id: Q8WW22
gene_symbol: DNAJA4
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  DNAJA4 is a class I J-domain protein (HSP40 co-chaperone) belonging to the DNAJA
  subfamily. It contains an N-terminal J-domain (with conserved HPD motif) that
  stimulates the ATPase activity of HSP70 family members, a glycine/phenylalanine-rich
  region, a cysteine-rich zinc finger domain (CR-type, with four CXXCXGXG repeats
  coordinating two zinc ions) involved in substrate recognition, two C-terminal
  beta-barrel substrate-binding domains (CTDI and CTDII), and a dimerization domain.
  As a co-chaperone, DNAJA4 binds unfolded or misfolded client proteins and delivers
  them to HSP70 (HSPA) partners for ATP-dependent protein folding. Hageman et al.
  (2011) demonstrated that DNAJA4 supports luciferase refolding and suppresses polyQ
  aggregation when co-expressed with HSP70 partners (PMID:21231916). Systematic
  interactome profiling of the human Hsp70 network (AP-MS and BioID) places DNAJA4
  in the densely connected cytoplasmic class A JDP core, with robust interactions
  with DNAJA1, DNAJA2, and DNAJB1 (DOI:10.1016/j.molcel.2021.04.012). DNAJA4 is
  farnesylated and membrane-associated, and is also found in the cytosol. It
  participates in the HSP90 chaperone cycle for steroid hormone receptors via the
  HSP70-HSP40-HOP-HSP90 relay pathway. DNAJA4 is transcriptionally upregulated
  during heat stress in human neuronal models (log2 fold-change 1.5-5 at 1 h
  post-heat shock; DOI:10.3390/biology12030416). Beyond generic chaperoning, DNAJA4
  has a specific role in suppressing epithelial-mesenchymal transition (EMT) and
  metastasis in nasopharyngeal carcinoma (NPC) by promoting PSMD2-mediated
  ubiquitin-proteasome degradation of MYH9, an interaction requiring the DnaJ domain
  (DOI:10.1038/s41419-023-06225-w). DNAJA4 promoter hypermethylation and silencing
  is observed in multiple cancers including NPC, stomach adenocarcinoma, and
  rhabdomyosarcoma (DOI:10.3390/ijms222413527).
alternative_products:
- name: '1'
  id: Q8WW22-1
- name: '2'
  id: Q8WW22-2
  sequence_note: VSP_038965
- name: '3'
  id: Q8WW22-3
  sequence_note: VSP_045696
existing_annotations:
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for cytosol localization propagated from orthologs including
      yeast Ydj1 (SGD:S000005008), S. pombe Mas5 (PomBase:SPBC1734.11), DNAJA2
      (UniProtKB:O60884), and DNAJA4 itself. This is well supported by direct
      experimental evidence: Hageman et al. (2011) showed that DNAJA4 is localized
      in the cytosol (PMID:21231916). The IDA annotation from the same paper
      (see below) independently confirms this localization. Cytosolic localization
      is consistent with DNAJA4's role as a cytosolic HSP70 co-chaperone.
    action: ACCEPT
    reason: >-
      Cytosol localization is a core localization for DNAJA4 as a cytosolic
      J-domain co-chaperone. This IBA annotation is independently confirmed by
      IDA evidence from 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:0001671
    label: ATPase activator activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for ATPase activator activity propagated from orthologs
      including yeast Ydj1 (SGD:S000005008), Sis1 (SGD:S000005021), DNAJA2
      (UniProtKB:O60884), and others. All class I J-domain proteins stimulate
      HSP70 ATPase activity through their conserved J-domain, which directly
      contacts the HSP70 ATPase domain and accelerates ATP hydrolysis. Kampinga
      and Craig (2010) describe that J-domain cochaperones stimulate "the ATPase
      activity of HSP70" (PMID:20651708). Hageman et al. (2011) confirmed that
      J-proteins including DNAJA4 stimulate the intrinsic ATPase activity of HSP70
      family members (PMID:21231916). The Reactome entry R-HSA-3371422 (ATP
      hydrolysis by HSP70) explicitly describes that "This ATPase activity of
      HSP70 is stimulated by protein substrates in synergism with J domain
      cochaperones (HSP40s)." This is a core molecular function of all J-domain
      proteins.
    action: ACCEPT
    reason: >-
      ATPase activator activity is a fundamental and well-established molecular
      function of J-domain proteins. DNAJA4 contains a conserved J-domain that
      stimulates HSP70 ATPase activity. This IBA annotation is phylogenetically
      sound and supported by the general biochemistry of J-domain proteins.
