id: Q8WXX5
gene_symbol: DNAJC9
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: DNAJC9 (also called HDJC9 or DnaJ protein SB73) is a type C DnaJ/Hsp40 (DNAJC) co-chaperone with an N-terminal J domain and a C-terminal histone-binding domain. It has a dual role as a histone H3-H4 chaperone and an HSP70 heat-shock co-chaperone. As a histone chaperone it forms a co-chaperone complex with MCM2 and histone H3-H4 heterodimers, binds H3 variants (H3.1, H3.2, H3.3) and H4, and integrates HSP70-mediated ATP-driven protein folding into the histone supply chain during replication- and transcription-coupled nucleosome assembly, helping to resolve aberrant histone-folding intermediates and assemble histones into nucleosomes. Its J domain recruits and stimulates the ATPase activity of HSP70-type chaperones (HSPA1A, HSPA1B, HSPA8). DNAJC9 is predominantly nuclear under normal conditions and translocates to the cytoplasm and plasma membrane after heat shock via a non-classical, lipid-dependent pathway; its expression is induced by heat shock, LPS, PMA and TNF.
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetically inferred nuclear localization, consistent with the experimentally established predominantly nuclear localization where DNAJC9 acts as a histone chaperone.
    action: ACCEPT
    reason: Nucleus is the principal site of DNAJC9's core histone-chaperone function and is supported by direct experimental evidence (PMID:17182002, PMID:33857403).
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:17182002}.'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetically inferred cytoplasmic localization. For DNAJC9, cytoplasmic localization arises mainly upon heat-shock translocation; the predominant resting compartment is the nucleus.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasmic localization reflects stress-induced relocalization rather than the predominant nuclear site of the core histone-chaperone function.
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-uniprot.txt
      supporting_text: Translocates to the cytoplasm and membrane after heat shock.
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: DNAJC9 binds HSP70-family chaperones (HSPA1A, HSPA1B, HSPA8) via its J domain, a core molecular function shared across the DNAJC9 orthologous group.
    action: ACCEPT
    reason: Direct binding of HSP70 chaperones via the J domain is experimentally documented and is core to DNAJC9's co-chaperone activity.
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-uniprot.txt
      supporting_text: Interacts (via J domain) with HSPA1A, HSPA1B and HSPA8
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Automated subcellular-location transfer of nuclear localization, the predominant compartment of DNAJC9.
    action: ACCEPT
    reason: Nucleus is the experimentally supported principal compartment of DNAJC9's histone-chaperone function.
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:17182002}.'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Automated transfer of cytoplasmic localization, which for DNAJC9 reflects heat-shock-induced translocation rather than the resting nuclear pool.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasmic localization is a stress-induced, non-core context for this predominantly nuclear histone chaperone.
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-uniprot.txt
      supporting_text: Translocates to the cytoplasm and membrane after heat shock.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Automated transfer of plasma membrane localization, which for DNAJC9 reflects a heat-shock-induced, non-classical lipid-dependent translocation.
    action: KEEP_AS_NON_CORE
    reason: Plasma membrane localization is a specialized stress-induced context, peripheral to the core nuclear histone-chaperone function.
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-uniprot.txt
      supporting_text: it is transported into cytoplasm and plasma membrane upon heat shock stress through a non-classical and lipid-dependent pathway
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19410544
  qualifier: enables
  review:
    summary: High-throughput interaction (IntAct WITH histone H3, P68431). The bare protein binding term records a real interaction but is uninformative; it reflects histone binding.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding is uninformative; the informative function (histone binding) is captured by the dedicated histone binding annotation.
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:19410544 UniProtKB:P68431
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25281560
  qualifier: enables
  review:
    summary: High-throughput interaction (IntAct WITH histone H3, P68431). Bare protein binding term reflecting histone binding.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding is uninformative; the informative histone-binding function is captured separately.
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25281560 UniProtKB:P68431
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29568061
  qualifier: enables
  review:
    summary: High-throughput interaction (IntAct WITH histone H3, P68431). Bare protein binding term reflecting histone binding.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding is uninformative; the informative histone-binding function is captured separately.
