DNAJC10

UniProt ID: Q8IXB1
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

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.

Existing Annotations Review

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

Core Functions

Endoplasmic reticulum disulfide reductase that binds substrate proteins and catalyzes reduction/removal of improper (non-native) disulfide bonds (EC 1.8.4.2), enabling both correct folding and ERAD-targeted degradation.

Molecular Function:
protein-disulfide reductase activity
Cellular Locations:
endoplasmic reticulum lumen
Supporting Evidence:
  • PMID:23769672
    ERdj5 acts as the ER reductase
  • file:human/DNAJC10/DNAJC10-uniprot.txt
    binds to substrate proteins and specifically catalyzes the reduction and removal of improper (non-native) disulfide bonds

J-domain co-chaperone of the ER Hsp70 BiP/HSPA5; binds BiP via its J domain in an ATP-dependent manner and stimulates BiP ATPase activity, an interaction required for DNAJC10 function in folding and degradation.

Molecular Function:
Hsp70 protein binding
Cellular Locations:
endoplasmic reticulum lumen
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.
  • PMID:18400946
    this activity is dependent on their ability to stimulate BiP ATPase activity

Functions in ER-associated degradation (ERAD) by reducing disulfides in misfolded glycoproteins recognized by EDEM1, enabling their retrotranslocation and proteasomal degradation.

Molecular Function:
protein-disulfide reductase activity
Directly Involved In:
ERAD pathway
Cellular Locations:
endoplasmic reticulum lumen
Supporting Evidence:
  • PMID:18400946
    Knockdown of ERdj4 and ERdj5 expression increased ER retention and inhibited degradation of misfolded SP-C

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
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:0000044
Gene Ontology annotation through association of InterPro records with GO terms
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:12411443
ERdj5, an endoplasmic reticulum (ER)-resident protein containing DnaJ and thioredoxin domains, is expressed in secretory cells or following ER stress.
  • ERdj5 is an ER-resident protein with DnaJ, PDI and thioredoxin domains; it interacts via its DnaJ domain with BiP in an ATP-dependent manner and is induced during ER stress.
PMID:18400946
ERdj4 and ERdj5 are required for endoplasmic reticulum-associated protein degradation of misfolded surfactant protein C.
  • ERdj5 shows prolonged specific association with misfolded SP-C and is required for its ERAD; knockdown increases ER retention and inhibits degradation.
  • ERdj5 promotes turnover of misfolded SP-C in a manner dependent on its ability to stimulate BiP ATPase activity.
PMID:19122239
ERdj5 sensitizes neuroblastoma cells to endoplasmic reticulum stress-induced apoptosis.
  • Overexpressed ERdj5 promotes ER-stress-induced apoptosis and down-regulates the UPR by inhibiting PERK-mediated eIF2alpha phosphorylation.
PMID:19706418
A luminal flavoprotein in endoplasmic reticulum-associated degradation.
PMID:19815549
Meckel-Gruber syndrome protein MKS3 is required for endoplasmic reticulum-associated degradation of surfactant protein C.
PMID:19946888
Defining the membrane proteome of NK cells.
PMID:23769672
ERdj5 is the ER reductase that catalyzes the removal of non-native disulfides and correct folding of the LDL receptor.
  • ERdj5 is the ER reductase that removes non-native disulfides, both preparing misfolded proteins for degradation and catalyzing folding of proteins with obligatory non-native disulfides (e.g. LDLR).
  • ERdj5's role in LDLR folding is dependent on its interaction with BiP; the J-domain HPD->QPD (H63Q) mutation prevents BiP binding.
PMID:37739037
Mechanistic characterization of disulfide bond reduction of an ERAD substrate mediated by cooperation between ERdj5 and BiP.
  • ERdj5 cooperates with BiP to reduce disulfide bonds in an ERAD substrate; thioredoxin domain 4 is the most efficient reductase domain.
file:human/DNAJC10/DNAJC10-uniprot.txt
UniProt entry Q8IXB1 (DJC10_HUMAN), Endoplasmic reticulum disulfide reductase DNAJC10 / ERdj5
  • ER disulfide reductase (EC 1.8.4.2) that collaborates with BiP/HSPA5 to reduce non-native disulfides for correct folding or ERAD degradation; J domain binds BiP, four thioredoxin domains are redox-active; ER-lumen localized.

Suggested Questions for Experts

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?

Suggested Experiments

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.