    supported_by:
    - reference_id: PMID:20651708
      supporting_text: >-
        Much of the functional diversity of the HSP70s is driven by a diverse class
        of cofactors: J proteins
    - 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:0034605
    label: cellular response to heat
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for cellular response to heat propagated from orthologs
      including yeast Ydj1 (SGD:S000005008) and S. pombe Mas5
      (PomBase:SPBC1734.11). HSP40/DNAJ proteins are heat shock proteins by
      definition -- they are induced by and function during heat stress to
      assist in protein folding and prevent aggregation. Hageman et al. (2011)
      specifically tested DNAJA4 in the context of heat-denatured substrates,
      showing it supports refolding of heat-denatured luciferase (PMID:21231916).
      The IEA annotation for response to heat (GO:0009408, a parent term) via
      InterPro also supports this. This is a broader but appropriate term given
      the IBA evidence.
    action: ACCEPT
    reason: >-
      Cellular response to heat is an appropriate annotation for a heat shock
      co-chaperone. DNAJA4 functions in protein refolding after heat denaturation,
      which is a core aspect of the cellular heat stress response. The IBA
      annotation is phylogenetically well supported.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        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:0042026
    label: protein refolding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for protein refolding propagated from orthologs including
      yeast Ydj1 (SGD:S000005008), S. pombe Mas5 (PomBase:SPBC1734.11), DNAJA2
      (UniProtKB:O60884), and DNAJA4 itself. Hageman et al. (2011) directly
      demonstrated that DNAJA4 supports HSP70-dependent refolding of
      heat-denatured luciferase (PMID:21231916). This is a core biological
      process for J-domain co-chaperones that assist HSP70 in the ATP-dependent
      refolding cycle.
    action: ACCEPT
    reason: >-
      Protein refolding is a core function of J-domain co-chaperones working
      with HSP70. This IBA is directly confirmed by experimental evidence from
      Hageman et al. (2011) showing DNAJA4 supports luciferase refolding.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        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: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      GO:0051082 (unfolded protein binding) is being obsoleted (go-ontology#30962).
      This IBA annotation was propagated via phylogenetic inference from orthologs
      including yeast Ydj1 (SGD:S000005008, S000005021), DNAJA2 (UniProtKB:O60884),
      and DNAJA4 itself (UniProtKB:Q8WW22). While it is true that class I J-domain
      proteins like DNAJA4 bind unfolded substrates, the term "unfolded protein binding"
      is being replaced because it does not capture the functional role of the protein
      as a chaperone. DNAJA4 functions as an HSP70 co-chaperone: it binds client proteins
      and delivers them to HSP70, stimulating HSP70 ATPase activity via its J-domain
      (PMID:21231916). Kampinga and Craig (2010) describe how J proteins "bind client
      proteins directly, thereby delivering specific clients to HSP70 and directly
      determining their fate" (PMID:20651708). 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."
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted. DNAJA4 is a class I J-domain protein that functions
      as a protein folding chaperone, not merely as an unfolded protein binder. The
      replacement term GO:0044183 (protein folding chaperone) accurately captures the
      functional role of DNAJA4 in binding client proteins and delivering them to HSP70
      for ATP-dependent refolding.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - PMID:20651708
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        Overexpressed chaperones that suppressed polyQ aggregation were found not to
        be able to stimulate luciferase refolding. Inversely, chaperones that supported
        luciferase refolding were poor suppressors of polyQ aggregation.
    - reference_id: PMID:20651708
      supporting_text: >-
        others bind client proteins directly, thereby delivering specific clients to
        HSP70 and directly determining their fate
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for protein-folding chaperone binding propagated from orthologs
      including DNAJA2 (UniProtKB:O60884), DNAJA1 (UniProtKB:P31689), and DNAJA4
      itself. This term captures the binding of DNAJA4 to HSP70 chaperone partners.
      Hageman et al. (2011) demonstrated that DNAJA4 physically interacts with
      multiple HSP70 family members including HSPA1A (P0DMV8), HSPA1B (P0DMV9),
      and HSPA6 (P17066) (PMID:21231916). The IPI annotations from the same paper
      independently confirm this interaction. Binding to HSP70 chaperones is a core
      molecular function of all J-domain proteins, mediated through the J-domain
      interaction with the HSP70 ATPase domain.
    action: ACCEPT
    reason: >-
      Protein-folding chaperone binding (i.e., binding to HSP70 partners) is a
      core function of J-domain co-chaperones. DNAJA4 has been experimentally
      shown to interact with multiple HSP70 family members. This IBA is well
      supported by direct experimental evidence.
