{"gene":"DNAJC10","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2002,"finding":"ERdj5 (DNAJC10) interacts with BiP via its DnaJ domain in an ATP-dependent manner, and localizes to the ER lumen; it contains DnaJ, protein-disulfide isomerase, and thioredoxin domains.","method":"In vitro binding assay (DnaJ domain-BiP interaction), immunofluorescence/subcellular fractionation for ER localization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro interaction demonstrated, ER localization confirmed, single lab with two orthogonal methods","pmids":["12411443"],"is_preprint":false},{"year":2008,"finding":"ERdj5 functions as a disulfide reductase that cleaves disulfide bonds of misfolded proteins in the ER, physically associates with EDEM and BiP as part of a supramolecular ERAD complex, and accelerates retrotranslocation of ERAD substrates.","method":"In vitro reductase assay, co-immunoprecipitation (ERdj5-EDEM and ERdj5-BiP), siRNA knockdown with ERAD substrate degradation readout","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro enzymatic assay plus reciprocal co-IP plus functional knockdown, replicated across multiple approaches in the same study","pmids":["18653895"],"is_preprint":false},{"year":2008,"finding":"ERdj5 and ERdj4 associate with misfolded surfactant protein C (SP-C) and coprecipitate with p97/VCP, remaining associated until substrate dislocation to the cytosol; HPD motif mutations abolishing BiP ATPase stimulation prevent ERdj5-mediated ERAD of misfolded SP-C.","method":"Co-immunoprecipitation, siRNA knockdown with ERAD readout, dominant-negative HPD mutant rescue experiment in XBP1−/− MEFs","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional knockdown, mutagenesis rescue, two independent orthogonal approaches in same study","pmids":["18400946"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of full-length ERdj5 revealed an N-terminal J domain followed by six tandem thioredoxin domains organized into N- and C-terminal clusters; the C-terminal cluster forms the highly reducing platform that interacts with EDEM1 and reduces EDEM1-recruited ERAD substrates; pulse-chase experiments showed sequential substrate movement from calnexin → EDEM1-ERdj5 complex → retrotranslocation channel via BiP.","method":"X-ray crystallography, systematic biochemical analyses (reductase activity, binding assays), pulse-chase experiment","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with biochemical functional validation and pulse-chase, multiple orthogonal methods in one rigorous study","pmids":["21329881"],"is_preprint":false},{"year":2007,"finding":"Knockdown of ERdj5 by RNA interference in neuroectodermal tumour cells increased the apoptotic response to fenretinide, indicating ERdj5 normally protects against ER stress-induced apoptosis in these cells.","method":"siRNA knockdown with apoptosis readout (cell viability, apoptosis assays) following fenretinide treatment","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional knockdown with specific phenotypic readout, single lab, limited mechanistic depth","pmids":["17353921"],"is_preprint":false},{"year":2009,"finding":"ERdj5 overexpression sensitizes neuroblastoma cells to ER stress-induced apoptosis by abolishing eIF2α phosphorylation and inactivating PERK, thereby compromising the integrated stress response; ER-targeted Bcl-2 prevented this apoptosis, confirming ER-stress-regulated apoptosis pathway.","method":"Overexpression with ER stress inducers, phosphorylation assays (eIF2α), ER-targeted Bcl-2 rescue experiment","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression with pathway readout and genetic rescue, single lab, two orthogonal methods","pmids":["19122239"],"is_preprint":false},{"year":2009,"finding":"ERdj5 knockout mice show activated ER stress responses specifically in salivary glands; re-expression of ERdj5 (but not thioredoxin-like motif mutants) mitigated ER stress caused by overproduction of alpha-amylase, demonstrating that ERdj5's reductase activity is required for ER quality control in secretory cells in vivo.","method":"ERdj5 knockout mouse generation and analysis, ER stress markers (qPCR/western), rescue with wild-type vs thioredoxin-motif mutant ERdj5","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout mouse with defined phenotype, functional rescue with domain mutants demonstrating mechanism, multiple orthogonal methods","pmids":["19788412"],"is_preprint":false},{"year":2013,"finding":"ERdj5 forms mixed disulfides