📚 Additional Documentation

Notes

(DNAJC10-notes.md)

DNAJC10 (ERdj5 / Macrothioredoxin) research notes

Identity

  • UniProt Q8IXB1 (DJC10_HUMAN), 793 aa precursor (signal 1-32). HGNC:24637. EC 1.8.4.2.
  • RecName: "Endoplasmic reticulum disulfide reductase DNAJC10". KDEL-type ER retention (790-793).
  • Domain architecture: N-terminal J domain (35-100, HPD motif 63-65) + SIX thioredoxin-fold domains;
    four redox-active Trx domains (Trx1-4) with CXXC active sites (disulfides 158-161, 480-483, 588-591,
    700-703); two redox-inactive Trxb regions. [file:human/DNAJC10/DNAJC10-uniprot.txt FT DOMAIN/DISULFID]
  • Trx domains 3 and 4 are the primary reductase domains (Trx4 most efficient). [uniprot DOMAIN]

DUAL function (the key point): reductase + BiP co-chaperone

  • ER disulfide reductase: binds substrates and catalyzes reduction/removal of non-native (improper)
    disulfide bonds. EC 1.8.4.2 (protein-disulfide + 2 glutathione = protein-dithiol + GSSG).
    PMID:23769672
  • J-domain co-chaperone of BiP/HSPA5 (ER Hsp70): interacts via J domain/HPD in an ATP-dependent manner;
    required for ERdj5 activity in both folding and degradation.
    PMID:12411443
    [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."]
    H63Q (HPD->QPD) prevents BiP binding [uniprot MUTAGEN His-63].

Roles

  • ERAD: reduces disulfides in misfolded glycoproteins recognized by EDEM1, enabling retrotranslocation
    and degradation. [PMID:18400946 "ERdj4 and ERdj5 are required for endoplasmic reticulum-associated
    protein degradation of misfolded surfactant protein C." ; "ERdj4 and ERdj5 promote turnover of
    misfolded SP-C and this activity is dependent on their ability to stimulate BiP ATPase activity."]
  • Productive folding: required for efficient folding/secretion of LDLR by reducing non-native disulfides.
    PMID:23769672
  • ER-stress apoptosis: ERdj5 overexpression promotes ER-stress-induced apoptosis in neuroblastoma by
    down-regulating the UPR. PMID:19122239 -- this is an overexpression phenotype; KEEP_AS_NON_CORE.
  • Cooperation with BiP for ERAD substrate reduction. PMID:37739037

GOA WITH-partner key

  • P11021 = BiP/HSPA5 (ER Hsp70). Q8IWF2 = FOXRED2. Q5HYA8 = ? (interactome).

Review logic

CORE MFs (dual):
- protein-disulfide reductase activity (GO:0015035, IDA PMID:23769672): ACCEPT, CORE.
- Hsp70 protein binding (GO:0030544, IPI BiP): ACCEPT, CORE (J-domain BiP co-chaperone).
Other MF:
- disulfide oxidoreductase activity (GO:0015036, ISS/IEA): ACCEPT (parent of reductase activity).
- oxidoreductase activity acting on sulfur group disulfide acceptor (GO:0016671, IBA/ISS): ACCEPT.
- protein-disulfide reductase (glutathione) activity (GO:0019153, IEA RHEA EC:1.8.4.2): ACCEPT (the EC reaction).
- misfolded protein binding (GO:0051787, IDA/IBA): ACCEPT (binds misfolded substrates).
- protein-folding chaperone binding (GO:0051087, IDA): ACCEPT (binds BiP).
- ATPase binding (GO:0051117, IPI BiP): ACCEPT/KEEP_AS_NON_CORE (binds BiP ATPase; informative-ish).
- ATPase activator activity (GO:0001671, IEA Ensembl): J domain stimulates BiP ATPase -> ACCEPT (supported
by PMID:18400946 "stimulate BiP ATPase activity").
- protein binding (GO:0005515, IPI x2 FOXRED2/Q5HYA8): bare term KEEP_AS_NON_CORE.
BP:
- ERAD pathway (GO:0036503, IMP PMID:18400946 / IEA): ACCEPT, CORE BP.
- protein folding in ER (GO:0034975, IDA): ACCEPT.
- response to ER stress (GO:0034976, IDA): KEEP_AS_NON_CORE.
- IRE1-mediated UPR (GO:0036498, IBA): KEEP_AS_NON_CORE.
- intrinsic apoptotic signaling in response to ER stress (GO:0070059, IDA): KEEP_AS_NON_CORE (overexpression).
CC:
- ER lumen (GO:0005788, IBA/IEA/EXP/IDA): ACCEPT.
- ER (GO:0005783, IEA/IDA): ACCEPT.
- ER chaperone complex (GO:0034663, IDA part_of): ACCEPT.
- membrane (GO:0016020, HDA): MARK_AS_OVER_ANNOTATED (soluble ER-lumenal protein; proteomics fraction).