    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
    - reference_id: PMID:20651708
      supporting_text: >-
        Some target HSP70 activity to clients at precise locations in cells and
        others bind client proteins directly, thereby delivering specific clients to
        HSP70 and directly determining their fate
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation for ATP binding inferred from InterPro domain IPR012724
      (DnaJ). While the DnaJ/J-domain does interact with the HSP70 ATPase domain
      and stimulates its ATPase activity, the J-domain protein itself does not
      bind ATP. It is the HSP70 partner that binds and hydrolyzes ATP. DNAJA4 does
      not have an ATPase domain or ATP-binding domain. The InterPro2GO mapping
      from IPR012724 to GO:0005524 appears to be an incorrect transitive
      annotation -- the DnaJ domain stimulates the ATPase of HSP70, but does not
      itself bind ATP.
    action: REMOVE
    reason: >-
      J-domain proteins like DNAJA4 do not bind ATP themselves. The J-domain
      stimulates the ATPase activity of HSP70 partners, but it is the HSP70
      that binds ATP, not the co-chaperone. This IEA annotation based on the
      DnaJ InterPro domain is an incorrect transitive inference.
    supported_by:
    - reference_id: PMID:20651708
      supporting_text: >-
        Heat shock 70 kDa proteins (HSP70s) are ubiquitous molecular chaperones that
        function in a myriad of biological processes, modulating polypeptide folding,
        degradation and translocation across membranes, and protein-protein
        interactions. This multitude of roles is not easily reconciled with the
        universality of the activity of HSP70s in ATP-dependent client protein-binding
        and release cycles
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for protein folding inferred from multiple sources (ARBA,
      InterPro IPR008971 HSP40/DnaJ_pept-bd, IPR012724 DnaJ, IPR044713
      DNJA1/2-like). As a J-domain co-chaperone, DNAJA4 participates in
      protein folding by binding client proteins and delivering them to HSP70
      for ATP-dependent folding. Hageman et al. (2011) showed DNAJA4 supports
      refolding of heat-denatured luciferase (PMID:21231916). The more specific
      term GO:0042026 (protein refolding) is already annotated with IDA and IBA
      evidence. This broader term is acceptable as a parent-level IEA annotation.
    action: ACCEPT
    reason: >-
      Protein folding is an appropriate broad process annotation for DNAJA4.
      The more specific child term protein refolding (GO:0042026) is already
      annotated with experimental evidence. This IEA correctly captures the
      general biological process in which DNAJA4 participates.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        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:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for zinc ion binding inferred from UniProtKB keyword
      KW-0863 (Zinc). DNAJA4 contains a CR-type zinc finger domain (residues
      122-206) with four CXXCXGXG repeats that coordinate two zinc ions. This
      is confirmed by the UniProt feature annotations showing eight cysteine
      residues that bind Zn(2+) ions (positions 135, 138, 151, 154, 178, 181,
      194, 197). The zinc finger domain is characteristic of class I J-domain
      proteins and is important for client protein recognition and binding.
    action: ACCEPT
    reason: >-
      Zinc ion binding is structurally confirmed for DNAJA4 via its CR-type
      zinc finger domain with four CXXCXGXG repeats coordinating two zinc ions.
      This is a well-characterized structural feature of class I J-domain proteins.
- term:
    id: GO:0009408
    label: response to heat
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation for response to heat inferred from InterPro domain IPR012724
      (DnaJ). This is a broader parent term of GO:0034605 (cellular response to
      heat), which is already annotated by IBA evidence. As a heat shock
      co-chaperone, DNAJA4 is involved in the cellular response to heat stress
      through its role in protein refolding and prevention of aggregation.
      Hageman et al. (2011) tested DNAJA4 function using heat-denatured substrates
      (PMID:21231916). This broader IEA annotation is acceptable alongside the
      more specific IBA annotation.
    action: ACCEPT
    reason: >-
      Response to heat is an appropriate broad annotation for a heat shock
      co-chaperone. The more specific child term cellular response to heat
      (GO:0034605) is already annotated by IBA. This broader IEA is acceptable.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        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:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation for membrane localization inferred from UniProt subcellular
      location vocabulary (SL-0162). DNAJA4 is farnesylated at Cys-394 (S-farnesyl
      cysteine, by sequence similarity) and is annotated as membrane-associated via
      lipid anchor in UniProt. Hageman et al. (2011) provided IDA evidence for
      membrane localization (PMID:21231916), independently confirming this IEA.
