DNAJC10 (also called ERdj5 or macrothioredoxin) is an endoplasmic reticulum (ER)-lumenal protein that is both a J-domain co-chaperone and a thioredoxin-family disulfide reductase. It has an N-terminal J domain (with an HPD motif) followed by six thioredoxin-fold domains, four of which carry redox-active CXXC motifs and constitute its reductase active sites. As an enzyme (EC 1.8.4.2), it binds substrate proteins and catalyzes the reduction and removal of improper (non-native) disulfide bonds. Through its J domain it binds the ER Hsp70 chaperone BiP/HSPA5 in an ATP-dependent manner and stimulates its ATPase activity; this BiP interaction is required for DNAJC10 function in both protein folding and degradation. DNAJC10 supports ER protein quality control in two ways. In ER-associated degradation (ERAD) it reduces disulfides in misfolded glycoproteins recognized by EDEM1 to enable their retrotranslocation and degradation, and during productive folding it reduces obligatory non-native disulfides to allow correct maturation of clients such as the LDL receptor. Its expression is induced by ER stress, and it can modulate ER-stress (UPR/apoptotic) signaling.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005788 endoplasmic reticulum lumen | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred ER-lumen localization, consistent with the experimentally established ER-lumenal localization where DNAJC10 acts. Reason: ER lumen is the experimentally supported site of action of this KDEL-retained ER reductase/co-chaperone. Supporting Evidence: file:human/DNAJC10/DNAJC10-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0015035 protein-disulfide reductase activity | IBA GO_REF:0000033 | ACCEPT | Summary: DNAJC10/ERdj5 catalyzes reduction of disulfide bonds in substrate proteins, a core molecular function shared across the orthologous group. Reason: Protein-disulfide reductase activity is the defining catalytic activity of ERdj5, directly demonstrated experimentally (PMID:23769672). Supporting Evidence: PMID:23769672 ERdj5 acts as the ER reductase |
| GO:0016671 oxidoreductase activity, acting on a sulfur group of donors, disulfide as acceptor | IBA GO_REF:0000033 | ACCEPT | Summary: Parent oxidoreductase term describing DNAJC10's disulfide reductase chemistry, inferred phylogenetically and consistent with experimental data. Reason: This oxidoreductase activity accurately captures the disulfide-reductase chemistry of ERdj5. Supporting Evidence: PMID:23769672 ERdj5 acts as the ER reductase |
| GO:0036498 IRE1-mediated unfolded protein response | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically inferred role in the IRE1-mediated UPR. DNAJC10 is induced by ER stress and participates in ER proteostasis, but its direct molecular role is disulfide reduction rather than UPR signal transduction. Reason: UPR involvement is a process-level association downstream of/concurrent with ER stress; not the core catalytic function. Supporting Evidence: file:human/DNAJC10/DNAJC10-uniprot.txt INDUCTION: By endoplasmic reticulum stress. |
| GO:0051787 misfolded protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: DNAJC10 binds misfolded substrate proteins (forming mixed disulfides) prior to reducing their non-native disulfides, a core substrate-recognition function. Reason: Binding of misfolded substrate proteins is directly demonstrated (e.g. misfolded SP-C, LDLR) and is integral to ERdj5's quality-control function. Supporting Evidence: file:human/DNAJC10/DNAJC10-uniprot.txt binds to substrate proteins and specifically catalyzes the reduction and removal of improper (non-native) disulfide bonds |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | ACCEPT | Summary: Automated annotation of ER localization, consistent with the experimentally established ER-resident localization of DNAJC10. Reason: ER localization is well supported experimentally (PMID:12411443 IDA). Supporting Evidence: file:human/DNAJC10/DNAJC10-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000044 | ACCEPT | Summary: Automated subcellular-location transfer of ER-lumen localization, the compartment where DNAJC10 acts. Reason: ER lumen is the experimentally supported compartment of DNAJC10. Supporting Evidence: file:human/DNAJC10/DNAJC10-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0015036 disulfide oxidoreductase activity | IEA GO_REF:0000120 | ACCEPT | Summary: General disulfide oxidoreductase activity, consistent with DNAJC10's thioredoxin-domain redox chemistry. Reason: Disulfide oxidoreductase activity accurately describes the redox chemistry of the thioredoxin domains of ERdj5. Supporting Evidence: file:human/DNAJC10/DNAJC10-uniprot.txt catalyzes the reduction and removal of improper (non-native) disulfide bonds |