Pn Notes

(DNAJC10-pn-notes.md)

DNAJC10 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q8IXB1
  • 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: 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.
  • Existing/core annotation action counts: ACCEPT: 28; KEEP_AS_NON_CORE: 5; MARK_AS_OVER_ANNOTATED: 1

PN Consistency Summary

  • Consistency: Row1 is fully consistent — review and notes confirm J-domain binding of BiP/HSPA5 and GO:0030544 is in GOA (already_in_goa_exact is correct). Row2 contains a mechanistic contradiction: PN files ERdj5 under "Protein disulfide isomerases" and projects GO:0003756 (PDI = isomerase activity), but the review, notes, UniProt (RecName "ER disulfide reductase"), and literature (PMID:23769672, PMID:37739037) establish ERdj5 as a disulfide reductase (GO:0015035, EC 1.8.4.2), not an isomerase. The review correctly annotates reductase activity and never asserts GO:0003756.
  • PN story / NEW pressure: GO:0003756 is a verified real term but sits in the isomerase branch (GO:0016853 → GO:0016864 transposing S-S bonds), whereas GO:0015035 is in the oxidoreductase branch (GO:0016491). They are mechanistically distinct. ERdj5 removes/reduces non-native disulfides; it does not rearrange them. Projecting GO:0003756 onto DNAJC10 over-reaches and is the wrong activity. The correct, already-captured term is GO:0015035 (IDA, in GOA).
  • Evidence alignment: PN row carries no titles; review evidence (PMID:12411443, 18400946, 23769672, 37739037 — all verified) uniformly supports reductase + BiP co-chaperone, none supports isomerase activity. Divergence is in the PN group label, not the literature.
  • Verdict: Row1 consistent/captured; Row2 over-reaches (PDI isomerase ≠ ERdj5 reductase). Recommended edits: [MAP] retarget DNAJC10 row2 from GO:0003756 (PDI activity) to GO:0015035 (protein-disulfide reductase activity), or exclude ERdj5 from the "Protein disulfide isomerases" PN group as a reductase exception.

Full Consistency Review

  • UniProt: Q8IXB1 (ERdj5) · batch: proteostasis-batch-2026-06-07b · review status: COMPLETE
  • PN placement: row1 ER proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone (GO:0030544); row2 ER proteostasis|Folding enzyme|Protein disulfide isomerases (group=mapped GO:0003756 protein disulfide isomerase activity, new_to_goa)
  • Consistency: Row1 is fully consistent — review and notes confirm J-domain binding of BiP/HSPA5 and GO:0030544 is in GOA (already_in_goa_exact is correct). Row2 contains a mechanistic contradiction: PN files ERdj5 under "Protein disulfide isomerases" and projects GO:0003756 (PDI = isomerase activity), but the review, notes, UniProt (RecName "ER disulfide reductase"), and literature (PMID:23769672, PMID:37739037) establish ERdj5 as a disulfide reductase (GO:0015035, EC 1.8.4.2), not an isomerase. The review correctly annotates reductase activity and never asserts GO:0003756.
  • PN story / NEW pressure: GO:0003756 is a verified real term but sits in the isomerase branch (GO:0016853 → GO:0016864 transposing S-S bonds), whereas GO:0015035 is in the oxidoreductase branch (GO:0016491). They are mechanistically distinct. ERdj5 removes/reduces non-native disulfides; it does not rearrange them. Projecting GO:0003756 onto DNAJC10 over-reaches and is the wrong activity. The correct, already-captured term is GO:0015035 (IDA, in GOA).
  • Mapping strategy: Row2 group mapping should be reconsidered for ERdj5 — the "Protein disulfide isomerases" PN group conflates reductases with isomerases. For DNAJC10 specifically the propagated term should be GO:0015035 (protein-disulfide reductase activity), not GO:0003756.
  • Evidence alignment: PN row carries no titles; review evidence (PMID:12411443, 18400946, 23769672, 37739037 — all verified) uniformly supports reductase + BiP co-chaperone, none supports isomerase activity. Divergence is in the PN group label, not the literature.
  • Verdict: Row1 consistent/captured; Row2 over-reaches (PDI isomerase ≠ ERdj5 reductase). Recommended edits: [MAP] retarget DNAJC10 row2 from GO:0003756 (PDI activity) to GO:0015035 (protein-disulfide reductase activity), or exclude ERdj5 from the "Protein disulfide isomerases" PN group as a reductase exception.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07b
  • review_yaml: genes/human/DNAJC10/DNAJC10-ai-review.yaml
  • PN workbook rows: 2

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

  • UniProt: Q8IXB1
  • 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.