      The lipid anchor (farnesylation) is a distinctive feature of DNAJA4 among
      the DNAJA subfamily members and mediates its membrane association.
    action: ACCEPT
    reason: >-
      Membrane localization is supported by the farnesylation of DNAJA4 at
      Cys-394 and is independently confirmed by IDA evidence from
      PMID:21231916. This is a valid localization for DNAJA4.
- term:
    id: GO:0030544
    label: Hsp70 protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation for Hsp70 protein binding inferred from InterPro domain
      IPR044713 (DNJA1/2-like). DNAJA4 is a J-domain co-chaperone whose primary
      molecular function involves binding HSP70 family members via its J-domain.
      Hageman et al. (2011) demonstrated that DNAJA4 physically interacts with
      HSP70 family members HSPA1A, HSPA1B, and HSPA6 (PMID:21231916). However,
      GO:0030544 (Hsp70 protein binding) is a less informative term than
      GO:0051087 (protein-folding chaperone binding), which is already annotated
      with IBA and IPI evidence. The term GO:0030544 simply describes binding
      without capturing the functional context. Nevertheless, as an IEA annotation
      it is not incorrect and can be accepted alongside the more specific IBA/IPI
      annotations.
    action: ACCEPT
    reason: >-
      Hsp70 protein binding is correct -- DNAJA4 binds HSP70 partners via its
      J-domain. While the more informative term protein-folding chaperone binding
      (GO:0051087) is already annotated, this IEA is not incorrect and reflects
      the InterPro domain-based inference.
    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
    - reference_id: PMID:20651708
      supporting_text: >-
        Often, multiple J proteins function with a single HSP70
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation for heat shock protein binding inferred from InterPro domain
      IPR001305 (HSP_DnaJ_Cys-rich_dom). This is a broader parent of GO:0030544
      (Hsp70 protein binding) and a broader relative of GO:0051087 (protein-folding
      chaperone binding), both of which are already annotated with higher-quality
      evidence. As a J-domain co-chaperone, DNAJA4 binds HSP70 (and participates
      in the HSP90 chaperone cycle via HOP). This annotation is not incorrect but
      is less informative than the existing more specific annotations.
    action: ACCEPT
    reason: >-
      Heat shock protein binding is a broad but correct annotation. DNAJA4 binds
      HSP70 partners and participates in the HSP90 chaperone cycle. More specific
      terms are already annotated (GO:0030544, GO:0051087), but this broader IEA
      is acceptable.
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for metal ion binding inferred from UniProtKB keyword
      KW-0479 (Metal-binding). DNAJA4 contains a CR-type zinc finger domain
      coordinating two zinc ions. The more specific term GO:0008270 (zinc ion
      binding) is already annotated with the same evidence type (IEA). This
      broader term is redundant but not incorrect.
    action: ACCEPT
    reason: >-
      Metal ion binding is correct but overly broad compared to the already
      annotated GO:0008270 (zinc ion binding). As an IEA annotation it is
      acceptable even though it provides less specificity.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      GO:0051082 (unfolded protein binding) is being obsoleted (go-ontology#30962).
      This IEA annotation was inferred from InterPro domain matches (IPR001305
      HSP_DnaJ_Cys-rich_dom, IPR008971 HSP40/DnaJ_pept-bd, IPR012724 DnaJ). These
      domains are characteristic of class I J-domain proteins that function as HSP70
      co-chaperones. The InterPro domains correctly identify DNAJA4 as a DnaJ family
      member with substrate-binding capability, but the GO term "unfolded protein
      binding" is being replaced because it fails to convey the chaperone function.
      Kampinga and Craig (2010) explain that J proteins function with HSP70 through
      "ATP-dependent client protein-binding and release cycles" and that some J proteins
      "bind client proteins directly, thereby delivering specific clients to HSP70"
      (PMID:20651708). The correct replacement is GO:0044183 (protein folding chaperone).