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:29568061 UniProtKB:P68431
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput interactions (IntAct WITH histone H3 P68431, H3-5 Q6NXT2, and MORN4 Q8NDC4). Bare protein binding term; the histone interactions reflect histone binding.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding is uninformative; the histone interactions are captured by the dedicated histone binding annotation, and the MORN4 hit is an isolated high-throughput partner.
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32296183 UniProtKB:P68431
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence showing nucleoplasmic localization, consistent with the predominantly nuclear histone-chaperone function.
    action: ACCEPT
    reason: Nucleoplasm is a precise cellular-component annotation matching DNAJC9's principal nuclear site of action.
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-goa.tsv
      supporting_text: GO:0005654 nucleoplasm cellular_component ECO:0000314 IDA GO_REF:0000052
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence showing cytosolic localization, consistent with the cytoplasmic pool of DNAJC9 (enhanced after heat shock).
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization is a genuine but secondary compartment relative to the predominant nuclear site of action.
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-goa.tsv
      supporting_text: GO:0005829 cytosol cellular_component ECO:0000314 IDA GO_REF:0000052
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence showing plasma membrane localization, consistent with the heat-shock-induced translocation of DNAJC9.
    action: KEEP_AS_NON_CORE
    reason: Plasma membrane localization is a stress-induced, non-core context for this predominantly nuclear histone chaperone.
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-goa.tsv
      supporting_text: GO:0005886 plasma membrane cellular_component ECO:0000314 IDA GO_REF:0000052
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33857403
  qualifier: enables
  review:
    summary: Structure-guided proteomics (Hammond et al.) capturing direct DNAJC9 interactions with histones H3.1/H3.2/H3.3 and H4, MCM2 and HSP70 (HSPA8). The bare term is uninformative; the central interaction is direct histone binding.
    action: MODIFY
    reason: Bare protein binding is uninformative. The biologically informative interaction demonstrated here is direct binding of histone H3-H4 substrates, best captured by histone binding (GO:0042393).
    proposed_replacement_terms:
    - id: GO:0042393
      label: histone binding
    supported_by:
    - reference_id: PMID:33857403
      supporting_text: this dual histone and heat shock co-chaperone binds histone substrates
- term:
    id: GO:0006334
    label: nucleosome assembly
  evidence_type: IDA
  original_reference_id: PMID:33857403
  qualifier: involved_in
  review:
    summary: DNAJC9 functions in the histone supply chain during replication- and transcription-coupled nucleosome assembly and can assemble histones onto DNA in vitro, supporting this process annotation.
    action: ACCEPT
    reason: Direct experimental evidence places DNAJC9 in nucleosome assembly as part of its histone-chaperone function.
    supported_by:
    - reference_id: PMID:33857403
      supporting_text: during replication- and transcription-coupled nucleosome assembly
- term:
    id: GO:0042393
    label: histone binding
  evidence_type: IDA
  original_reference_id: PMID:33857403
  qualifier: enables
  review:
    summary: DNAJC9 binds histone H3-H4 substrates directly (structurally defined in complex with MCM2 and H3.3-H4). This is a core molecular function.
    action: ACCEPT
    reason: Direct, structurally defined binding of histone H3-H4 substrates is a core molecular function of DNAJC9 as a histone chaperone.
    supported_by:
    - reference_id: PMID:33857403
      supporting_text: this dual histone and heat shock co-chaperone binds histone substrates
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IDA
  original_reference_id: PMID:33857403
  qualifier: enables
  review:
    summary: DNAJC9 binds chaperone partners (MCM2 and HSP70-type enzymes) within the histone co-chaperone complex, consistent with chaperone-binding function.
    action: ACCEPT
    reason: DNAJC9 directly binds the histone chaperone MCM2 and recruits HSP70 enzymes, supporting protein-folding chaperone binding.
    supported_by:
    - reference_id: PMID:33857403
      supporting_text: DNAJC9 recruits HSP70-type enzymes via its J domain to fold histone H3-H4 substrates
- term:
    id: GO:0101031
    label: protein folding chaperone complex
  evidence_type: IDA
  original_reference_id: PMID:33857403
  qualifier: part_of
  review:
    summary: DNAJC9 is part of a co-chaperone complex with MCM2 and histone H3-H4, a bona fide protein-folding chaperone complex defined structurally.