PN row 2: ER proteostasis | Folding enzyme | Protein disulfide isomerases

  • UniProt: Q8IXB1
  • In branches: ER
  • PN-node mapping records (path + ancestors):
    • [group] ER proteostasis|Folding enzyme|Protein disulfide isomerases
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0003756 protein disulfide isomerase activity]
      rationale: This PN group captures the canonical ER protein-disulfide-isomerase folding enzymes. GO protein disulfide isomerase activity is the cleanest propagation target for the catalytically active family members.
    • [class] ER proteostasis|Folding enzyme
      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 (2)

  • GO:0030544 Hsp70 protein binding | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=ER proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone
  • GO:0003756 protein disulfide isomerase activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Folding enzyme|Protein disulfide isomerases

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: Q8IXB1
gene_symbol: DNAJC10
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
alternative_products:
- name: '1'
  id: Q8IXB1-1
- name: '2'
  id: Q8IXB1-2
  sequence_note: VSP_024011
- name: '3'
  id: Q8IXB1-3
  sequence_note: VSP_054434, VSP_054435
existing_annotations:
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetically inferred ER-lumen localization, consistent with the experimentally established ER-lumenal localization where DNAJC10 acts.
    action: ACCEPT
    reason: ER lumen is the experimentally supported site of action of this KDEL-retained ER reductase/co-chaperone.
    supported_by:
    - reference_id: file:human/DNAJC10/DNAJC10-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0015035
    label: protein-disulfide reductase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: DNAJC10/ERdj5 catalyzes reduction of disulfide bonds in substrate proteins, a core molecular function shared across the orthologous group.
    action: ACCEPT
    reason: Protein-disulfide reductase activity is the defining catalytic activity of ERdj5, directly demonstrated experimentally (PMID:23769672).
    supported_by:
    - reference_id: PMID:23769672
      supporting_text: ERdj5 acts as the ER reductase
- term:
    id: GO:0016671
    label: oxidoreductase activity, acting on a sulfur group of donors, disulfide as acceptor
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Parent oxidoreductase term describing DNAJC10's disulfide reductase chemistry, inferred phylogenetically and consistent with experimental data.
    action: ACCEPT
    reason: This oxidoreductase activity accurately captures the disulfide-reductase chemistry of ERdj5.
    supported_by:
    - reference_id: PMID:23769672
      supporting_text: ERdj5 acts as the ER reductase
- term:
    id: GO:0036498
    label: IRE1-mediated unfolded protein response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: UPR involvement is a process-level association downstream of/concurrent with ER stress; not the core catalytic function.
    supported_by:
    - reference_id: file:human/DNAJC10/DNAJC10-uniprot.txt
      supporting_text: 'INDUCTION: By endoplasmic reticulum stress.'
- term:
    id: GO:0051787
    label: misfolded protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: DNAJC10 binds misfolded substrate proteins (forming mixed disulfides) prior to reducing their non-native disulfides, a core substrate-recognition function.
    action: ACCEPT
    reason: Binding of misfolded substrate proteins is directly demonstrated (e.g. misfolded SP-C, LDLR) and is integral to ERdj5's quality-control function.
    supported_by:
    - reference_id: file:human/DNAJC10/DNAJC10-uniprot.txt
      supporting_text: binds to substrate proteins and specifically catalyzes the reduction and removal of improper (non-native) disulfide bonds
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Automated annotation of ER localization, consistent with the experimentally established ER-resident localization of DNAJC10.
    action: ACCEPT
    reason: ER localization is well supported experimentally (PMID:12411443 IDA).
    supported_by:
    - reference_id: file:human/DNAJC10/DNAJC10-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Automated subcellular-location transfer of ER-lumen localization, the compartment where DNAJC10 acts.
    action: ACCEPT
    reason: ER lumen is the experimentally supported compartment of DNAJC10.
    supported_by:
    - reference_id: file:human/DNAJC10/DNAJC10-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0015036
    label: disulfide oxidoreductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: General disulfide oxidoreductase activity, consistent with DNAJC10's thioredoxin-domain redox chemistry.
    action: ACCEPT
    reason: Disulfide oxidoreductase activity accurately describes the redox chemistry of the thioredoxin domains of ERdj5.
    supported_by:
    - reference_id: file:human/DNAJC10/DNAJC10-uniprot.txt