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted. The InterPro-based annotation correctly identifies
      DNAJA4 as having substrate-binding domains characteristic of J-domain protein
      co-chaperones, but the term should be replaced with GO:0044183 (protein folding
      chaperone) which properly captures the functional role of binding client proteins
      to assist in the protein folding process.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - PMID:20651708
    supported_by:
    - reference_id: PMID:20651708
      supporting_text: >-
        Much of the functional diversity of the HSP70s is driven by a diverse class
        of cofactors: J proteins
    - reference_id: PMID:20651708
      supporting_text: >-
        others bind client proteins directly, thereby delivering specific clients to
        HSP70 and directly determining their fate
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation for protein-folding chaperone binding inferred by ARBA
      machine learning model (ARBA:ARBA00088077). This is consistent with
      DNAJA4's well-established role as a J-domain co-chaperone that binds
      HSP70 chaperone partners. This annotation is independently confirmed
      by IBA (GO_REF:0000033) and IPI (PMID:21231916) evidence for the same
      GO term. Hageman et al. (2011) showed DNAJA4 interacts with HSPA1A,
      HSPA1B, and HSPA6 (PMID:21231916).
    action: ACCEPT
    reason: >-
      Protein-folding chaperone binding is a core function of J-domain
      co-chaperones. This IEA annotation is independently confirmed by both
      IBA and IPI evidence.
    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:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  review:
    summary: >-
      IPI annotation for protein binding from Taipale et al. (2014), a large-scale
      quantitative chaperone interaction network study. The GOA data shows
      interactions with DNAJA2 (UniProtKB:O60884) and ENDOG (UniProtKB:Q14249).
      The DNAJA2 interaction (homodimerization/heterodimerization between DNAJA
      family members) is plausible for co-chaperone function. The ENDOG interaction
      is from a high-throughput screen. However, "protein binding" (GO:0005515) is
      uninformative -- the DNAJA2 interaction could be more accurately captured
      by a more specific binding term, and the interaction with ENDOG lacks
      functional context.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 (protein binding) is uninformative and does not convey the
      functional significance of the interactions. The DNAJA2 interaction
      is better captured by existing annotations for protein-folding chaperone
      binding. Per curation guidelines, protein binding should be avoided in
      favor of more specific MF terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: >-
      IPI annotation for protein binding from Huttlin et al. (2021), a dual
      proteome-scale interaction network study. The GOA data shows an interaction
      with DNAJA2 (UniProtKB:O60884). This DNAJA4-DNAJA2 interaction is also
      supported by the UniProt interaction data (4 experiments in IntAct). While
      the interaction may be real, "protein binding" is uninformative and the
      interaction between DNAJA co-chaperones is better captured by existing
      chaperone binding annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 (protein binding) is uninformative. The DNAJA4-DNAJA2
      interaction detected in this high-throughput study does not add
      functional information beyond what is captured by the existing
      protein-folding chaperone binding annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  review:
    summary: >-
      IPI annotation for protein binding from a multimodal cell maps study.
      The GOA data shows an interaction with DNAJA2 (UniProtKB:O60884). This
      is the third independent detection of the DNAJA4-DNAJA2 interaction
      (also seen in PMID:25036637 and PMID:33961781), suggesting it is a
      robust interaction. However, "protein binding" remains uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 (protein binding) is uninformative. While the DNAJA4-DNAJA2
      interaction is robustly detected across multiple studies, the functional
      significance is better captured by existing chaperone binding annotations.
      Per curation guidelines, protein binding should be avoided.
- term:
    id: GO:0010596
    label: negative regulation of endothelial cell migration
  evidence_type: IMP
  original_reference_id: PMID:23142051
  review:
    summary: >-
      IMP annotation from Pencheva et al. (2012), which studied miRNA-mediated
      regulation of melanoma metastasis. The study found that miR-1908,
      miR-199a-5p, and miR-199a-3p convergently target DNAJA4 and ApoE. DNAJA4
      was shown to promote ApoE expression, and ApoE suppresses metastatic
      endothelial recruitment (MER). The negative regulation of endothelial cell
      migration is an indirect downstream consequence of DNAJA4 promoting ApoE
      expression, rather than a direct molecular function of DNAJA4 as a
      co-chaperone. This is a context-specific phenotypic observation in melanoma
      cells, not a core function of DNAJA4.
    action: KEEP_AS_NON_CORE
    reason: >-
      The negative regulation of endothelial cell migration is a downstream
      phenotypic consequence observed in the specific context of melanoma
      metastasis. DNAJA4 promotes ApoE expression, and ApoE is the effector
      that suppresses endothelial migration. This is not a core evolved function
      of DNAJA4 as a J-domain co-chaperone, but the IMP evidence from
      PMID:23142051 supports the annotation in this specific biological context.