with multiple endogenous ER client proteins including the LDL receptor (LDLR); for LDLR, ERdj5 reduces non-native disulfides formed during productive folding (not only for ERAD), and this function requires ERdj5's interaction with BiP.","method":"Trapping of mixed disulfides (substrate trapping mutant), co-immunoprecipitation, LDLR folding assay, BiP interaction analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — substrate trapping combined with functional folding assays and interaction studies, multiple orthogonal methods, extends substrate repertoire beyond ERAD","pmids":["23769672"],"is_preprint":false},{"year":2013,"finding":"ERdj5 interacts directly with the Sel1L N-terminal lumenal domain, linking it to the Hrd1 ERAD complex; ERdj5 promotes CTA1 retrotranslocation partly via its J domain by regulating BiP-CTA interaction proximal to the Hrd1 complex.","method":"Co-immunoprecipitation (ERdj5-Sel1L interaction), loss-of-function and gain-of-function approaches, retrotranslocation assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional assays (loss/gain of function), single lab, two orthogonal methods","pmids":["23363602"],"is_preprint":false},{"year":2013,"finding":"Redox partners of ERdj5 were identified from mouse epididymis tissue by combining acid quenching and thiol-alkylation to capture disulfide-linked complexes; two identified proteins were confirmed to interact with ERdj5 via intermolecular disulfide bonds in vivo.","method":"Acid quenching, thiol-alkylation, affinity purification followed by mass spectrometry, validation by western blot of disulfide-linked complexes","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo tissue trapping method with MS identification plus biochemical validation, single lab","pmids":["24055038"],"is_preprint":false},{"year":2013,"finding":"In C. elegans, dnj-27/ERdj5 ortholog is an ER luminal protein whose expression is induced by ER stress via IRE-1/XBP-1; its knockdown increases aggregation and pathological phenotypes of Aβ, α-synuclein, and polyQ proteins, and causes mitochondrial fragmentation.","method":"RNAi knockdown in C. elegans disease models, fluorescence microscopy of protein aggregation, motility/paralysis assays, mitochondrial morphology analysis","journal":"Antioxidants & redox signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined phenotypic readouts, multiple disease models, C. elegans ortholog study","pmids":["23641861"],"is_preprint":false},{"year":2014,"finding":"ERdj5 (DNAJC10) regulates P23H rod opsin biogenesis; overexpression promoted degradation and prevented aggregation of P23H rod opsin, while shRNA knockdown delayed degradation and promoted aggregation; both reductase and co-chaperone activities of ERdj5 were required, and mutations in these domains acted as dominant negatives affecting wild-type rod opsin biogenesis.","method":"Overexpression and shRNA knockdown with fluorescence microscopy (FRAP, aggregation), domain mutant analysis including dominant negative effects, ER retention assays","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with domain mutants demonstrating mechanistic requirements, single lab","pmids":["25055872"],"is_preprint":false},{"year":2015,"finding":"ERdj5 reduces disulfide bonds of SV40 virus in the ER lumen, a reaction required for ER membrane transport and infection; ERdj5 cooperates with PDI to induce structural rearrangements in SV40 enabling engagement of BAP31 for membrane penetration; ERdj5 also mediates BK PyV infection.","method":"Loss-of-function (siRNA), infection assays, negative-stain electron microscopy of ER-localized SV40, co-immunoprecipitation (SV40-BAP31)","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with EM structural evidence and infection readout, single lab, two orthogonal methods","pmids":["26085143"],"is_preprint":false},{"year":2016,"finding":"ERdj5 activates SERCA2b calcium pump function by reducing its luminal disulfide bond; at lower ER luminal Ca2+ concentrations ERdj5 is active, while higher Ca2+ induces ERdj5 oligomerization preventing SERCA2b interaction; BiP binding to the J domain of ERdj5 regulates this oligomerization, providing Ca2+-dependent feedback regulation of ER Ca2+ homeostasis.","method":"In vitro reductase activity assay, SERCA2b activity assay, co-immunoprecipitation, Ca2+ measurement, oligomerization analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro enzymatic reconstitution of SERCA2b activation, mechanistic dissection of oligomerization