      supporting_text: catalyzes the reduction and removal of improper (non-native) disulfide bonds
- term:
    id: GO:0019153
    label: protein-disulfide reductase (glutathione) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: The specific EC 1.8.4.2 reaction (protein-disulfide + 2 glutathione = protein-dithiol + GSSG) catalyzed by DNAJC10, mapped from RHEA/EC.
    action: ACCEPT
    reason: This is the precise enzymatic reaction (EC 1.8.4.2) assigned to ERdj5 and supported by catalytic-activity evidence.
    supported_by:
    - reference_id: file:human/DNAJC10/DNAJC10-uniprot.txt
      supporting_text: EC=1.8.4.2
- term:
    id: GO:0034975
    label: protein folding in endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: DNAJC10 contributes to ER protein folding by reducing non-native disulfides that would otherwise block correct maturation (e.g. of LDLR).
    action: ACCEPT
    reason: Direct evidence shows ERdj5 is required for efficient folding of obligatory-non-native-disulfide clients such as LDLR.
    supported_by:
    - reference_id: PMID:23769672
      supporting_text: catalyzing the folding of proteins that form obligatory non-native disulfides
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19706418
  qualifier: enables
  review:
    summary: High-throughput interaction (IntAct WITH FOXRED2, Q8IWF2). The bare protein binding term records a real interaction but is uninformative about function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding is uninformative; retained as a recorded interaction, not elevated to core.
    supported_by:
    - reference_id: file:human/DNAJC10/DNAJC10-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:19706418 UniProtKB:Q8IWF2
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: As a J-domain protein, DNAJC10 stimulates the ATPase activity of the ER Hsp70 BiP/HSPA5, an activity shared by J proteins.
    action: ACCEPT
    reason: DNAJC10's J domain stimulates BiP ATPase activity, directly supported by PMID:18400946; this is a core J-domain co-chaperone function.
    supported_by:
    - reference_id: PMID:18400946
      supporting_text: this activity is dependent on their ability to stimulate BiP ATPase activity
- term:
    id: GO:0015035
    label: protein-disulfide reductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated transfer of protein-disulfide reductase activity, redundant with the experimentally supported (IDA) annotation.
    action: ACCEPT
    reason: Protein-disulfide reductase activity is the core catalytic function of ERdj5.
    supported_by:
    - reference_id: PMID:23769672
      supporting_text: ERdj5 acts as the ER reductase
- term:
    id: GO:0016671
    label: oxidoreductase activity, acting on a sulfur group of donors, disulfide as acceptor
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Automated transfer of the disulfide-acceptor oxidoreductase parent term, consistent with DNAJC10's reductase chemistry.
    action: ACCEPT
    reason: Accurately captures the disulfide-reductase chemistry of ERdj5.
    supported_by:
    - reference_id: PMID:23769672
      supporting_text: ERdj5 acts as the ER reductase
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: DNAJC10 functions in ERAD by reducing disulfides in misfolded glycoproteins to enable their retrotranslocation and degradation.
    action: ACCEPT
    reason: ERAD involvement is directly supported by loss-of-function evidence (PMID:18400946 IMP) and is a core biological process for ERdj5.
    supported_by:
    - reference_id: file:human/DNAJC10/DNAJC10-uniprot.txt
      supporting_text: 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
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: DNAJC10 binds the ER Hsp70 chaperone BiP/HSPA5, supporting chaperone-binding function.
    action: ACCEPT
    reason: Binding of the BiP chaperone is directly documented and integral to DNAJC10's function.
    supported_by:
    - reference_id: file:human/DNAJC10/DNAJC10-uniprot.txt
      supporting_text: Interacts (via its J domain) with HSPA5
- term:
    id: GO:0051117
    label: ATPase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: DNAJC10 binds the ATPase BiP/HSPA5 via its J domain; ATPase binding reflects this BiP interaction.
    action: ACCEPT
    reason: J-domain-mediated binding of the BiP ATPase is experimentally documented; this is a meaningful interaction underlying ERdj5's co-chaperone role.
    supported_by:
    - reference_id: file:human/DNAJC10/DNAJC10-uniprot.txt
      supporting_text: Interacts (via its J domain) with HSPA5
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: EXP
  original_reference_id: PMID:12411443
  qualifier: located_in
  review:
    summary: Experimental evidence for ER-lumen localization of DNAJC10/ERdj5.
    action: ACCEPT
    reason: ER lumen is the experimentally established compartment of DNAJC10.
    supported_by:
    - reference_id: PMID:12411443