    supported_by:
    - reference_id: PMID:23142051
      supporting_text: >-
        Cancer-secreted ApoE suppresses invasion and metastatic endothelial
        recruitment (MER) by engaging melanoma cell LRP1 and endothelial cell
        LRP8 receptors, respectively, while DNAJA4 promotes ApoE expression
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:23142051
  review:
    summary: >-
      IMP annotation from Pencheva et al. (2012) showing that DNAJA4 promotes
      ApoE expression. The study demonstrated that miRNAs targeting DNAJA4
      reduce ApoE expression, and DNAJA4 promotes ApoE expression. However,
      GO:0010628 (positive regulation of gene expression) is extremely broad
      and does not specify what gene expression is being regulated. The mechanism
      by which a J-domain co-chaperone regulates gene expression is unclear --
      it could be through chaperoning a transcription factor or signaling
      protein. The annotation is overly vague and the mechanism is indirect.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0010628 (positive regulation of gene expression) is overly broad and
      does not capture the specificity of what was observed. DNAJA4 promotes
      ApoE expression, but the mechanism is not well characterized and could
      involve chaperoning of upstream regulators. This vague process annotation
      does not add meaningful information about DNAJA4's function. The connection
      to ApoE regulation in melanoma is a context-specific observation.
    supported_by:
    - reference_id: PMID:23142051
      supporting_text: >-
        DNAJA4 promotes ApoE expression
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IPI
  original_reference_id: PMID:21231916
  review:
    summary: >-
      IPI annotation for protein-folding chaperone binding based on physical
      interaction evidence from Hageman et al. (2011). The GOA data shows
      three separate IPI entries from this paper with different interactors:
      HSPA1A (UniProtKB:P0DMV8), HSPA1B (UniProtKB:P0DMV9), and HSPA6
      (UniProtKB:P17066). This annotation entry corresponds to the interaction
      with HSPA1A. DNAJA4 binds HSP70 chaperone partners through its J-domain,
      which is a core molecular function of all J-domain co-chaperones.
      Hageman et al. systematically tested interactions between mammalian
      HSP40 and HSP70 family members and found that DNAJA4 functionally
      interacts with these HSP70 partners to support protein refolding.
    action: ACCEPT
    reason: >-
      Protein-folding chaperone binding is a core molecular function of DNAJA4.
      The IPI evidence from Hageman et al. (2011) directly demonstrates physical
      interaction between DNAJA4 and HSP70 family member HSPA1A.
    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
    - reference_id: PMID:20651708
      supporting_text: >-
        Often, multiple J proteins function with a single HSP70
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371422
  review:
    summary: >-
      TAS annotation for cytosol localization from Reactome pathway
      R-HSA-3371422 (ATP hydrolysis by HSP70). The Reactome entry describes
      the HSP70 chaperone cycle in which HSP40 co-chaperones (including DNAJA4)
      stimulate HSP70 ATPase activity in the cytosol. This localization is
      independently confirmed by IDA evidence from PMID:21231916 and IBA
      evidence from GO_REF:0000033.
    action: ACCEPT
    reason: >-
      Cytosol localization is well supported for DNAJA4 by multiple independent
      evidence sources. This Reactome TAS annotation is consistent with the
      IDA and IBA evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371503
  review:
    summary: >-
      TAS annotation for cytosol localization from Reactome pathway
      R-HSA-3371503 (STIP1/HOP binds HSP90 and HSP70:HSP40:nascent protein).
      The Reactome entry describes the HSP70-HSP40-HOP-HSP90 relay pathway
      in the cytosol, in which DNAJA4 participates as a HSP40 co-chaperone.
      This localization is independently confirmed by IDA (PMID:21231916)
      and IBA evidence.
    action: ACCEPT
    reason: >-
      Cytosol localization is well established. This Reactome TAS annotation
      is consistent with the HSP90 chaperone cycle in which DNAJA4 participates
      as part of the HSP70-HSP40-HOP-HSP90 relay.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371590
  review:
    summary: >-
      TAS annotation for cytosol localization from Reactome pathway
      R-HSA-3371590 (HSP70 binds to HSP40:nascent protein). The Reactome
      entry describes the initial step of client protein binding by HSP40
      co-chaperones followed by HSP70 recruitment in the cytosol. DNAJA4
      is included as one of the HSP40 family members. This localization is
      independently confirmed by IDA and IBA evidence.
    action: ACCEPT
    reason: >-
      Cytosol localization is well established for DNAJA4 as a cytosolic
      HSP70 co-chaperone. This is the third Reactome TAS annotation for the
      same localization, all consistent with experimental evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      IDA annotation for cytosol localization from Hageman et al. (2011).
