DNAJC3

UniProt ID: Q13217
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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 Review

GO Term Evidence Action Reason
GO:0051087 protein-folding chaperone binding
IBA
GO_REF:0000033 		ACCEPT
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.
Reason: Binding of the HSP70 chaperones BiP/HSC70 through the J domain is a core molecular function of DNAJC3, supported by direct interaction data.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
The J domain mediates interaction with HSPA8
GO:0005783 endoplasmic reticulum
IBA
GO_REF:0000033 		ACCEPT
Summary: DNAJC3/ERdj6 is an ER-resident J-protein; the ER is its principal site of action, supported by phylogeny and experiment.
Reason: ER residence is well documented for DNAJC3 and is the compartment where it acts as a BiP co-chaperone in the UPR.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum
GO:0034975 protein folding in endoplasmic reticulum
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: As an ER co-chaperone of BiP, DNAJC3 participates in ER protein folding. Supported by phylogeny and its documented chaperone role.
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).
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
Involved in the unfolded protein response (UPR)
GO:0051787 misfolded protein binding
IBA
GO_REF:0000033 		ACCEPT
Summary: DNAJC3 binds misfolded proteins via a hydrophobic groove in its first two TPR repeats, a core substrate-recognition molecular function.
Reason: Misfolded-protein binding through the TPR groove is a documented molecular function of DNAJC3, supporting its co-chaperone substrate-delivery role.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
Binding to misfolded proteins is mediated by a hydrophobic patch
GO:0005783 endoplasmic reticulum
IEA
GO_REF:0000120 		ACCEPT
Summary: Automated ER localization, consistent with the established ER residence of DNAJC3.
Reason: Correct compartment; agrees with ISS/IBA/TAS ER evidence.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum
GO:0004860 protein kinase inhibitor activity
IEA
GO_REF:0000107 		ACCEPT
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.
Reason: Inhibition of eIF2-alpha kinase autophosphorylation/activity is a defining, experimentally established molecular function of DNAJC3.
Supporting Evidence:
PMID:8576172
protein inhibits both the autophosphorylation of PKR and the phosphorylation of
GO:0005737 cytoplasm
IEA
GO_REF:0000107 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-goa.tsv
GO:0005737 cytoplasm cellular_component ECO:0000265 IEA GO_REF:0000107
GO:0005788 endoplasmic reticulum lumen
IEA
GO_REF:0000107 		ACCEPT
Summary: Ortholog-projected ER-lumen localization, consistent with DNAJC3's signal-peptide-driven ER residence.
Reason: ER lumen is a precise, correct localization for this ER-resident J-protein.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-goa.tsv
GO:0005788 endoplasmic reticulum lumen cellular_component ECO:0000265 IEA GO_REF:0000107
GO:0005829 cytosol
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Ortholog-projected cytosolic localization, consistent with the documented cytosolic pool engaging PKR. Secondary to ER residence.
Reason: Cytosolic localization reflects DNAJC3's PKR-inhibition role but is secondary to its primary ER residence.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-goa.tsv
GO:0005829 cytosol cellular_component ECO:0000265 IEA GO_REF:0000107
GO:0019901 protein kinase binding
IEA
GO_REF:0000107 		ACCEPT
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.
Reason: Binding to PKR/PERK/GCN2 is experimentally documented and is the basis of DNAJC3's eIF2-alpha kinase inhibition.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
Interacts with EIF2AK2
GO:0030968 endoplasmic reticulum unfolded protein response
IEA
GO_REF:0000107 		ACCEPT
Summary: DNAJC3 is an ER-stress-inducible component of the UPR that modulates eIF2-alpha signaling. Well supported.
Reason: DNAJC3's induction during ER stress and regulation of eIF2-alpha kinases place it squarely in the ER UPR.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
Involved in the unfolded protein response (UPR)
GO:0034976 response to endoplasmic reticulum stress
IEA
GO_REF:0000107 		ACCEPT
Summary: DNAJC3 is up-regulated during ER stress (via ATF6) and functions in the ER stress response.
Reason: ER-stress induction and function are documented; a correct process annotation.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