regulation by Ca2+ and BiP, multiple orthogonal methods in one study","pmids":["27694578"],"is_preprint":false},{"year":2017,"finding":"A new crystal structure of ERdj5 revealed a largely different cluster arrangement relative to the original structure; high-speed atomic force microscopy showed rapid cluster movement around the flexible linker loop; ERdj5 mutants with fixed-cluster orientation compromised ERAD enhancement activity, indicating that conformational dynamics are required for efficient reduction of aberrantly formed disulfide bonds and substrate transfer.","method":"X-ray crystallography, high-speed atomic force microscopy (single-molecule observation), ERAD activity assays with fixed-cluster mutants","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus single-molecule imaging plus functional mutagenesis, multiple orthogonal high-quality methods in one study","pmids":["28479060"],"is_preprint":false},{"year":2019,"finding":"ERdj5 ablation in mice produces a Sjögren's syndrome-like phenotype including spontaneous inflammation in salivary glands with T and B lymphocyte infiltration, reduced saliva flow, production of anti-SSA/Ro and anti-SSB/La autoantibodies, and a distinct cytokine signature, demonstrating ERdj5 is required for salivary gland homeostasis and prevention of autoimmune inflammatory responses.","method":"ERdj5 knockout mouse model, histopathology, serological assays (ANA, cytokine profiling), saliva flow rate measurement","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout with multiple defined phenotypic readouts, single lab","pmids":["30967862"],"is_preprint":false},{"year":2019,"finding":"ERdj5 in innate immune cells (particularly dendritic cells) is required for full immune activation by cholera toxin; ERdj5-knockout DCs show decreased costimulatory molecule expression (MHC II, CD80, CD86) and reduced pro-inflammatory cytokine secretion (IL-1β, TNF-α, IL-6), and ERdj5 KO mice show impaired antigen-specific IgG/IgA responses after CT immunization, specifically through CTA1 retro-translocation.","method":"ERdj5 knockout mouse model, DC activation assays (flow cytometry, ELISA), intranasal immunization with CT, cytokine profiling","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout with multiple immune readouts, single lab","pmids":["31275300"],"is_preprint":false},{"year":2020,"finding":"AAV-mediated overexpression of ERdj5 in P23H-3 rats reduced visual function loss and preserved photoreceptor cells, correlating with reduced rhodopsin retention in the outer nuclear layer, demonstrating in vivo therapeutic benefit of ERdj5 overexpression for P23H rhodopsin-mediated retinal degeneration.","method":"AAV subretinal injection, electroretinogram (ERG), optical coherence tomography, outer nuclear layer morphometry, rhodopsin immunolocalization","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gene augmentation with multiple functional and structural readouts, single lab","pmids":["32196553"],"is_preprint":false},{"year":2021,"finding":"ERdj5 deletion causes intracellular Ca2+ imbalance, which activates Drp1 (a cytosolic GTPase involved in mitochondrial fission), leading to aberrant mitochondrial fragmentation and a cellular senescence phenotype, demonstrating that ERdj5-mediated Ca2+ regulation is essential for mitochondrial homeostasis.","method":"ERdj5 knockout cell lines, Ca2+ measurement, Drp1 activation assays (phosphorylation), mitochondrial morphology (fluorescence microscopy), senescence markers","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic deletion with mechanistic pathway readout (Ca2+→Drp1→mitochondrial fission), single lab, multiple assays","pmids":["34728782"],"is_preprint":false},{"year":2022,"finding":"ERdj5 (Dnajc10) loss in mice exacerbates alcohol-induced liver injury and promotes oxidative stress; mechanistically, ERdj5 deficiency reduces nuclear Nrf2 and downstream antioxidant gene expression, and decreases hepatic glutathione content, placing ERdj5 upstream of the Nrf2 antioxidant pathway.","method":"Dnajc10 knockout mouse (chronic-binge ethanol model), H2O2 measurement, Nrf2 nuclear fractionation/western blot, antioxidant gene expression (qRT-PCR), glutathione assay","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout with mechanistic pathway readout (Nrf2 nuclear translocation), single lab, multiple orthogonal assays","pmids":["35390453"],"is_preprint":false},{"year":2023,"finding":"ERdj5 and BiP cooperate in a reconstituted in vitro system to