| GO:0019153 protein-disulfide reductase (glutathione) activity | IEA GO_REF:0000120 | ACCEPT | Summary: The specific EC 1.8.4.2 reaction (protein-disulfide + 2 glutathione = protein-dithiol + GSSG) catalyzed by DNAJC10, mapped from RHEA/EC. Reason: This is the precise enzymatic reaction (EC 1.8.4.2) assigned to ERdj5 and supported by catalytic-activity evidence. Supporting Evidence: file:human/DNAJC10/DNAJC10-uniprot.txt EC=1.8.4.2 |
| GO:0034975 protein folding in endoplasmic reticulum | IEA GO_REF:0000002 | ACCEPT | Summary: DNAJC10 contributes to ER protein folding by reducing non-native disulfides that would otherwise block correct maturation (e.g. of LDLR). Reason: Direct evidence shows ERdj5 is required for efficient folding of obligatory-non-native-disulfide clients such as LDLR. Supporting Evidence: PMID:23769672 catalyzing the folding of proteins that form obligatory non-native disulfides |
| GO:0005515 protein binding | IPI PMID:19706418 A luminal flavoprotein in endoplasmic reticulum-associated d... | KEEP AS NON CORE | Summary: High-throughput interaction (IntAct WITH FOXRED2, Q8IWF2). The bare protein binding term records a real interaction but is uninformative about function. Reason: Bare protein binding is uninformative; retained as a recorded interaction, not elevated to core. Supporting Evidence: file:human/DNAJC10/DNAJC10-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:19706418 UniProtKB:Q8IWF2 |
| GO:0001671 ATPase activator activity | IEA GO_REF:0000107 | ACCEPT | Summary: As a J-domain protein, DNAJC10 stimulates the ATPase activity of the ER Hsp70 BiP/HSPA5, an activity shared by J proteins. Reason: DNAJC10's J domain stimulates BiP ATPase activity, directly supported by PMID:18400946; this is a core J-domain co-chaperone function. Supporting Evidence: PMID:18400946 this activity is dependent on their ability to stimulate BiP ATPase activity |
| GO:0015035 protein-disulfide reductase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated transfer of protein-disulfide reductase activity, redundant with the experimentally supported (IDA) annotation. Reason: Protein-disulfide reductase activity is the core catalytic function of ERdj5. Supporting Evidence: PMID:23769672 ERdj5 acts as the ER reductase |
| GO:0016671 oxidoreductase activity, acting on a sulfur group of donors, disulfide as acceptor | IEA GO_REF:0000107 | ACCEPT | Summary: Automated transfer of the disulfide-acceptor oxidoreductase parent term, consistent with DNAJC10's reductase chemistry. Reason: Accurately captures the disulfide-reductase chemistry of ERdj5. Supporting Evidence: PMID:23769672 ERdj5 acts as the ER reductase |
| GO:0036503 ERAD pathway | IEA GO_REF:0000120 | ACCEPT | Summary: DNAJC10 functions in ERAD by reducing disulfides in misfolded glycoproteins to enable their retrotranslocation and degradation. Reason: ERAD involvement is directly supported by loss-of-function evidence (PMID:18400946 IMP) and is a core biological process for ERdj5. Supporting Evidence: file:human/DNAJC10/DNAJC10-uniprot.txt DNAJC10 reduces incorrect disulfide bonds specifically in misfolded glycoproteins that have been recognized by EDEM1, a key component of the ERAD pathway, thereby enabling their retrotranslocation and degradation |
| GO:0051087 protein-folding chaperone binding | IEA GO_REF:0000120 | ACCEPT | Summary: DNAJC10 binds the ER Hsp70 chaperone BiP/HSPA5, supporting chaperone-binding function. Reason: Binding of the BiP chaperone is directly documented and integral to DNAJC10's function. Supporting Evidence: file:human/DNAJC10/DNAJC10-uniprot.txt Interacts (via its J domain) with HSPA5 |
| GO:0051117 ATPase binding | IEA GO_REF:0000120 | ACCEPT | Summary: DNAJC10 binds the ATPase BiP/HSPA5 via its J domain; ATPase binding reflects this BiP interaction. Reason: J-domain-mediated binding of the BiP ATPase is experimentally documented; this is a meaningful interaction underlying ERdj5's co-chaperone role. Supporting Evidence: file:human/DNAJC10/DNAJC10-uniprot.txt Interacts (via its J domain) with HSPA5 |
