id: Q13217
gene_symbol: DNAJC3
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: DNAJC3 (p58IPK, also ERdj6/PRKRI) is an ER-resident J-domain co-chaperone with an N-terminal TPR-repeat region (nine TPR motifs) and a C-terminal J domain. It has two interlinked roles. As a co-chaperone it binds the HSP70 chaperones BiP (HSPA5) and HSC70 (HSPA8) via its J domain, stimulates their ATPase activity, and binds misfolded proteins through its TPR groove, functioning in ER protein folding and the unfolded protein response. As a stress-inducible inhibitor of the eIF2-alpha protein kinases, it binds and inhibits PKR (EIF2AK2), PERK (EIF2AK3) and GCN2 (EIF2AK4), preventing eIF2-alpha (Ser-51/52) phosphorylation and thereby restoring/attenuating protein synthesis during ER, viral, hypothermic and amino-acid-starvation stress. It is broadly expressed (high in pancreas and testis), induced via ATF6 during ER stress, and its loss causes an autosomal-recessive syndrome of juvenile-onset diabetes mellitus with multisystem neurodegeneration (ACPHD).
existing_annotations:
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: DNAJC3 binds the HSP70 chaperones BiP (HSPA5) and HSC70 (HSPA8) via its J domain, a defining co-chaperone molecular function. Supported by experiment and phylogeny.
    action: ACCEPT
    reason: Binding of the HSP70 chaperones BiP/HSC70 through the J domain is a core molecular function of DNAJC3, supported by direct interaction data.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: The J domain mediates interaction with HSPA8
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: DNAJC3/ERdj6 is an ER-resident J-protein; the ER is its principal site of action, supported by phylogeny and experiment.
    action: ACCEPT
    reason: ER residence is well documented for DNAJC3 and is the compartment where it acts as a BiP co-chaperone in the UPR.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum'
- term:
    id: GO:0034975
    label: protein folding in endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: As an ER co-chaperone of BiP, DNAJC3 participates in ER protein folding. Supported by phylogeny and its documented chaperone role.
    action: KEEP_AS_NON_CORE
    reason: ER protein folding is a genuine process outcome of DNAJC3's BiP co-chaperone activity, but downstream of its direct molecular roles (chaperone binding, kinase inhibition).
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: Involved in the unfolded protein response (UPR)
- term:
    id: GO:0051787
    label: misfolded protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: DNAJC3 binds misfolded proteins via a hydrophobic groove in its first two TPR repeats, a core substrate-recognition molecular function.
    action: ACCEPT
    reason: Misfolded-protein binding through the TPR groove is a documented molecular function of DNAJC3, supporting its co-chaperone substrate-delivery role.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: Binding to misfolded proteins is mediated by a hydrophobic patch
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Automated ER localization, consistent with the established ER residence of DNAJC3.
    action: ACCEPT
    reason: Correct compartment; agrees with ISS/IBA/TAS ER evidence.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum'
- term:
    id: GO:0004860
    label: protein kinase inhibitor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: DNAJC3/p58IPK inhibits the eIF2-alpha protein kinases (PKR/EIF2AK2, PERK/EIF2AK3, GCN2/EIF2AK4). This is a core molecular function, also supported experimentally (PubMed:8576172) and by ISS.
    action: ACCEPT
    reason: Inhibition of eIF2-alpha kinase autophosphorylation/activity is a defining, experimentally established molecular function of DNAJC3.
    supported_by:
    - reference_id: PMID:8576172
      supporting_text: protein inhibits both the autophosphorylation of PKR and the phosphorylation of
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ortholog-projected cytoplasmic localization. DNAJC3 inhibits the cytosolic kinase PKR and is reported in the cytoplasm in the original p58IPK literature, though its primary residence is the ER.
    action: KEEP_AS_NON_CORE
    reason: A cytoplasmic pool is consistent with DNAJC3's documented inhibition of cytosolic PKR, but the ER is its primary compartment; retained as non-core.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-goa.tsv
      supporting_text: GO:0005737 cytoplasm cellular_component ECO:0000265 IEA GO_REF:0000107
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ortholog-projected ER-lumen localization, consistent with DNAJC3's signal-peptide-driven ER residence.
