findings:
  - statement: >-
      HSPA1L protein was induced approximately 2.5-3.5-fold in SH-SY5Y and
      differentiated SH-SY5Y neuronal cells under heat stress, with gene expression
      peaking at approximately 1 hour post-stress and protein at approximately 5-6
      hours. Co-expression network analysis linked HSPA1L with PRKN (Parkin) and
      STUB1, connecting it to protein quality control pathways.
- id: DOI:10.1167/iovs.65.13.9
  title: Silencing METTL3 Increases HSP70 Expression and Alleviates Fibrosis in
    Keratocytes
  findings:
  - statement: >-
      HSPA1L expression decreased after alkali burn and TGF-beta1 stimulation in
      keratocytes. METTL3 silencing increased HSPA1L mRNA and HSP70 protein levels,
      with reduced fibrotic markers. Eight potential m6A sites predicted in HSPA1L
      RNA.
- id: DOI:10.3389/fimmu.2024.1394438
  title: Genetic associations in ankylosing spondylitis - circulating proteins as
    drug targets and biomarkers
  findings:
  - statement: >-
      Proteome-wide Mendelian randomization identified circulating HSPA1L as
      inversely associated with ankylosing spondylitis risk (OR=0.089, P=1.76e-15)
      with substantial colocalization support (PPH4 approximately 0.743).
- id: DOI:10.1007/s44272-024-00024-w
  title: Causal associations of plasma proteins with lung squamous cell carcinoma
    risk
  findings:
  - statement: >-
      Proteome-wide Mendelian randomization identified HSPA1L as inversely
      associated with LUSC risk (discovery OR=0.47, combined replication OR
      approximately 0.51).
- id: DOI:10.1016/j.ejogrb.2019.06.014
  title: HSPA1L and HSPA1B gene polymorphisms and haplotypes are associated with
    idiopathic male infertility in Iranian population
  findings:
  - statement: >-
      HSPA1L rs2227956 was significantly associated with idiopathic male infertility
      in a case-control study (308 infertile men vs 208 controls). CT vs TT OR=2.049,
      CC vs TT OR=3.028.
- id: DOI:10.62347/cwpe7813
  title: Bioinformatics analysis and alternative polyadenylation in Heat Shock Proteins
    70 (HSP70) family members
  findings:
  - statement: >-
      Reports HSPA1L length 641 aa and molecular weight approximately 70.4 kDa.
      HSPA1L is located in the MHC class III region within approximately 14 kb of
      HSPA1A and HSPA1B in reverse orientation. Predicted phosphorylation sites
      at multiple serine and threonine positions.