| GO:0005788 endoplasmic reticulum lumen | EXP PMID:12411443 ERdj5, an endoplasmic reticulum (ER)-resident protein contai... | ACCEPT | Summary: Experimental evidence for ER-lumen localization of DNAJC10/ERdj5. Reason: ER lumen is the experimentally established compartment of DNAJC10. Supporting Evidence: PMID:12411443 ERdj5 is a ubiquitous protein localized in the ER |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: High-throughput proteomics detection in a membrane fraction. DNAJC10 is a soluble ER-lumenal protein with no transmembrane region. Reason: Membrane localization from a proteomics dataset conflicts with the soluble, ER-lumenal nature of DNAJC10 and likely reflects fractionation carryover. Supporting Evidence: file:human/DNAJC10/DNAJC10-goa.tsv GO:0016020 membrane cellular_component ECO:0007005 HDA PMID:19946888 |
| GO:0005788 endoplasmic reticulum lumen | IDA PMID:23769672 ERdj5 is the ER reductase that catalyzes the removal of non-... | ACCEPT | Summary: Direct experimental (immunofluorescence) evidence for ER-lumen localization of DNAJC10. Reason: ER lumen is the experimentally supported compartment of DNAJC10's activity. Supporting Evidence: PMID:23769672 localized to the endoplasmic reticulum (ER) |
| GO:0015035 protein-disulfide reductase activity | IDA PMID:23769672 ERdj5 is the ER reductase that catalyzes the removal of non-... | ACCEPT | Summary: Direct experimental demonstration that DNAJC10/ERdj5 reduces disulfide bonds in substrate proteins, the core catalytic function. Reason: Direct evidence establishes protein-disulfide reductase activity as the defining molecular function of ERdj5. Supporting Evidence: PMID:23769672 ERdj5 acts as the ER reductase |
| GO:0016671 oxidoreductase activity, acting on a sulfur group of donors, disulfide as acceptor | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity-based annotation of the disulfide-acceptor oxidoreductase parent term, consistent with the experimental reductase activity. Reason: Accurately captures the disulfide-reductase chemistry of ERdj5. Supporting Evidence: PMID:23769672 ERdj5 acts as the ER reductase |
| GO:0030544 Hsp70 protein binding | IPI PMID:23769672 ERdj5 is the ER reductase that catalyzes the removal of non-... | ACCEPT | Summary: DNAJC10 binds the ER Hsp70 BiP/HSPA5 (P11021) via its J domain, a core co-chaperone molecular function. Reason: Direct J-domain-mediated binding of the ER Hsp70 BiP is central to DNAJC10's co-chaperone activity and is required for its function in folding and degradation. Supporting Evidence: file:human/DNAJC10/DNAJC10-uniprot.txt Interacts (via its J domain) with HSPA5; this interaction is required for DNAJC10 activity in both protein folding and degradation. |
| GO:0034975 protein folding in endoplasmic reticulum | IDA PMID:23769672 ERdj5 is the ER reductase that catalyzes the removal of non-... | ACCEPT | Summary: DNAJC10 is required for efficient folding of clients that form obligatory non-native disulfides (e.g. LDLR) by reducing those disulfides. Reason: Direct evidence places ERdj5 in productive ER protein folding via its reductase activity. Supporting Evidence: PMID:23769672 ERdj5 is required not for degradation, but rather for efficient folding |
| GO:0005783 endoplasmic reticulum | IDA PMID:12411443 ERdj5, an endoplasmic reticulum (ER)-resident protein contai... | ACCEPT | Summary: Direct experimental evidence for ER localization of DNAJC10/ERdj5. Reason: ER localization is experimentally established. Supporting Evidence: PMID:12411443 ERdj5 is a ubiquitous protein localized in the ER |
| GO:0015036 disulfide oxidoreductase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity-based annotation of disulfide oxidoreductase activity, consistent with the experimental reductase function. Reason: Accurately captures the disulfide-redox chemistry of ERdj5's thioredoxin domains. Supporting Evidence: file:human/DNAJC10/DNAJC10-uniprot.txt catalyzes the reduction and removal of improper (non-native) disulfide bonds |
| GO:0034663 endoplasmic reticulum chaperone complex | IDA PMID:18400946 ERdj4 and ERdj5 are required for endoplasmic reticulum-assoc... | ACCEPT | Summary: DNAJC10 is part of an ER chaperone complex (with BiP and other co-chaperones) acting on misfolded substrates such as SP-C. Reason: DNAJC10 associates with BiP and the ERAD machinery in a chaperone complex, supporting this complex annotation. Supporting Evidence: PMID:18400946 ERdj4 and ERdj5 coprecipitated with p97/VCP indicating that the cochaperones remain associated with the misfolded proprotein |