    action: ACCEPT
    reason: ER lumen is a precise, correct localization for this ER-resident J-protein.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-goa.tsv
      supporting_text: GO:0005788 endoplasmic reticulum lumen cellular_component ECO:0000265 IEA GO_REF:0000107
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ortholog-projected cytosolic localization, consistent with the documented cytosolic pool engaging PKR. Secondary to ER residence.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization reflects DNAJC3's PKR-inhibition role but is secondary to its primary ER residence.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-goa.tsv
      supporting_text: GO:0005829 cytosol cellular_component ECO:0000265 IEA GO_REF:0000107
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: DNAJC3 binds the eIF2-alpha protein kinases (PKR, PERK, GCN2). A core molecular function underlying its kinase-inhibitor activity; supported experimentally (PubMed:8576172) and by ISS.
    action: ACCEPT
    reason: Binding to PKR/PERK/GCN2 is experimentally documented and is the basis of DNAJC3's eIF2-alpha kinase inhibition.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: Interacts with EIF2AK2
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: DNAJC3 is an ER-stress-inducible component of the UPR that modulates eIF2-alpha signaling. Well supported.
    action: ACCEPT
    reason: DNAJC3's induction during ER stress and regulation of eIF2-alpha kinases place it squarely in the ER UPR.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: Involved in the unfolded protein response (UPR)
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: DNAJC3 is up-regulated during ER stress (via ATF6) and functions in the ER stress response.
    action: ACCEPT
    reason: ER-stress induction and function are documented; a correct process annotation.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: Up-regulated during an endoplasmic reticulum stress via
- term:
    id: GO:0036494
    label: positive regulation of translation initiation in response to endoplasmic reticulum stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: By inhibiting eIF2-alpha kinases and preventing eIF2-alpha phosphorylation, DNAJC3 restores cap-dependent translation initiation during late ER stress. Consistent with its negative regulation of eIF2-alpha kinases.
    action: ACCEPT
    reason: Preventing eIF2-alpha phosphorylation relieves translational repression, so promotion of translation initiation in late ER stress is a supported process role.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: attenuating general protein synthesis
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ortholog-projected chaperone-binding function, redundant with the IBA and experimental evidence that DNAJC3 binds BiP/HSC70.
    action: ACCEPT
    reason: DNAJC3 binds the HSP70 chaperones; this is a correct, core molecular function.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: The J domain mediates interaction with HSPA8
- term:
    id: GO:0051787
    label: misfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ortholog-projected misfolded-protein binding, redundant with the IBA misfolded-protein binding annotation and the TPR-groove substrate-binding mechanism.
    action: ACCEPT
    reason: DNAJC3 binds misfolded proteins via its TPR groove; a correct molecular function.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: Binding to misfolded proteins is mediated by a hydrophobic patch
- term:
    id: GO:0070417
    label: cellular response to cold
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: DNAJC3 inhibits GCN2 under hypothermic stress, attenuating eIF2-alpha phosphorylation; a documented (by-similarity) role in the cold response.
    action: KEEP_AS_NON_CORE
    reason: The cold-response role is a specific stress context of DNAJC3's eIF2-alpha kinase regulation; genuine but specialized/non-core.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: hypothermic and amino acid starving stress conditions
- term:
    id: GO:1902010
    label: negative regulation of translation in response to endoplasmic reticulum stress
  evidence_type: IMP
  original_reference_id: PMID:22064321
  qualifier: involved_in
  review:
    summary: DNAJC3 modulates translation during ER stress through its eIF2-alpha kinase regulation. The cited study reports p58IPK upregulation downstream of ERp29-induced growth arrest, so the evidence for this specific direction is indirect, though a translation-regulatory role is mechanistically well supported.
    action: KEEP_AS_NON_CORE
    reason: DNAJC3 regulates eIF2-alpha-dependent translation during ER stress; the specific IMP citation is correlative (p58IPK as a downstream marker), so retained as a non-core process annotation.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: attenuating general protein synthesis
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952289
  qualifier: located_in
  review:
    summary: Reactome-curated ER-lumen localization, consistent with DNAJC3's ER residence.