      The study included subcellular localization analysis of mammalian HSP70
      and HSP40 family members, reporting that "most of the corresponding
      proteins are localized in the cytosol" (PMID:21231916). This direct
      experimental evidence confirms the cytosolic localization of DNAJA4,
      consistent with its role as a cytosolic co-chaperone.
    action: ACCEPT
    reason: >-
      Direct experimental evidence (IDA) confirms cytosol localization.
      This is the strongest evidence for DNAJA4's cytosolic localization
      and is consistent with its function as a cytosolic HSP70 co-chaperone.
    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:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      IDA annotation for membrane localization from Hageman et al. (2011).
      DNAJA4 is farnesylated at Cys-394 (S-farnesyl cysteine), which anchors
      it to cellular membranes. UniProt annotates the subcellular location
      as "Membrane; Lipid-anchor." Hageman et al. (2011) provided direct
      assay evidence confirming membrane association (PMID:21231916). This
      dual localization (cytosol and membrane) is distinctive for DNAJA4
      among DNAJA subfamily members and may reflect regulation of its
      availability for different substrates.
    action: ACCEPT
    reason: >-
      Membrane localization is directly supported by IDA evidence and is
      consistent with the farnesylation of DNAJA4 at Cys-394. This is a
      distinctive and functionally relevant localization for this co-chaperone.
    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 from Hageman et al. (2011). The
      study directly demonstrated that overexpression of DNAJA4 with HSP70
      partners supports refolding of heat-denatured luciferase. The authors
      "assessed the effect of overexpression of each of these HSPs on refolding
      of heat-denatured luciferase" (PMID:21231916). This is a core function
      of J-domain co-chaperones that assist HSP70 in the ATP-dependent
      protein refolding cycle.
    action: ACCEPT
    reason: >-
      Protein refolding is a core biological process for J-domain co-chaperones.
      Hageman et al. (2011) directly demonstrated DNAJA4's ability to support
      luciferase refolding with HSP70 partners. This IDA annotation represents
      strong experimental evidence for a fundamental function.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        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 from PMID:21231916 (Hageman et al. 2011) is based on direct
      experimental evidence showing that DNAJA4 functions as an HSP70 co-chaperone.
      The study demonstrated that DNAJA4 supports HSP70-dependent luciferase refolding
      and suppresses polyQ aggregation, activities that reflect its role as a protein
      folding chaperone rather than simply binding unfolded proteins. 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). The same
      paper provides evidence for DNAJA4 interacting with multiple HSP70 family members
      (HSPA1A/P0DMV8, HSPA1B/P0DMV9, HSPA6/P17066) as IPI evidence for GO:0051087
      (protein-folding chaperone binding). The correct replacement term is GO:0044183
      (protein folding chaperone), which captures the functional role of DNAJA4 as a
      co-chaperone that binds client proteins and delivers them to HSP70 for
      ATP-dependent refolding.
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted. The experimental evidence from Hageman et al.
      (2011) demonstrates that DNAJA4 functions as a protein folding chaperone --
      it supports luciferase refolding and suppresses polyQ aggregation in cooperation
      with HSP70 partners. This is consistent with the well-established role of class I
      J-domain proteins as co-chaperones that bind unfolded substrates and deliver them
      to HSP70. The replacement term GO:0044183 (protein folding chaperone) accurately
      describes this molecular function.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - PMID:20651708
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        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: >-
        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
    - reference_id: PMID:20651708
      supporting_text: >-
        others bind client proteins directly, thereby delivering specific clients to
        HSP70 and directly determining their fate
- term:
    id: GO:0090084
    label: negative regulation of inclusion body assembly
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      IDA annotation for negative regulation of inclusion body assembly from
      Hageman et al. (2011). The study demonstrated that DNAJA4 suppresses
      aggregation of polyQ-expanded Huntingtin fragments, which form inclusion
      bodies. The authors specifically tested "suppression of aggregation of a
      non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment"
      (PMID:21231916). This is a direct experimental observation and reflects
      DNAJA4's anti-aggregation chaperone activity. However, it is worth noting
      that this is a specific experimental readout rather than a primary evolved
      function, as polyQ expansion is a pathological context. The ability to
      suppress aggregation is a general property of chaperones that bind
      misfolded substrates.
    action: ACCEPT
    reason: >-
      The IDA evidence directly demonstrates that DNAJA4 suppresses polyQ
      inclusion body formation. While this is tested in a pathological context
      (polyQ-expanded Huntingtin), it reflects the genuine anti-aggregation
      chaperone activity of DNAJA4. Suppression of protein aggregation is a
      core function of J-domain co-chaperones.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        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
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:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF: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:20651708
  title: 'The HSP70 chaperone machinery: J proteins as drivers of functional specificity.'