      supporting_text: ERdj5 is a ubiquitous protein localized in the ER
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput proteomics detection in a membrane fraction. DNAJC10 is a soluble ER-lumenal protein with no transmembrane region.
    action: MARK_AS_OVER_ANNOTATED
    reason: Membrane localization from a proteomics dataset conflicts with the soluble, ER-lumenal nature of DNAJC10 and likely reflects fractionation carryover.
    supported_by:
    - reference_id: file:human/DNAJC10/DNAJC10-goa.tsv
      supporting_text: GO:0016020 membrane cellular_component ECO:0007005 HDA PMID:19946888
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: IDA
  original_reference_id: PMID:23769672
  qualifier: located_in
  review:
    summary: Direct experimental (immunofluorescence) evidence for ER-lumen localization of DNAJC10.
    action: ACCEPT
    reason: ER lumen is the experimentally supported compartment of DNAJC10's activity.
    supported_by:
    - reference_id: PMID:23769672
      supporting_text: localized to the endoplasmic reticulum (ER)
- term:
    id: GO:0015035
    label: protein-disulfide reductase activity
  evidence_type: IDA
  original_reference_id: PMID:23769672
  qualifier: enables
  review:
    summary: Direct experimental demonstration that DNAJC10/ERdj5 reduces disulfide bonds in substrate proteins, the core catalytic function.
    action: ACCEPT
    reason: Direct evidence establishes protein-disulfide reductase activity as the defining molecular function of ERdj5.
    supported_by:
    - reference_id: PMID:23769672
      supporting_text: ERdj5 acts as the ER reductase
- term:
    id: GO:0016671
    label: oxidoreductase activity, acting on a sulfur group of donors, disulfide as acceptor
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Sequence-similarity-based annotation of the disulfide-acceptor oxidoreductase parent term, consistent with the experimental reductase activity.
    action: ACCEPT
    reason: Accurately captures the disulfide-reductase chemistry of ERdj5.
    supported_by:
    - reference_id: PMID:23769672
      supporting_text: ERdj5 acts as the ER reductase
- term:
    id: GO:0030544
    label: Hsp70 protein binding
  evidence_type: IPI
  original_reference_id: PMID:23769672
  qualifier: enables
  review:
    summary: DNAJC10 binds the ER Hsp70 BiP/HSPA5 (P11021) via its J domain, a core co-chaperone molecular function.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/DNAJC10/DNAJC10-uniprot.txt
      supporting_text: Interacts (via its J domain) with HSPA5; this interaction is required for DNAJC10 activity in both protein folding and degradation.
- term:
    id: GO:0034975
    label: protein folding in endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:23769672
  qualifier: involved_in
  review:
    summary: DNAJC10 is required for efficient folding of clients that form obligatory non-native disulfides (e.g. LDLR) by reducing those disulfides.
    action: ACCEPT
    reason: Direct evidence places ERdj5 in productive ER protein folding via its reductase activity.
    supported_by:
    - reference_id: PMID:23769672
      supporting_text: ERdj5 is required not for degradation, but rather for efficient folding
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:12411443
  qualifier: located_in
  review:
    summary: Direct experimental evidence for ER localization of DNAJC10/ERdj5.
    action: ACCEPT
    reason: ER localization is experimentally established.
    supported_by:
    - reference_id: PMID:12411443
      supporting_text: ERdj5 is a ubiquitous protein localized in the ER
- term:
    id: GO:0015036
    label: disulfide oxidoreductase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Sequence-similarity-based annotation of disulfide oxidoreductase activity, consistent with the experimental reductase function.
    action: ACCEPT
    reason: Accurately captures the disulfide-redox chemistry of ERdj5's thioredoxin domains.
    supported_by:
    - reference_id: file:human/DNAJC10/DNAJC10-uniprot.txt
      supporting_text: catalyzes the reduction and removal of improper (non-native) disulfide bonds
- term:
    id: GO:0034663
    label: endoplasmic reticulum chaperone complex
  evidence_type: IDA
  original_reference_id: PMID:18400946
  qualifier: part_of
  review:
    summary: DNAJC10 is part of an ER chaperone complex (with BiP and other co-chaperones) acting on misfolded substrates such as SP-C.
    action: ACCEPT
    reason: DNAJC10 associates with BiP and the ERAD machinery in a chaperone complex, supporting this complex annotation.
    supported_by:
    - reference_id: PMID:18400946
      supporting_text: ERdj4 and ERdj5 coprecipitated with p97/VCP indicating that the cochaperones remain associated with the misfolded proprotein
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IDA
  original_reference_id: PMID:12411443
  qualifier: enables
  review:
    summary: DNAJC10 binds the ER Hsp70 chaperone BiP, directly demonstrated in vitro.