Up-regulated during an endoplasmic reticulum stress via
GO:0036494 positive regulation of translation initiation in response to endoplasmic reticulum stress
IEA
GO_REF:0000107 		ACCEPT
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.
Reason: Preventing eIF2-alpha phosphorylation relieves translational repression, so promotion of translation initiation in late ER stress is a supported process role.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
attenuating general protein synthesis
GO:0051087 protein-folding chaperone binding
IEA
GO_REF:0000107 		ACCEPT
Summary: Ortholog-projected chaperone-binding function, redundant with the IBA and experimental evidence that DNAJC3 binds BiP/HSC70.
Reason: DNAJC3 binds the HSP70 chaperones; this is a correct, core molecular function.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
The J domain mediates interaction with HSPA8
GO:0051787 misfolded protein binding
IEA
GO_REF:0000107 		ACCEPT
Summary: Ortholog-projected misfolded-protein binding, redundant with the IBA misfolded-protein binding annotation and the TPR-groove substrate-binding mechanism.
Reason: DNAJC3 binds misfolded proteins via its TPR groove; a correct molecular function.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
Binding to misfolded proteins is mediated by a hydrophobic patch
GO:0070417 cellular response to cold
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: DNAJC3 inhibits GCN2 under hypothermic stress, attenuating eIF2-alpha phosphorylation; a documented (by-similarity) role in the cold response.
Reason: The cold-response role is a specific stress context of DNAJC3's eIF2-alpha kinase regulation; genuine but specialized/non-core.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
hypothermic and amino acid starving stress conditions
GO:1902010 negative regulation of translation in response to endoplasmic reticulum stress
IMP
PMID:22064321
ERp29 induces breast cancer cell growth arrest and survival ... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
attenuating general protein synthesis
GO:0005788 endoplasmic reticulum lumen
TAS
Reactome:R-HSA-8952289 		ACCEPT
Summary: Reactome-curated ER-lumen localization, consistent with DNAJC3's ER residence.
Reason: ER lumen is a precise, correct localization for this ER-resident J-protein.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum
GO:0005576 extracellular region
TAS
Reactome:R-HSA-6798751 		KEEP AS NON CORE
Summary: Reactome annotation from neutrophil-degranulation curation. This reflects a secretome/granule context, not DNAJC3's core ER co-chaperone function.
Reason: Curated localization from degranulation proteomics; peripheral to and not reflective of DNAJC3's principal ER role.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-goa.tsv
GO:0005576 extracellular region cellular_component ECO:0000304 TAS Reactome:R-HSA-6798751
GO:0035578 azurophil granule lumen
TAS
Reactome:R-HSA-6798751 		KEEP AS NON CORE
Summary: Reactome annotation from neutrophil azurophil-granule curation; a specialized context distinct from DNAJC3's ER co-chaperone role.
Reason: Curated granule-lumen localization peripheral to DNAJC3's core ER function.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-goa.tsv
GO:0035578 azurophil granule lumen cellular_component ECO:0000304 TAS Reactome:R-HSA-6798751
GO:0004860 protein kinase inhibitor activity
ISS
GO_REF:0000024 		ACCEPT
Summary: Sequence/ortholog-based protein kinase inhibitor activity, redundant with the experimental PKR-inhibition evidence. A core molecular function.
Reason: DNAJC3 inhibits the eIF2-alpha kinases; this ISS annotation is correct and core.
Supporting Evidence:
PMID:8576172
protein inhibits both the autophosphorylation of PKR and the phosphorylation of
GO:0005783 endoplasmic reticulum
ISS
GO_REF:0000024 		ACCEPT
Summary: Sequence/ortholog-based ER localization, consistent with the established ER residence.
Reason: Correct compartment for this ER-resident J-protein.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum
GO:0005829 cytosol
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Sequence/ortholog-based cytosolic localization, consistent with the cytosolic pool that engages PKR. Secondary to ER residence.
Reason: Cytosolic localization reflects the PKR-inhibition role but is secondary to DNAJC3's primary ER residence.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-goa.tsv
GO:0005829 cytosol cellular_component ECO:0000250 ISS GO_REF:0000024
GO:0019901 protein kinase binding
ISS
GO_REF:0000024 		ACCEPT
