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.