    action: ACCEPT
    reason: DNAJC9 is a structurally characterized component of an MCM2-histone co-chaperone complex, supporting this complex annotation.
    supported_by:
    - reference_id: PMID:33857403
      supporting_text: in a histone H3-H4 co-chaperone complex with MCM2
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:17182002
  qualifier: located_in
  review:
    summary: Detection at the cell surface/extracellular context following heat-shock-induced translocation. Peripheral to DNAJC9's nuclear histone-chaperone role.
    action: KEEP_AS_NON_CORE
    reason: Extracellular/cell-surface localization arises from a stress-induced non-classical translocation and is not part of the core function.
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-uniprot.txt
      supporting_text: it is transported into cytoplasm and plasma membrane upon heat shock stress through a non-classical and lipid-dependent pathway
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:17182002
  qualifier: located_in
  review:
    summary: Direct experimental evidence that DNAJC9 is mainly localized in cell nuclei under normal conditions.
    action: ACCEPT
    reason: Nucleus is the experimentally established predominant compartment of DNAJC9.
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-uniprot.txt
      supporting_text: HDJC9 is mainly localized in cell nuclei under normal culture conditions
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:17182002
  qualifier: located_in
  review:
    summary: Direct evidence for cytoplasmic localization, observed mainly after heat-shock translocation from the nucleus.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasmic localization is a stress-induced relocalization, secondary to the predominant nuclear site of action.
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-uniprot.txt
      supporting_text: Translocates to the cytoplasm and membrane after heat shock.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:17182002
  qualifier: located_in
  review:
    summary: Direct evidence for plasma membrane localization following heat-shock-induced non-classical translocation.
    action: KEEP_AS_NON_CORE
    reason: Plasma membrane localization is a specialized stress-induced context, peripheral to the core nuclear histone-chaperone function.
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-uniprot.txt
      supporting_text: it is transported into cytoplasm and plasma membrane upon heat shock stress through a non-classical and lipid-dependent pathway
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IPI
  original_reference_id: PMID:17182002
  qualifier: enables
  review:
    summary: DNAJC9 directly interacts with HSP70-family proteins (HSPA1A, HSPA1B, HSPA8, HSPA1L) through its J domain, a core molecular function.
    action: ACCEPT
    reason: Direct J-domain-dependent binding of HSP70 chaperones is experimentally documented and central to DNAJC9's co-chaperone activity.
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-uniprot.txt
      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:0032781
    label: positive regulation of ATP-dependent activity
  evidence_type: IDA
  original_reference_id: PMID:17182002
  qualifier: involved_in
  review:
    summary: DNAJC9's J domain activates the ATPase activity of HSP70, the defining activity of J-domain co-chaperones. This is the core molecular activity, captured here as a process-level term.
    action: ACCEPT
    reason: J-domain-dependent stimulation of HSP70 ATPase activity is directly demonstrated and is central to DNAJC9's function.
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-uniprot.txt
      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:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  qualifier: located_in
  review:
    summary: High-throughput proteomics detection of nuclear localization, consistent with the predominant nuclear localization of DNAJC9.
    action: ACCEPT
    reason: Nuclear localization is corroborated by direct experimental evidence and is the core compartment of DNAJC9.
    supported_by:
    - reference_id: file:human/DNAJC9/DNAJC9-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:17182002}.'
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:17182002
  title: HDJC9, a novel human type C DnaJ/HSP40 member interacts with and cochaperones HSP70 through the J domain.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publication (publications/PMID_17182002.md) PubMed title matches the YAML title exactly; abstract reports HDJC9/DNAJC9 interacts with HSP70 and activates its ATPase activity in a J-domain-dependent manner, directly supporting the HSP70 co-chaperone core molecular function."
  findings:
  - statement: HDJC9/DNAJC9 interacts with HSP70s and activates their ATPase activity, both dependent on its J domain, identifying it as a novel HSP70 co-chaperone.