Summary: Sequence/ortholog-based protein kinase binding, redundant with the experimental PKR/PERK/GCN2 interaction evidence.
Reason: DNAJC3 binds the eIF2-alpha kinases; a correct, core molecular function.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
Interacts with EIF2AK2
GO:0036494 positive regulation of translation initiation in response to endoplasmic reticulum stress
ISS
GO_REF:0000024 		ACCEPT
Summary: Ortholog-based; consistent with the IEA call that DNAJC3 promotes translation initiation late in ER stress by relieving eIF2-alpha phosphorylation.
Reason: Supported by DNAJC3's prevention of eIF2-alpha phosphorylation, which relieves translational repression.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
attenuating general protein synthesis
GO:0070417 cellular response to cold
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Ortholog-based cold-response role via GCN2 inhibition under hypothermic stress.
Reason: A specific stress-context role of DNAJC3's eIF2-alpha kinase regulation; genuine but specialized.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
hypothermic and amino acid starving stress conditions
GO:1903912 negative regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation
ISS
GO_REF:0000024 		ACCEPT
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.
Reason: Negative regulation of ER-stress-induced eIF2-alpha phosphorylation is the core process effected by DNAJC3's kinase inhibition.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
preventing the phosphorylation of eIF-
GO:1903561 extracellular vesicle
HDA
PMID:24769233
Proteomic analysis of cerebrospinal fluid extracellular vesi... 		KEEP AS NON CORE
Summary: High-throughput detection in extracellular vesicles (CSF). Peripheral to DNAJC3's core ER function.
Reason: Proteomic vesicle detection; not reflective of DNAJC3's principal ER co-chaperone role.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-goa.tsv
GO:1903561 extracellular vesicle cellular_component ECO:0007005 HDA PMID:24769233
GO:0043066 negative regulation of apoptotic process
IMP
PMID:22064321
ERp29 induces breast cancer cell growth arrest and survival ... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-goa.tsv
GO:0043066 negative regulation of apoptotic process biological_process ECO:0000315 IMP PMID:22064321
GO:0016020 membrane
HDA
PMID:19946888
Defining the membrane proteome of NK cells. 		KEEP AS NON CORE
Summary: High-throughput membrane-proteome (NK cell) detection; uninformative as to specific compartment and peripheral to DNAJC3's ER function.
Reason: Generic membrane localization from a proteomics screen; non-core.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-goa.tsv
GO:0016020 membrane cellular_component ECO:0007005 HDA PMID:19946888
GO:0070062 extracellular exosome
HDA
PMID:19199708
Proteomic analysis of human parotid gland exosomes by multid... 		KEEP AS NON CORE
Summary: High-throughput detection in parotid-gland exosomes. Peripheral to DNAJC3's core ER function.
Reason: Proteomic exosome detection; not reflective of DNAJC3's principal ER co-chaperone role.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-goa.tsv
GO:0070062 extracellular exosome cellular_component ECO:0007005 HDA PMID:19199708
GO:0005788 endoplasmic reticulum lumen
TAS
Reactome:R-HSA-1791157 		ACCEPT
Summary: Reactome-curated ER-lumen localization, consistent with DNAJC3's ER residence.
Reason: ER lumen is a precise, correct localization for DNAJC3.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum
GO:0005829 cytosol
TAS
Reactome:R-HSA-9835454 		KEEP AS NON CORE
Summary: Reactome-curated cytosolic localization, consistent with the cytosolic pool engaging PKR. Secondary to ER residence.
Reason: Cytosolic localization reflects DNAJC3's PKR-inhibition role but is secondary to its ER residence.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-goa.tsv
GO:0005829 cytosol cellular_component ECO:0000304 TAS Reactome:R-HSA-9835454
GO:0005737 cytoplasm
TAS
PMID:8666242
Cloning, expression, and cellular localization of the oncoge... 		KEEP AS NON CORE
Summary: The original p58IPK characterization reported cytoplasmic localization, consistent with its inhibition of the cytosolic kinase PKR. Secondary to ER residence.
Reason: Cytoplasmic localization is documented in early p58IPK studies and reflects its PKR-inhibition role, but the ER is its primary compartment.
Supporting Evidence:
file:human/DNAJC3/DNAJC3-goa.tsv
GO:0005737 cytoplasm cellular_component ECO:0000304 TAS PMID:8666242