    action: ACCEPT
    reason: ER lumen is a precise, correct localization for this ER-resident J-protein.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum'
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798751
  qualifier: located_in
  review:
    summary: Reactome annotation from neutrophil-degranulation curation. This reflects a secretome/granule context, not DNAJC3's core ER co-chaperone function.
    action: KEEP_AS_NON_CORE
    reason: Curated localization from degranulation proteomics; peripheral to and not reflective of DNAJC3's principal ER role.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-goa.tsv
      supporting_text: GO:0005576 extracellular region cellular_component ECO:0000304 TAS Reactome:R-HSA-6798751
- term:
    id: GO:0035578
    label: azurophil granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798751
  qualifier: located_in
  review:
    summary: Reactome annotation from neutrophil azurophil-granule curation; a specialized context distinct from DNAJC3's ER co-chaperone role.
    action: KEEP_AS_NON_CORE
    reason: Curated granule-lumen localization peripheral to DNAJC3's core ER function.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-goa.tsv
      supporting_text: GO:0035578 azurophil granule lumen cellular_component ECO:0000304 TAS Reactome:R-HSA-6798751
- term:
    id: GO:0004860
    label: protein kinase inhibitor activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Sequence/ortholog-based protein kinase inhibitor activity, redundant with the experimental PKR-inhibition evidence. A core molecular function.
    action: ACCEPT
    reason: DNAJC3 inhibits the eIF2-alpha kinases; this ISS annotation is correct and core.
    supported_by:
    - reference_id: PMID:8576172
      supporting_text: protein inhibits both the autophosphorylation of PKR and the phosphorylation of
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence/ortholog-based ER localization, consistent with the established ER residence.
    action: ACCEPT
    reason: Correct compartment for this ER-resident J-protein.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence/ortholog-based cytosolic localization, consistent with the cytosolic pool that engages PKR. Secondary to ER residence.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization reflects the PKR-inhibition role but is secondary to DNAJC3's primary ER residence.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-goa.tsv
      supporting_text: GO:0005829 cytosol cellular_component ECO:0000250 ISS GO_REF:0000024
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Sequence/ortholog-based protein kinase binding, redundant with the experimental PKR/PERK/GCN2 interaction evidence.
    action: ACCEPT
    reason: DNAJC3 binds the eIF2-alpha kinases; a correct, core molecular function.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: Interacts with EIF2AK2
- term:
    id: GO:0036494
    label: positive regulation of translation initiation in response to endoplasmic reticulum stress
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Ortholog-based; consistent with the IEA call that DNAJC3 promotes translation initiation late in ER stress by relieving eIF2-alpha phosphorylation.
    action: ACCEPT
    reason: Supported by DNAJC3's prevention of eIF2-alpha phosphorylation, which relieves translational repression.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: attenuating general protein synthesis
- term:
    id: GO:0070417
    label: cellular response to cold
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Ortholog-based cold-response role via GCN2 inhibition under hypothermic stress.
    action: KEEP_AS_NON_CORE
    reason: A specific stress-context role of DNAJC3's eIF2-alpha kinase regulation; genuine but specialized.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: hypothermic and amino acid starving stress conditions
- term:
    id: GO:1903912
    label: negative regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: DNAJC3 prevents phosphorylation of eIF2-alpha by inhibiting the eIF2-alpha kinases during ER stress. This is the central biological-process role of DNAJC3.
    action: ACCEPT
    reason: Negative regulation of ER-stress-induced eIF2-alpha phosphorylation is the core process effected by DNAJC3's kinase inhibition.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: preventing the phosphorylation of eIF-
- term:
    id: GO:1903561
    label: extracellular vesicle
  evidence_type: HDA
  original_reference_id: PMID:24769233
  qualifier: located_in
  review:
    summary: High-throughput detection in extracellular vesicles (CSF). Peripheral to DNAJC3's core ER function.