  findings: []
- id: PMID:21231916
  title: The diverse members of the mammalian HSP70 machine show distinct chaperone-like
    activities.
  findings: []
- id: PMID:23142051
  title: Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma
    metastasis and angiogenesis.
  findings: []
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of
    cellular protein homeostasis pathways.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: Reactome:R-HSA-3371422
  title: ATP hydrolysis by HSP70
  findings: []
- id: Reactome:R-HSA-3371503
  title: STIP1(HOP) binds HSP90 and HSP70:HSP40:nascent protein
  findings: []
- id: Reactome:R-HSA-3371590
  title: HSP70 binds to HSP40:nascent protein
  findings: []
- id: DOI:10.1016/j.molcel.2021.04.012
  title: Comprehensive interactome profiling of the human Hsp70 network highlights
    functional differentiation of J domains.
  findings:
    - statement: >-
        DNAJA4 is positioned in the densely connected cytoplasmic class A JDP core
        of the human Hsp70 network, with robust interactions with DNAJA1, DNAJA2,
        and DNAJB1.
- id: DOI:10.3390/biology12030416
  title: Profiling the Hsp70 chaperone network in heat-induced proteotoxic stress
    models of human neurons.
  findings:
    - statement: >-
        DNAJA4 is among the chaperone/co-chaperone genes commonly upregulated across
        three neuronal models after heat stress (log2 fold-change 1.5-5 at 1 h
        post-heat shock).
- id: DOI:10.1038/s41419-023-06225-w
  title: DNAJA4 suppresses epithelial-mesenchymal transition and metastasis in
    nasopharyngeal carcinoma via PSMD2-mediated MYH9 degradation.
  findings:
    - statement: >-
        DNAJA4 promotes ubiquitin-proteasome-dependent degradation of MYH9 via
        PSMD2 recruitment, suppressing EMT and metastasis in NPC.
    - statement: >-
        DNAJA4 promoter hypermethylation and downregulation in NPC; DAC
        demethylation restores DNAJA4 levels at least 15-fold in NPC cell lines.
- id: DOI:10.3390/ijms222413527
  title: Regulation of p53 and cancer signaling by heat shock protein 40/J-domain
    protein family members.
  findings:
    - statement: >-
        DNAJA4 can be epigenetically silenced in cancers; reduced DNAJA4 expression
        due to promoter methylation correlates with poorer disease-free survival in
        stomach adenocarcinoma, and hypermethylation is observed in rhabdomyosarcoma.
- id: DOI:10.1098/rstb.2016.0534
  title: DNAJ proteins in neurodegeneration - essential and protective factors.
  findings:
    - statement: >-
        Review situating DNAJA4 within the DNAJA subfamily with canonical class A
        JDP domain composition (J-domain, G/F region, Zn-binding region, and
        C-terminal client-binding/dimerization region).
core_functions:
  - description: >-
      DNAJA4 functions as a cytoplasmic class A HSP70 co-chaperone (J-domain protein)
      that stimulates the ATPase activity of HSP70 family members via its conserved
      J-domain HPD motif, binds unfolded client proteins through its zinc finger
      cysteine-rich domain and C-terminal beta-barrel substrate-binding domains (CTDI
      and CTDII), and delivers them to HSP70 for ATP-dependent refolding. It supports
      refolding of heat-denatured substrates and suppresses protein aggregation
      (PMID:21231916). Systematic Hsp70 network profiling places DNAJA4 in the densely
      connected cytoplasmic JDP core (DOI:10.1016/j.molcel.2021.04.012), and it is
      acutely upregulated during heat stress in human neuronal models
      (DOI:10.3390/biology12030416). DNAJA4 also has a specific role in promoting
      PSMD2-mediated ubiquitin-proteasome degradation of MYH9, linking its co-chaperone
      function to cytoskeletal remodeling and EMT suppression in NPC
      (DOI:10.1038/s41419-023-06225-w). DNAJA4 is farnesylated at Cys-394, providing
      dual cytosol/membrane localization.
    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
    locations:
      - id: GO:0005829
        label: cytosol
      - id: GO:0016020
        label: membrane
    supported_by:
      - reference_id: PMID:21231916
        supporting_text: >-
          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:20651708
        supporting_text: >-
          others bind client proteins directly, thereby delivering specific clients to
          HSP70 and directly determining their fate