Core Functions

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:
protein kinase inhibitor activity
Cellular Locations:
endoplasmic reticulum cytosol
Supporting Evidence:
  • PMID:8576172
    protein inhibits both the autophosphorylation of PKR and the phosphorylation of
  • file:human/DNAJC3/DNAJC3-uniprot.txt
    preventing the phosphorylation of eIF-

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:
protein-folding chaperone binding
Cellular Locations:
endoplasmic reticulum
Supporting Evidence:
  • file:human/DNAJC3/DNAJC3-uniprot.txt
    The J domain mediates interaction with HSPA8
  • file:human/DNAJC3/DNAJC3-uniprot.txt
    Binding to misfolded proteins is mediated by a hydrophobic patch

References

GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:8576172
The P58 cellular inhibitor complexes with the interferon-induced, double-stranded RNA-dependent protein kinase, PKR, to regulate its autophosphorylation and activity.
  • 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.
PMID:8666242
Cloning, expression, and cellular localization of the oncogenic 58-kDa inhibitor of the RNA-activated human and mouse protein kinase.
  • p58IPK/DNAJC3 was cloned and localized to the cytoplasm; widely expressed with high levels in pancreas and testis.
PMID:12601012
P58IPK, a novel endoplasmic reticulum stress-inducible protein and potential negative regulator of eIF2alpha signaling.
  • P58IPK/DNAJC3 is induced by ER stress and acts as a negative regulator of eIF2-alpha signaling.
PMID:22064321
ERp29 induces breast cancer cell growth arrest and survival through modulation of activation of p38 and upregulation of ER stress protein p58IPK.
  • 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.
PMID:19199708
Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).
PMID:19946888
Defining the membrane proteome of NK cells.
PMID:24769233
Proteomic analysis of cerebrospinal fluid extracellular vesicles: a comprehensive dataset.
PMID:25466870
Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration.
  • Loss of the BiP co-chaperone DNAJC3 causes an autosomal-recessive syndrome of juvenile-onset diabetes mellitus with multisystem neurodegeneration (ataxia, neuropathy, hearing loss).
Reactome:R-HSA-1791157
Reactome annotation (ER lumen localization of DNAJC3)
Reactome:R-HSA-6798751
Neutrophil degranulation (Reactome)
Reactome:R-HSA-8952289
Reactome annotation (ER lumen localization of DNAJC3)
Reactome:R-HSA-9835454
PKR-mediated signaling (Reactome)

Suggested Questions for Experts

Q: 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?

Q: Which activity loss (BiP co-chaperone versus eIF2-alpha kinase inhibition) drives the beta-cell failure and neurodegeneration in DNAJC3-deficient ACPHD?

Suggested Experiments

Experiment: 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.

Experiment: 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.

📚 Additional Documentation

Notes

(DNAJC3-notes.md)

DNAJC3 (p58IPK / PRKRI / ERdj6) research notes

UniProt: Q13217. 504 aa, precursor (signal 1-31). Domain architecture: 9 TPR repeats (37-373) +
C-terminal J domain (394-462). ER-resident HSP40/J-protein (ERdj6). Crystal structure 2Y4T/2Y4U.