    action: KEEP_AS_NON_CORE
    reason: Proteomic vesicle detection; not reflective of DNAJC3's principal ER co-chaperone role.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-goa.tsv
      supporting_text: GO:1903561 extracellular vesicle cellular_component ECO:0007005 HDA PMID:24769233
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IMP
  original_reference_id: PMID:22064321
  qualifier: involved_in
  review:
    summary: An anti-apoptotic/survival role is annotated from a study where p58IPK is up-regulated downstream of ERp29-induced growth arrest. The evidence is correlative rather than a direct DNAJC3 perturbation, so this is weakly grounded.
    action: KEEP_AS_NON_CORE
    reason: The apoptosis-regulation annotation rests on correlative p58IPK upregulation in the cited study, not a direct DNAJC3 loss/gain experiment; retained as non-core.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-goa.tsv
      supporting_text: GO:0043066 negative regulation of apoptotic process biological_process ECO:0000315 IMP PMID:22064321
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput membrane-proteome (NK cell) detection; uninformative as to specific compartment and peripheral to DNAJC3's ER function.
    action: KEEP_AS_NON_CORE
    reason: Generic membrane localization from a proteomics screen; non-core.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-goa.tsv
      supporting_text: GO:0016020 membrane cellular_component ECO:0007005 HDA PMID:19946888
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19199708
  qualifier: located_in
  review:
    summary: High-throughput detection in parotid-gland exosomes. Peripheral to DNAJC3's core ER function.
    action: KEEP_AS_NON_CORE
    reason: Proteomic exosome detection; not reflective of DNAJC3's principal ER co-chaperone role.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-goa.tsv
      supporting_text: GO:0070062 extracellular exosome cellular_component ECO:0007005 HDA PMID:19199708
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1791157
  qualifier: located_in
  review:
    summary: Reactome-curated ER-lumen localization, consistent with DNAJC3's ER residence.
    action: ACCEPT
    reason: ER lumen is a precise, correct localization for DNAJC3.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9835454
  qualifier: located_in
  review:
    summary: Reactome-curated cytosolic localization, consistent with the cytosolic pool engaging PKR. Secondary to ER residence.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization reflects DNAJC3's PKR-inhibition role but is secondary to its ER residence.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-goa.tsv
      supporting_text: GO:0005829 cytosol cellular_component ECO:0000304 TAS Reactome:R-HSA-9835454
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: TAS
  original_reference_id: PMID:8666242
  qualifier: located_in
  review:
    summary: The original p58IPK characterization reported cytoplasmic localization, consistent with its inhibition of the cytosolic kinase PKR. Secondary to ER residence.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasmic localization is documented in early p58IPK studies and reflects its PKR-inhibition role, but the ER is its primary compartment.
    supported_by:
    - reference_id: file:human/DNAJC3/DNAJC3-goa.tsv
      supporting_text: GO:0005737 cytoplasm cellular_component ECO:0000304 TAS PMID:8666242
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:8576172
  title: The P58 cellular inhibitor complexes with the interferon-induced, double-stranded RNA-dependent protein kinase, PKR, to regulate its autophosphorylation and activity.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publication (publications/PMID_8576172.md) PubMed title matches the YAML title exactly and directly establishes that P58/DNAJC3 complexes with PKR and regulates its autophosphorylation/activity, supporting the core MF protein kinase inhibitor activity (GO:0004860). Full text not cached, but the title/abstract anchor the inhibitory-complex claim."
  findings:
  - statement: P58IPK/DNAJC3 is a TPR-family protein that complexes with PKR (EIF2AK2) and inhibits both PKR autophosphorylation and PKR-catalyzed phosphorylation of eIF-2-alpha.
    reference_section_type: RESULTS
- id: PMID:8666242
  title: Cloning, expression, and cellular localization of the oncogenic 58-kDa inhibitor of the RNA-activated human and mouse protein kinase.
  findings:
  - statement: p58IPK/DNAJC3 was cloned and localized to the cytoplasm; widely expressed with high levels in pancreas and testis.
    reference_section_type: RESULTS
- id: PMID:12601012
  title: P58IPK, a novel endoplasmic reticulum stress-inducible protein and potential negative regulator of eIF2alpha signaling.