reduce disulfide-linked J-chain oligomers in a stepwise manner (large oligomers → trimers → dimers → monomers); BiP synergistically enhances ERdj5-mediated reduction in an ATP-dependent manner; single-molecule AFM showed stochastic release of small oligomers through repeated ERdj5 actions on peripheral/flexible regions of aggregates; systematic mutagenesis dissected the molecular requirements.","method":"In vitro reconstitution with purified proteins, biochemical reduction assays, high-speed atomic force microscopy (single-molecule), systematic mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified proteins plus single-molecule imaging plus mutagenesis, multiple rigorous orthogonal methods in one study","pmids":["37739037"],"is_preprint":false},{"year":2023,"finding":"ERdj5 (DNAJC10) functions specifically as a reductase (not isomerase) in ER disulfide bond processing; ERp57 is required for isomerisation of non-native disulfides in glycoproteins; ERdj5 is required to provide the reductive pathway that enables alternative PDIs to compensate for absence of ERp57, indicating ERdj5's essential cellular function is reduction of non-native disulfides.","method":"Knockout cell lines (ERdj5 and ERp57), disulfide bond formation/isomerization assays, metabolic labeling, substrate folding analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout cells with defined biochemical readouts distinguishing reduction vs isomerization, replication of ERdj5 reductase role, multiple orthogonal approaches","pmids":["36655611"],"is_preprint":false},{"year":2024,"finding":"DNAJC10 deficiency in AML specifically induces ER stress and activates the PERK-EIF2α-ATF4 branch of the UPR, leading to apoptosis of leukemia stem cells; blocking PERK (with GSK2606414 or shRNA) rescued the DNAJC10 loss-of-function phenotype both in vitro and in vivo, placing DNAJC10 upstream of PERK in the UPR.","method":"shRNA knockdown and CRISPR knockout in human AML lines and LSC-enriched populations, MLL-AF9 murine leukemia model in Dnajc10 knockout mice, PERK inhibitor rescue (GSK2606414), apoptosis assays, UPR pathway analysis","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (PERK inhibitor rescues DNAJC10 KO phenotype) in vitro and in vivo, single lab, two orthogonal approaches","pmids":["37496439"],"is_preprint":false},{"year":2025,"finding":"DNAJC10 overexpression suppresses EGFR transcription in glioblastoma by inhibiting the IRE1α-XBP-1s axis of the UPR; XBP-1s binds the EGFR promoter and recruits SET7/9 methyltransferase, promoting H3K4me3 and H3K4me1 marks; XBP-1s overexpression reverses DNAJC10-mediated EGFR downregulation; pharmacological histone methylation inhibition attenuates XBP-1s-induced EGFR transcription.","method":"Overexpression and knockdown of DNAJC10, XBP-1s overexpression rescue, ChIP (XBP-1s binding to EGFR promoter, H3K4me3/me1), pharmacological inhibition of histone methylation, in vitro and xenograft invasion assays","journal":"Molecular biomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue (XBP-1s reverses DNAJC10 effect), ChIP evidence, pharmacological validation, single lab, multiple orthogonal methods","pmids":["41191192"],"is_preprint":false}],"current_model":"DNAJC10 (ERdj5) is an ER-resident protein disulfide reductase and BiP co-chaperone that, through its N-terminal J domain and six tandem thioredoxin domains, accelerates ERAD by reducing incorrect disulfide bonds in misfolded glycoproteins recognized by EDEM1, promotes productive folding of clients such as the LDL receptor, activates the ER calcium pump SERCA2b by reducing its luminal disulfide bond (with activity regulated by ER Ca2+ levels and BiP-dependent oligomerization), and facilitates retrotranslocation of bacterial toxins and viruses; its conformational dynamics are essential for substrate disaggregation, and loss of ERdj5 function disrupts Ca2+ homeostasis, activates Drp1-mediated mitochondrial fragmentation, sensitizes cells to PERK-dependent ER stress, and in vivo causes salivary gland dysfunction and Sjögren's syndrome-like autoimmunity."