    action: ACCEPT
    reason: Direct binding of the BiP chaperone is experimentally documented and integral to DNAJC10's function.
    supported_by:
    - reference_id: PMID:12411443
      supporting_text: ERdj5 interacts via its DnaJ domain with BiP in an ATP-dependent manner
- term:
    id: GO:0051117
    label: ATPase binding
  evidence_type: IPI
  original_reference_id: PMID:12411443
  qualifier: enables
  review:
    summary: DNAJC10 binds the ATPase BiP/HSPA5 (P11021) via its J domain in an ATP-dependent manner.
    action: ACCEPT
    reason: J-domain-mediated binding of the BiP ATPase is directly demonstrated and underlies ERdj5's co-chaperone role.
    supported_by:
    - reference_id: PMID:12411443
      supporting_text: ERdj5 interacts via its DnaJ domain with BiP in an ATP-dependent manner
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IDA
  original_reference_id: PMID:19122239
  qualifier: involved_in
  review:
    summary: DNAJC10 is induced by and functions during ER stress; it can modulate ER-stress signaling. A genuine but non-core process association.
    action: KEEP_AS_NON_CORE
    reason: ER-stress response is a process-level context downstream of DNAJC10's core reductase/co-chaperone activity.
    supported_by:
    - reference_id: file:human/DNAJC10/DNAJC10-uniprot.txt
      supporting_text: 'INDUCTION: By endoplasmic reticulum stress.'
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:18400946
  qualifier: involved_in
  review:
    summary: Knockdown of DNAJC10/ERdj5 increases ER retention and inhibits degradation of misfolded SP-C, directly establishing its role in ERAD.
    action: ACCEPT
    reason: Loss-of-function evidence directly establishes DNAJC10's role in ERAD, a core biological process.
    supported_by:
    - reference_id: PMID:18400946
      supporting_text: Knockdown of ERdj4 and ERdj5 expression increased ER retention and inhibited degradation of misfolded SP-C
- term:
    id: GO:0051787
    label: misfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:18400946
  qualifier: enables
  review:
    summary: DNAJC10 associates specifically with the misfolded SP-C proprotein, demonstrating misfolded-protein binding.
    action: ACCEPT
    reason: Direct evidence of specific, prolonged association with a misfolded substrate supports this molecular function.
    supported_by:
    - reference_id: PMID:18400946
      supporting_text: exhibited prolonged and specific association with the misfolded proprotein
- term:
    id: GO:0070059
    label: intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
  evidence_type: IDA
  original_reference_id: PMID:19122239
  qualifier: involved_in
  review:
    summary: Overexpressed DNAJC10/ERdj5 promotes ER-stress-induced apoptosis in neuroblastoma cells by down-regulating the UPR. This is an overexpression phenotype.
    action: KEEP_AS_NON_CORE
    reason: The pro-apoptotic effect is observed under overexpression and is a context-specific, non-core consequence rather than DNAJC10's primary function.
    supported_by:
    - reference_id: PMID:19122239
      supporting_text: ERdj5 promoted apoptosis in tunicamycin, thapsigargin, and bortezomib-treated cells
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19815549
  qualifier: enables
  review:
    summary: High-throughput interaction (IntAct WITH Q5HYA8). The bare protein binding term records a real interaction but is uninformative about function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding is uninformative; retained as a recorded interaction.
    supported_by:
    - reference_id: file:human/DNAJC10/DNAJC10-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:19815549 UniProtKB:Q5HYA8
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- 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:0000044
  title: Gene Ontology annotation through association of InterPro records with GO terms
  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:12411443
  title: ERdj5, an endoplasmic reticulum (ER)-resident protein containing DnaJ and thioredoxin domains, is expressed in secretory cells or following ER stress.
  findings:
  - statement: ERdj5 is an ER-resident protein with DnaJ, PDI and thioredoxin domains; it interacts via its DnaJ domain with BiP in an ATP-dependent manner and is induced during ER stress.
    reference_section_type: ABSTRACT
- id: PMID:18400946
  title: ERdj4 and ERdj5 are required for endoplasmic reticulum-associated protein degradation of misfolded surfactant protein C.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed; body confirms ERdj5/DNAJC10 is required for ERAD of misfolded substrate and acts via stimulation of BiP ATPase. GOA anchors this PMID to GO:0036503 (ERAD pathway, IMP), GO:0034663 and GO:0051787, supporting DNAJC10's ER-chaperone/ERAD role.
  findings:
  - statement: ERdj5 shows prolonged specific association with misfolded SP-C and is required for its ERAD; knockdown increases ER retention and inhibits degradation.