  findings:
  - statement: P58IPK/DNAJC3 is induced by ER stress and acts as a negative regulator of eIF2-alpha signaling.
    reference_section_type: RESULTS
- id: PMID:22064321
  title: ERp29 induces breast cancer cell growth arrest and survival through modulation of activation of p38 and upregulation of ER stress protein p58IPK.
  findings:
  - statement: p58IPK/DNAJC3 is up-regulated downstream of ERp29-induced growth arrest; cited for negative regulation of translation and apoptosis but the link to DNAJC3 is correlative.
    reference_section_type: RESULTS
- id: PMID:19199708
  title: Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:24769233
  title: 'Proteomic analysis of cerebrospinal fluid extracellular vesicles: a comprehensive dataset.'
  findings: []
- id: PMID:25466870
  title: Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publication (publications/PMID_25466870.md) PubMed title matches the YAML title exactly and establishes the in vivo physiological role of DNAJC3 as a BiP (HSPA5) co-chaperone: loss-of-function causes recessive diabetes mellitus with multisystemic neurodegeneration, corroborating the ER chaperone/UPR core function."
  findings:
  - statement: Loss of the BiP co-chaperone DNAJC3 causes an autosomal-recessive syndrome of juvenile-onset diabetes mellitus with multisystem neurodegeneration (ataxia, neuropathy, hearing loss).
    reference_section_type: RESULTS
- id: Reactome:R-HSA-1791157
  title: Reactome annotation (ER lumen localization of DNAJC3)
  findings: []
- id: Reactome:R-HSA-6798751
  title: Neutrophil degranulation (Reactome)
  findings: []
- id: Reactome:R-HSA-8952289
  title: Reactome annotation (ER lumen localization of DNAJC3)
  findings: []
- id: Reactome:R-HSA-9835454
  title: PKR-mediated signaling (Reactome)
  findings: []
core_functions:
- description: Inhibitor of the eIF2-alpha protein kinases PKR (EIF2AK2), PERK (EIF2AK3) and GCN2 (EIF2AK4); binds these kinases and blocks their autophosphorylation and their phosphorylation of eIF2-alpha, attenuating translational repression during ER, viral and other stresses.
  molecular_function:
    id: GO:0004860
    label: protein kinase inhibitor activity
  locations:
  - id: GO:0005783
    label: endoplasmic reticulum
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:8576172
    supporting_text: protein inhibits both the autophosphorylation of PKR and the phosphorylation of
  - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
    supporting_text: preventing the phosphorylation of eIF-
- description: ER J-domain co-chaperone that binds the HSP70 chaperones BiP (HSPA5) and HSC70 (HSPA8) via its J domain (stimulating their ATPase activity) and binds misfolded proteins via its TPR groove, functioning in ER protein folding and the unfolded protein response.
  molecular_function:
    id: GO:0051087
    label: protein-folding chaperone binding
  locations:
  - id: GO:0005783
    label: endoplasmic reticulum
  supported_by:
  - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
    supporting_text: The J domain mediates interaction with HSPA8
  - reference_id: file:human/DNAJC3/DNAJC3-uniprot.txt
    supporting_text: Binding to misfolded proteins is mediated by a hydrophobic patch
proposed_new_terms: []
suggested_questions:
- question: How does DNAJC3 partition between the ER lumen (BiP co-chaperone) and the cytosol (PKR inhibition), and is the same molecule responsible for both activities?
- question: Which activity loss (BiP co-chaperone versus eIF2-alpha kinase inhibition) drives the beta-cell failure and neurodegeneration in DNAJC3-deficient ACPHD?
suggested_experiments:
- description: In vitro kinase assays measuring DNAJC3 inhibition of PKR, PERK and GCN2 autophosphorylation and eIF2-alpha phosphorylation, with TPR-domain and J-domain variants to map the inhibitory determinants.
- description: Tissue-specific (beta-cell, neuron) DNAJC3 knockout with separation-of-function alleles (chaperone-dead versus kinase-inhibition-dead) to dissect which function underlies the diabetes/neurodegeneration phenotype.