Dual function: BiP/HSP70 co-chaperone AND eIF2-alpha kinase (PKR/PERK/GCN2) inhibitor

  • [UniProt FUNCTION "Involved in the unfolded protein response (UPR) during endoplasmic reticulum (ER)
    stress. Acts as a negative regulator of the EIF2AK4/GCN2 kinase activity by preventing the
    phosphorylation of eIF-2-alpha at 'Ser-52'... Co-chaperone of HSPA8/HSC70, it stimulates its ATPase
    activity. May inhibit both the autophosphorylation of EIF2AK2/PKR and the ability of EIF2AK2 to
    catalyze phosphorylation of the EIF2A. May inhibit EIF2AK3/PERK activity."]
  • PKR inhibition (the original p58IPK function): PMID:8576172; [PMID:8576172 "P58 is a member of the tetratricopeptide"
    family]. => GO:0004860 protein kinase inhibitor activity; GO:0019901 protein kinase binding.
  • ER-stress inducible negative regulator of eIF2alpha: PMID:12601012.
  • HSC70 co-chaperone: forms trimeric complex with DNAJB1 + HSPA8 (PMID:9920933); J domain mediates
    HSPA8 interaction. => GO:0051087 protein-folding chaperone binding.

Disease

  • PMID:25466870 — ACPHD (MIM:616192): juvenile diabetes + ataxia + neuropathy + hearing loss.

Localization

  • ER / ER lumen — CORE (UniProt ISS; Reactome TAS; Ensembl IEA). Note J-domain topology and the
    classic cytosolic PKR-inhibition role mean DNAJC3 is reported in BOTH ER and cytosol.
  • Cytosol / cytoplasm (ISS GO_REF:0000024 from mouse Q91YW3; IEA Ensembl; TAS PMID:8666242 cytoplasm;
    TAS Reactome cytosol). The original p58IPK literature is cytoplasmic (PKR is cytosolic). KEEP_AS_NON_CORE
    (genuine dual localization but ER is primary per current UniProt).
  • Extracellular region / exosome / extracellular vesicle / azurophil granule lumen / membrane —
    secretome/HT proteomics (HDA, TAS Reactome neutrophil degranulation). KEEP_AS_NON_CORE.

Caveats on IMP annotations (PMID:22064321)

  • GO:1902010 neg reg translation in response to ER stress IMP and GO:0043066 neg reg apoptotic process
    IMP both cite PMID:22064321, which is about ERp29 inducing growth arrest with UPREGULATION of p58IPK
    — this is correlative (p58IPK is a downstream marker), not a direct DNAJC3 loss/gain perturbation
    defining these processes. The neg-reg-translation role IS well supported mechanistically (eIF2alpha
    kinase inhibition) so I ACCEPT/KEEP that term but note the apoptosis one is weakly grounded =>
    KEEP_AS_NON_CORE for apoptosis.

MF/BP assignment

  • Core MF: GO:0004860 protein kinase inhibitor activity (inhibits PKR/PERK/GCN2 eIF2alpha kinases).
  • Core MF: GO:0051087 protein-folding chaperone binding / GO:0051787 misfolded protein binding +
    HSPA8 ATPase stimulation (co-chaperone).
  • Core BP: negative regulation of translation / eIF2alpha phosphorylation in response to ER stress;
    protein folding in ER; UPR.

Pn Notes

(DNAJC3-pn-notes.md)

DNAJC3 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q13217
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07b
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • 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/core annotation action counts: ACCEPT: 19; KEEP_AS_NON_CORE: 15