    reference_section_type: ABSTRACT
  - statement: DNAJC9 is mainly nuclear under normal conditions and translocates to the cytoplasm and plasma membrane upon heat shock via a non-classical lipid-dependent pathway.
    reference_section_type: ABSTRACT
- id: PMID:19410544
  title: Centromere-specific assembly of CENP-a nucleosomes is mediated by HJURP.
  findings: []
- id: PMID:21630459
  title: Proteomic characterization of the human sperm nucleus.
  findings: []
- id: PMID:25281560
  title: Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes.
  findings: []
- id: PMID:29568061
  title: An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:33857403
  title: DNAJC9 integrates heat shock molecular chaperones into the histone chaperone network.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publication (publications/PMID_33857403.md, full text available) PubMed title matches the YAML title exactly; establishes DNAJC9 as a histone H3-H4 chaperone that binds H3-H4 in a complex with MCM2 and recruits HSP70 via its J domain for nucleosome assembly, directly supporting all three core functions (cited as their primary supported_by)."
  findings:
  - statement: DNAJC9 is a dual histone H3-H4 chaperone and heat shock co-chaperone; it binds histone H3-H4 substrates in a co-chaperone complex with MCM2.
    reference_section_type: ABSTRACT
  - statement: DNAJC9 recruits HSP70-type enzymes via its J domain to fold histone H3-H4 substrates during replication- and transcription-coupled nucleosome assembly, integrating ATP-driven folding into the histone supply pathway.
    reference_section_type: ABSTRACT
- id: file:human/DNAJC9/DNAJC9-uniprot.txt
  title: UniProt entry Q8WXX5 (DNJC9_HUMAN), DnaJ homolog subfamily C member 9 / HDJC9
  findings:
  - statement: Dual histone chaperone and HSP70 heat-shock co-chaperone; forms a co-chaperone complex with MCM2 and histone H3-H4; interacts with H3.1/H3.2/H3.3/H4 and HSPA1A/HSPA1B/HSPA8 via its J domain; predominantly nuclear, translocates to cytoplasm/membrane on heat shock.
    reference_section_type: OTHER
core_functions:
- description: Histone H3-H4 chaperone that directly binds histone H3-H4 substrates within a co-chaperone complex with MCM2, safeguarding the histone fold during the histone supply chain.
  molecular_function:
    id: GO:0042393
    label: histone binding
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:33857403
    supporting_text: this dual histone and heat shock co-chaperone binds histone substrates
- description: HSP70 co-chaperone whose J domain binds and stimulates the ATPase activity of HSP70-type chaperones, recruiting ATP-driven folding to histone H3-H4 substrates.
  molecular_function:
    id: GO:0031072
    label: heat shock protein binding
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: file:human/DNAJC9/DNAJC9-uniprot.txt
    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:33857403
    supporting_text: DNAJC9 recruits HSP70-type enzymes via its J domain to fold histone H3-H4 substrates
- description: Participates in replication- and transcription-coupled nucleosome assembly, integrating HSP70-mediated ATP-driven folding into the histone supply pathway and assembling histones into nucleosomes.
  molecular_function:
    id: GO:0042393
    label: histone binding
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:33857403
    supporting_text: during replication- and transcription-coupled nucleosome assembly
  directly_involved_in:
  - id: GO:0006334
    label: nucleosome assembly
proposed_new_terms: []
suggested_questions:
- question: How is the choice between DNAJC9's nuclear histone-chaperone role and its cytoplasmic/membrane heat-shock-stress role regulated, and is the J-domain ATPase stimulation of HSP70 used in both contexts?
- question: Does DNAJC9 act as a general quality-control "clean-up" factor that resolves aberrant histone-folding intermediates across multiple histone chaperone handover steps?
suggested_experiments:
- description: Reconstitute the DNAJC9-MCM2-H3-H4 complex with HSP70 and measure J-domain-dependent HSP70 ATPase stimulation and refolding of destabilized histone H3-H4, comparing wild-type with the HPD (J-domain) and histone-binding-region mutants.
- description: Acute degron depletion of DNAJC9 followed by genome-wide nucleosome occupancy and nascent-chromatin proteomics to define its requirement in replication- and transcription-coupled nucleosome assembly.