},"narrative":{"mechanistic_narrative":"DNAJC10 (ERdj5) is an ER-resident protein disulfide reductase and BiP co-chaperone that couples disulfide reduction to ER quality control, secretory homeostasis, and Ca2+ regulation [PMID:18653895, PMID:19788412]. It is organized as an N-terminal J domain that binds BiP in an ATP-dependent manner followed by six tandem thioredoxin domains arranged into N- and C-terminal clusters, with the C-terminal cluster forming a highly reducing platform that engages EDEM1 and reduces EDEM1-recruited misfolded substrates [PMID:12411443, PMID:21329881]. Through this activity ERdj5 acts within a supramolecular ERAD complex with EDEM, BiP, and the Hrd1 component Sel1L, cleaving non-native disulfide bonds in misfolded glycoproteins and accelerating their retrotranslocation from the calnexin cycle to the dislocation channel [PMID:18653895, PMID:21329881, PMID:23363602]. Its physiological role is reduction rather than isomerization of non-native disulfides, providing the reductive pathway that lets alternative PDIs compensate when ERp57 is absent [PMID:36655611]. Beyond ERAD, ERdj5 reduces non-native disulfides during productive folding of clients including the LDL receptor and P23H rod opsin, and activates the SERCA2b calcium pump by reducing its luminal disulfide bond, with this activity switched off at high luminal Ca2+ through BiP-regulated oligomerization to provide feedback control of ER Ca2+ homeostasis [PMID:23769672, PMID:25055872, PMID:27694578]. Conformational dynamics of the thioredoxin clusters around a flexible linker are required for efficient substrate reduction and for stepwise disaggregation of disulfide-linked oligomers in cooperation with BiP [PMID:28479060, PMID:37739037]. Loss of ERdj5 disrupts Ca2+ balance and triggers Drp1-mediated mitochondrial fragmentation and senescence, sensitizes cells to PERK-dependent ER stress, and in mice causes salivary gland ER stress and a Sjögren's syndrome-like autoimmune phenotype [PMID:19788412, PMID:30967862, PMID:34728782, PMID:37496439]. ERdj5 also reduces disulfide bonds of SV40 and facilitates retrotranslocation of cholera toxin CTA1, linking it to viral infection and toxin-driven immune activation [PMID:26085143, PMID:31275300].","teleology":[{"year":2002,"claim":"Established that ERdj5 is an ER luminal protein and a bona fide BiP co-chaperone, defining its domain architecture and placing it in the Hsp70 chaperone cycle.","evidence":"In vitro DnaJ domain-BiP binding assay plus immunofluorescence/fractionation in cells","pmids":["12411443"],"confidence":"Medium","gaps":["Enzymatic activity of the thioredoxin domains undefined","No substrate identified","BiP interaction shown in vitro only"]},{"year":2007,"claim":"First functional context: ERdj5 protects cells against ER stress-induced apoptosis, linking it to cell survival under proteostatic stress.","evidence":"siRNA knockdown with apoptosis readout after fenretinide in neuroectodermal tumour cells","pmids":["17353921"],"confidence":"Medium","gaps":["Molecular mechanism of protection not defined","Single cell type","Does not connect to disulfide chemistry"]},{"year":2008,"claim":"Defined ERdj5's core biochemical activity as a disulfide reductase acting within an EDEM-BiP ERAD complex to accelerate retrotranslocation of misfolded substrates.","evidence":"In vitro reductase assay, reciprocal Co-IP (EDEM, BiP), siRNA with ERAD degradation readout; parallel SP-C/p97 study with HPD-motif mutant rescue","pmids":["18653895","18400946"],"confidence":"High","gaps":["Structural basis of substrate selection unknown","How reduction is coordinated with dislocation channel unclear"]},{"year":2009,"claim":"Established physiological requirement in vivo and a dose-dependent influence on the UPR: reductase activity is needed for ER quality control in secretory cells, while overexpression compromises PERK/eIF2α-mediated stress signaling.","evidence":"ERdj5 knockout mice (salivary gland ER stress, mutant rescue) and overexpression studies with eIF2α phosphorylation and ER-targeted Bcl-2 rescue","pmids":["19788412","19122239"],"confidence":"High","gaps":["Tissue specificity of salivary gland phenotype unexplained","Mechanistic link between ERdj5 levels and PERK not resolved"]},{"year":2011,"claim":"Solved the full-length structure and ordered the ERAD pathway, showing the C-terminal thioredoxin cluster as the reducing platform receiving EDEM1-recruited substrates en route from calnexin to BiP-mediated retrotranslocation.","evidence":"X-ray crystallography, reductase/binding assays, pulse-chase substrate tracking","pmids":["21329881"],"confidence":"High","gaps":["Conformational behavior in solution not addressed","Dynamics of substrate handoff not captured by static structure"]},{"year":2013,"claim":"Broadened ERdj5 function beyond ERAD to productive folding and connected it to the Hrd1 complex and toxin retrotranslocation, while in-vivo