id: Q6Y2X3
gene_symbol: DNAJC14
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: DNAJC14 (DRIP78, "dopamine receptor-interacting protein of 78 kDa"; also HDJ3/hDj-3) is a multi-pass endoplasmic reticulum membrane protein of the DnaJ/HSP40 subfamily C. It contains a cytoplasmically oriented J domain and a family-defining Jiv (Jiv90) domain, and acts as an ER-resident co-chaperone that regulates the export of client membrane proteins from the ER to the cell surface. Its best-characterized client is the dopamine D1 receptor (DRD1), which it binds via an FxxxFxxxF ER-export motif through its C-terminal domain, controlling DRD1 maturation and delivery to the plasma membrane; it has been implicated more broadly in G-protein-coupled receptor trafficking. The Jiv domain is also a host factor exploited during flavivirus/pestivirus RNA replication. DNAJC14 is highly expressed in pancreas and is also expressed in brain, lung, liver, skeletal muscle and kidney.
existing_annotations:
- term:
    id: GO:0050780
    label: dopamine receptor binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) annotation that DNAJC14/DRIP78 binds the dopamine receptor, reflecting its founding role as the dopamine D1 receptor (DRD1)-interacting ER protein that controls DRD1 export. This is the most specific supported molecular function for this gene.
    action: ACCEPT
    reason: DNAJC14 directly binds DRD1 via the receptor's FxxxFxxxF motif using its C-terminal domain; dopamine receptor binding is a well-supported, specific molecular function and a core activity of the protein.
    supported_by:
    - reference_id: file:human/DNAJC14/DNAJC14-uniprot.txt
      supporting_text: Interacts with the FxxxFxxxF motif of DRD1 via its C-terminal domain.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Automated SubCell localization to the ER membrane, consistent with DNAJC14 being a multi-pass ER membrane protein.
    action: ACCEPT
    reason: DNAJC14 is an integral ER membrane protein with three predicted transmembrane helices; ER membrane is its core site of action as an ER-export chaperone.
    supported_by:
    - reference_id: file:human/DNAJC14/DNAJC14-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput binary-interactome screen capturing a DNAJC14-SARNP (P82979) interaction. SARNP is a nuclear SAP/RNA-binding protein; the bare protein binding term is uninformative and the partner is unrelated to DNAJC14's ER GPCR-trafficking function.
    action: KEEP_AS_NON_CORE
    reason: GO:0005515 is uninformative, and the captured partner (nuclear SARNP) is in a different compartment from this ER membrane protein, suggesting a likely high-throughput artifact rather than a functionally meaningful interaction.
    supported_by:
    - reference_id: file:human/DNAJC14/DNAJC14-uniprot.txt
      supporting_text: 'Q6Y2X3; P82979: SARNP; NbExp=3; IntAct=EBI-10038974, EBI-347495;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-purification interactome capturing the same DNAJC14-SARNP (P82979) interaction. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Uninformative GO:0005515 with a nuclear partner (SARNP) incongruent with DNAJC14's ER membrane localization; likely a high-throughput artifact, not core function.
    supported_by:
    - reference_id: file:human/DNAJC14/DNAJC14-uniprot.txt
      supporting_text: 'Q6Y2X3; P82979: SARNP; NbExp=3; IntAct=EBI-10038974, EBI-347495;'
- term:
    id: GO:0001664
    label: G protein-coupled receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Electronic (Ensembl orthology, from rat ortholog Q5XIX0) annotation that DNAJC14 binds a G-protein-coupled receptor. This is the parent generalization of its dopamine D1 receptor binding and is consistent with its broader role in GPCR ER export.
    action: ACCEPT
    reason: DNAJC14 binds the GPCR DRD1 (and is implicated in trafficking of other GPCRs); the general GPCR-binding term is supported and biologically appropriate, though dopamine receptor binding is the more specific captured activity.
    supported_by:
    - reference_id: file:human/DNAJC14/DNAJC14-uniprot.txt
      supporting_text: Interacts with the FxxxFxxxF motif of DRD1 via its C-terminal domain.
- term:
    id: GO:0050780
    label: dopamine receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Electronic (Ensembl orthology) annotation of dopamine receptor binding, redundant with the IBA annotation of the same term and supported by the DRD1 interaction.
    action: ACCEPT
    reason: Redundant with the IBA dopamine receptor binding annotation and corroborated by the documented DRD1 interaction; a core molecular function.
    supported_by:
    - reference_id: file:human/DNAJC14/DNAJC14-uniprot.txt
      supporting_text: Interacts with the FxxxFxxxF motif of DRD1 via its C-terminal domain.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput proteomics detection of DNAJC14 in a membrane fraction. A generic localization consistent with, but less informative than, the specific ER membrane annotation.
    action: KEEP_AS_NON_CORE
    reason: Correct but uninformative generic membrane localization superseded by the specific ER membrane annotation.
    supported_by:
    - reference_id: file:human/DNAJC14/DNAJC14-goa.tsv
      supporting_text: GO:0016020 membrane cellular_component ECO:0007005 HDA PMID:19946888
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs by Ensembl Compara
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Cached; this PMID is cited only for a high-throughput membrane proteomics inclusion (GOA GO:0016020 membrane, HDA) and does not establish DNAJC14's core dopamine-receptor-export function, which in this review rests on the UniProt record rather than any literature PMID present here.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: file:human/DNAJC14/DNAJC14-uniprot.txt
  title: UniProt entry Q6Y2X3 (DJC14_HUMAN), DnaJ homolog subfamily C member 14 / DRIP78
  findings:
  - statement: Multi-pass ER membrane J-protein that regulates export of target proteins such as DRD1 from the ER to the cell surface; binds the FxxxFxxxF motif of DRD1 via its C-terminal domain; contains a J domain and a Jiv90 domain.
    reference_section_type: OTHER
core_functions:
- description: ER-resident DnaJ/HSP40 co-chaperone that binds client G-protein-coupled receptors, notably the dopamine D1 receptor (via its FxxxFxxxF ER-export motif), to regulate their export from the endoplasmic reticulum to the cell surface.
  molecular_function:
    id: GO:0050780
    label: dopamine receptor binding
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/DNAJC14/DNAJC14-uniprot.txt
    supporting_text: Interacts with the FxxxFxxxF motif of DRD1 via its C-terminal domain.
  - reference_id: file:human/DNAJC14/DNAJC14-uniprot.txt
    supporting_text: Regulates the export of target proteins, such as DRD1, from the endoplasmic reticulum to the cell surface.
proposed_new_terms: []
suggested_questions:
- question: Does the DNAJC14 J domain recruit and stimulate an ER-associated HSP70 (e.g. BiP/HSPA5) to chaperone GPCR folding and ER export, and is the HPD motif required for DRD1 surface delivery?
- question: How broad is the DNAJC14 client repertoire beyond DRD1 (which other GPCRs or membrane proteins depend on DRIP78 for ER export), and is selectivity dictated by the FxxxFxxxF motif?
suggested_experiments:
- description: Co-immunoprecipitation and surface-biotinylation assays in DNAJC14-knockout cells expressing DRD1 (wild-type versus FxxxFxxxF-motif mutant) to quantify ER retention versus cell-surface delivery.
- description: J-domain HPD-motif mutagenesis combined with BiP/HSPA5 ATPase assays to test whether DNAJC14 functions as a bona fide HSP70 co-chaperone in regulating GPCR ER export.