PN Consistency Summary

  • Consistency: Consistent on the chaperone axis, but the PN node captures only half the gene. Notes/YAML describe a dual-function ER J-protein: (1) TPR+J-domain co-chaperone binding BiP (HSPA5)/HSC70 (HSPA8), stimulating their ATPase and binding misfolded substrates via the TPR groove (GO:0051087, GO:0051787 ACCEPT/core); and (2) a stress-inducible inhibitor of the eIF2-alpha kinases PKR/PERK/GCN2 (GO:0004860 protein kinase inhibitor activity, GO:0019901 protein kinase binding ACCEPT/core). The PN "J-domain HSP70 cochaperone" type correctly captures axis (1); the kinase-inhibition axis is outside this node (legitimately, since it is not an HSP70 function).
  • PN story / NEW pressure: PN's HSP70-binding assertion is fully captured (GO:0051087 ACCEPT/core, plus misfolded protein binding). PN-projected GO:0030544 (verified real, child of GO:0051087) is a defensible narrower specialization — DNAJC3 binds HSPA8/BiP directly via its J domain. No NEW proteostasis GO term needed; the second (kinase-inhibitor) function is already richly annotated. Verdict: already captured.
  • Evidence alignment: Review core PMIDs (8576172 PKR inhibition; 25466870 disease/BiP co-chaperone; 8666242/12601012 p58IPK) are dual-function focused; PN frames only the cochaperone half. Complementary, not contradictory.
  • Verdict: CONSISTENT — GO:0030544 sound for the cochaperone axis; PN node intentionally scopes out the (well-captured) eIF2-alpha-kinase-inhibitor function.

Full Consistency Review

  • UniProt: Q13217 (p58IPK/ERdj6/PRKRI) · batch: proteostasis-batch-2026-06-07b · review status: COMPLETE
  • PN placement: ER proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone (branch ER) ; PN-node mapping: type=mapped, scope=ok_for_propagation_to_go, GO:0030544 Hsp70 protein binding (parents no_mapping)
  • Consistency: Consistent on the chaperone axis, but the PN node captures only half the gene. Notes/YAML describe a dual-function ER J-protein: (1) TPR+J-domain co-chaperone binding BiP (HSPA5)/HSC70 (HSPA8), stimulating their ATPase and binding misfolded substrates via the TPR groove (GO:0051087, GO:0051787 ACCEPT/core); and (2) a stress-inducible inhibitor of the eIF2-alpha kinases PKR/PERK/GCN2 (GO:0004860 protein kinase inhibitor activity, GO:0019901 protein kinase binding ACCEPT/core). The PN "J-domain HSP70 cochaperone" type correctly captures axis (1); the kinase-inhibition axis is outside this node (legitimately, since it is not an HSP70 function).
  • PN story / NEW pressure: PN's HSP70-binding assertion is fully captured (GO:0051087 ACCEPT/core, plus misfolded protein binding). PN-projected GO:0030544 (verified real, child of GO:0051087) is a defensible narrower specialization — DNAJC3 binds HSPA8/BiP directly via its J domain. No NEW proteostasis GO term needed; the second (kinase-inhibitor) function is already richly annotated. Verdict: already captured.
  • Mapping strategy: GO:0030544 mapping appropriate; DNAJC3 has direct chaperone-binding evidence so the type-level propagation does not over-reach. The node legitimately omits the eIF2-alpha-kinase-inhibition function, which is not HSP70-system biology.
  • Evidence alignment: Review core PMIDs (8576172 PKR inhibition; 25466870 disease/BiP co-chaperone; 8666242/12601012 p58IPK) are dual-function focused; PN frames only the cochaperone half. Complementary, not contradictory.
  • Verdict: CONSISTENT — GO:0030544 sound for the cochaperone axis; PN node intentionally scopes out the (well-captured) eIF2-alpha-kinase-inhibitor function.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07b
  • review_yaml: genes/human/DNAJC3/DNAJC3-ai-review.yaml
  • PN workbook rows: 1

PN row 1: ER proteostasis | Chaperone | HSP70 system | J-domain containing HSP70 cochaperone

  • UniProt: Q13217
  • In branches: ER
  • PN-node mapping records (path + ancestors):
    • [type] ER proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0030544 Hsp70 protein binding]
      rationale: In the PN hierarchy, this type denotes J-domain cochaperones assigned to the HSP70 system. Their shared mechanistic role is direct interaction with HSP70-family chaperones, making Hsp70 protein binding the most defensible GO target in the current cache.
    • [group] ER proteostasis|Chaperone|HSP70 system
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
    • [class] ER proteostasis|Chaperone
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
    • [branch] ER proteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (1)

  • GO:0030544 Hsp70 protein binding | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=ER proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
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.