    reference_section_type: ABSTRACT
  - statement: ERdj5 promotes turnover of misfolded SP-C in a manner dependent on its ability to stimulate BiP ATPase activity.
    reference_section_type: ABSTRACT
- id: PMID:19122239
  title: ERdj5 sensitizes neuroblastoma cells to endoplasmic reticulum stress-induced apoptosis.
  findings:
  - statement: Overexpressed ERdj5 promotes ER-stress-induced apoptosis and down-regulates the UPR by inhibiting PERK-mediated eIF2alpha phosphorylation.
    reference_section_type: ABSTRACT
- id: PMID:19706418
  title: A luminal flavoprotein in endoplasmic reticulum-associated degradation.
  findings: []
- id: PMID:19815549
  title: Meckel-Gruber syndrome protein MKS3 is required for endoplasmic reticulum-associated degradation of surfactant protein C.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:23769672
  title: ERdj5 is the ER reductase that catalyzes the removal of non-native disulfides and correct folding of the LDL receptor.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed; body confirms ERdj5/DNAJC10 is the ER protein-disulfide reductase that removes non-native disulfides and folds LDLR in a BiP-dependent manner. GOA anchors this PMID to GO:0015035 (protein-disulfide reductase activity, IDA) - the core MF.
  findings:
  - statement: ERdj5 is the ER reductase that removes non-native disulfides, both preparing misfolded proteins for degradation and catalyzing folding of proteins with obligatory non-native disulfides (e.g. LDLR).
    reference_section_type: ABSTRACT
  - statement: ERdj5's role in LDLR folding is dependent on its interaction with BiP; the J-domain HPD->QPD (H63Q) mutation prevents BiP binding.
    reference_section_type: RESULTS
- id: PMID:37739037
  title: Mechanistic characterization of disulfide bond reduction of an ERAD substrate mediated by cooperation between ERdj5 and BiP.
  findings:
  - statement: ERdj5 cooperates with BiP to reduce disulfide bonds in an ERAD substrate; thioredoxin domain 4 is the most efficient reductase domain.
    reference_section_type: ABSTRACT
- id: file:human/DNAJC10/DNAJC10-uniprot.txt
  title: UniProt entry Q8IXB1 (DJC10_HUMAN), Endoplasmic reticulum disulfide reductase DNAJC10 / ERdj5
  findings:
  - statement: ER disulfide reductase (EC 1.8.4.2) that collaborates with BiP/HSPA5 to reduce non-native disulfides for correct folding or ERAD degradation; J domain binds BiP, four thioredoxin domains are redox-active; ER-lumen localized.
    reference_section_type: OTHER
core_functions:
- description: Endoplasmic reticulum disulfide reductase that binds substrate proteins and catalyzes reduction/removal of improper (non-native) disulfide bonds (EC 1.8.4.2), enabling both correct folding and ERAD-targeted degradation.
  molecular_function:
    id: GO:0015035
    label: protein-disulfide reductase activity
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  supported_by:
  - reference_id: PMID:23769672
    supporting_text: ERdj5 acts as the ER reductase
  - reference_id: file:human/DNAJC10/DNAJC10-uniprot.txt
    supporting_text: binds to substrate proteins and specifically catalyzes the reduction and removal of improper (non-native) disulfide bonds
- description: J-domain co-chaperone of the ER Hsp70 BiP/HSPA5; binds BiP via its J domain in an ATP-dependent manner and stimulates BiP ATPase activity, an interaction required for DNAJC10 function in folding and degradation.
  molecular_function:
    id: GO:0030544
    label: Hsp70 protein binding
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  supported_by:
  - reference_id: file:human/DNAJC10/DNAJC10-uniprot.txt
    supporting_text: Interacts (via its J domain) with HSPA5; this interaction is required for DNAJC10 activity in both protein folding and degradation.
  - reference_id: PMID:18400946
    supporting_text: this activity is dependent on their ability to stimulate BiP ATPase activity
- description: Functions in ER-associated degradation (ERAD) by reducing disulfides in misfolded glycoproteins recognized by EDEM1, enabling their retrotranslocation and proteasomal degradation.
  molecular_function:
    id: GO:0015035
    label: protein-disulfide reductase activity
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  supported_by:
  - reference_id: PMID:18400946
    supporting_text: Knockdown of ERdj4 and ERdj5 expression increased ER retention and inhibited degradation of misfolded SP-C
  directly_involved_in:
  - id: GO:0036503
    label: ERAD pathway
proposed_new_terms: []
suggested_questions:
- question: What determines whether ERdj5-mediated disulfide reduction commits a client to productive folding (e.g. LDLR) versus ERAD degradation (e.g. misfolded SP-C)?
- question: 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?
suggested_experiments:
- description: 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.
- description: 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.