| GO:0051087 protein-folding chaperone binding | IDA PMID:12411443 ERdj5, an endoplasmic reticulum (ER)-resident protein contai... | ACCEPT | Summary: DNAJC10 binds the ER Hsp70 chaperone BiP, directly demonstrated in vitro. Reason: Direct binding of the BiP chaperone is experimentally documented and integral to DNAJC10's function. Supporting Evidence: PMID:12411443 ERdj5 interacts via its DnaJ domain with BiP in an ATP-dependent manner |
| GO:0051117 ATPase binding | IPI PMID:12411443 ERdj5, an endoplasmic reticulum (ER)-resident protein contai... | ACCEPT | Summary: DNAJC10 binds the ATPase BiP/HSPA5 (P11021) via its J domain in an ATP-dependent manner. Reason: J-domain-mediated binding of the BiP ATPase is directly demonstrated and underlies ERdj5's co-chaperone role. Supporting Evidence: PMID:12411443 ERdj5 interacts via its DnaJ domain with BiP in an ATP-dependent manner |
| GO:0034976 response to endoplasmic reticulum stress | IDA PMID:19122239 ERdj5 sensitizes neuroblastoma cells to endoplasmic reticulu... | KEEP AS NON CORE | Summary: DNAJC10 is induced by and functions during ER stress; it can modulate ER-stress signaling. A genuine but non-core process association. Reason: ER-stress response is a process-level context downstream of DNAJC10's core reductase/co-chaperone activity. Supporting Evidence: file:human/DNAJC10/DNAJC10-uniprot.txt INDUCTION: By endoplasmic reticulum stress. |
| GO:0036503 ERAD pathway | IMP PMID:18400946 ERdj4 and ERdj5 are required for endoplasmic reticulum-assoc... | ACCEPT | Summary: Knockdown of DNAJC10/ERdj5 increases ER retention and inhibits degradation of misfolded SP-C, directly establishing its role in ERAD. Reason: Loss-of-function evidence directly establishes DNAJC10's role in ERAD, a core biological process. Supporting Evidence: PMID:18400946 Knockdown of ERdj4 and ERdj5 expression increased ER retention and inhibited degradation of misfolded SP-C |
| GO:0051787 misfolded protein binding | IDA PMID:18400946 ERdj4 and ERdj5 are required for endoplasmic reticulum-assoc... | ACCEPT | Summary: DNAJC10 associates specifically with the misfolded SP-C proprotein, demonstrating misfolded-protein binding. Reason: Direct evidence of specific, prolonged association with a misfolded substrate supports this molecular function. Supporting Evidence: PMID:18400946 exhibited prolonged and specific association with the misfolded proprotein |
| GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress | IDA PMID:19122239 ERdj5 sensitizes neuroblastoma cells to endoplasmic reticulu... | KEEP AS NON CORE | Summary: Overexpressed DNAJC10/ERdj5 promotes ER-stress-induced apoptosis in neuroblastoma cells by down-regulating the UPR. This is an overexpression phenotype. Reason: The pro-apoptotic effect is observed under overexpression and is a context-specific, non-core consequence rather than DNAJC10's primary function. Supporting Evidence: PMID:19122239 ERdj5 promoted apoptosis in tunicamycin, thapsigargin, and bortezomib-treated cells |
| GO:0005515 protein binding | IPI PMID:19815549 Meckel-Gruber syndrome protein MKS3 is required for endoplas... | KEEP AS NON CORE | Summary: High-throughput interaction (IntAct WITH Q5HYA8). The bare protein binding term records a real interaction but is uninformative about function. Reason: Bare protein binding is uninformative; retained as a recorded interaction. Supporting Evidence: file:human/DNAJC10/DNAJC10-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:19815549 UniProtKB:Q5HYA8 |
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Download this section (compressed HTML)Q: What determines whether ERdj5-mediated disulfide reduction commits a client to productive folding (e.g. LDLR) versus ERAD degradation (e.g. misfolded SP-C)?
Q: How is the redox state of ERdj5's four active-site thioredoxin domains maintained in the oxidizing ER, and what supplies the reducing equivalents in vivo?
Experiment: Reconstitute disulfide reduction of a model ERAD substrate in vitro with purified ERdj5 (wild-type vs active-site C/A and J-domain H63Q mutants) and BiP to dissect the contributions of reductase activity and BiP co-chaperone binding.
Experiment: Quantitative interactome and redox proteomics (mixed-disulfide trapping with the C/A mutant) in cells under basal and ER-stress conditions to map the in vivo client repertoire and partition clients between folding and degradation fates.
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