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).
| 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 |
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Download this section (compressed HTML)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?
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.
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