trapping mapped endogenous disulfide partners.","evidence":"Mixed-disulfide trapping with LDLR folding assays; Sel1L Co-IP with CTA1 retrotranslocation; tissue disulfide-partner capture with MS validation","pmids":["23769672","23363602","24055038"],"confidence":"Medium","gaps":["Full client repertoire still incomplete","How ERdj5 distinguishes folding from degradative reduction unclear"]},{"year":2013,"claim":"Demonstrated conserved cytoprotective function of the ERdj5 ortholog and an early link to mitochondrial integrity and proteotoxicity.","evidence":"RNAi in C. elegans dnj-27 disease models with aggregation, motility, and mitochondrial morphology readouts","pmids":["23641861"],"confidence":"Medium","gaps":["Mechanism of mitochondrial fragmentation not defined in this model","Ortholog findings not yet mapped to mammalian biochemistry"]},{"year":2014,"claim":"Showed ERdj5 controls biogenesis of a disease-relevant client (P23H rod opsin) requiring both reductase and co-chaperone activities, with domain mutants acting as dominant negatives.","evidence":"Overexpression/shRNA with FRAP, aggregation, ER retention, and domain-mutant analysis","pmids":["25055872"],"confidence":"Medium","gaps":["Single cell system","Whether effect translates in vivo not addressed here"]},{"year":2015,"claim":"Extended ERdj5 reductase activity to non-self substrates, reducing SV40 disulfides to enable ER-to-cytosol penetration and viral infection.","evidence":"siRNA, infection assays, negative-stain EM of ER-localized SV40, SV40-BAP31 Co-IP","pmids":["26085143"],"confidence":"Medium","gaps":["Generality across other viruses limited","Cooperation with PDI not fully reconstituted"]},{"year":2016,"claim":"Defined a non-folding role in Ca2+ homeostasis: ERdj5 activates SERCA2b by reducing its luminal disulfide, with BiP- and Ca2+-dependent oligomerization providing feedback regulation.","evidence":"In vitro reductase and SERCA2b activity assays, Co-IP, Ca2+ measurement, oligomerization analysis","pmids":["27694578"],"confidence":"High","gaps":["Structure of the oligomeric inactive state not solved","Quantitative thresholds in living cells not established"]},{"year":2017,"claim":"Established that conformational dynamics of the thioredoxin clusters, not a static arrangement, drive efficient reduction and substrate transfer.","evidence":"Second crystal structure, high-speed AFM single-molecule imaging, fixed-cluster mutant ERAD assays","pmids":["28479060"],"confidence":"High","gaps":["Energetics of cluster motion unquantified","Coupling of dynamics to BiP cycle not mapped"]},{"year":2019,"claim":"Connected ERdj5 loss to organ-level pathology and immune function: knockout causes Sjögren's-like salivary autoimmunity, and ERdj5 in dendritic cells is required for cholera toxin-driven immune activation via CTA1 retrotranslocation.","evidence":"Knockout mice with histopathology/serology/saliva measurements; DC activation, immunization, and cytokine assays","pmids":["30967862","31275300"],"confidence":"Medium","gaps":["Causal client(s) driving autoimmunity unidentified","Single-lab phenotypes"]},{"year":2020,"claim":"Provided in vivo proof-of-concept that restoring ERdj5 is protective, preserving photoreceptors in a P23H rhodopsin retinal degeneration model.","evidence":"AAV subretinal ERdj5 overexpression with ERG, OCT, morphometry, and rhodopsin localization","pmids":["32196553"],"confidence":"Medium","gaps":["Durability and dosing not optimized","Mechanism inferred from earlier cell work"]},{"year":2021,"claim":"Mechanistically linked ERdj5 loss to mitochondrial dysfunction, showing Ca2+ imbalance activates Drp1-driven fission and senescence.","evidence":"Knockout cells with Ca2+ measurement, Drp1 activation, mitochondrial morphology, and senescence markers","pmids":["34728782"],"confidence":"Medium","gaps":["Whether SERCA2b is the sole upstream node untested","Reversibility of senescence not addressed"]},{"year":2023,"claim":"Refined ERdj5's essential cellular role as a dedicated reductase and reconstituted its disaggregase-like cooperation with BiP on disulfide-linked oligomers.","evidence":"ERdj5/ERp57 knockout cells distinguishing reduction vs isomerization; in vitro reconstitution and single-molecule AFM of stepwise J-chain oligomer reduction with mutagenesis","pmids":["36655611","37739037"],"confidence":"High","gaps":["In vivo relevance of disaggregation activity not established","Substrate specificity rules for oligomer reduction incomplete"]},{"year":2024,"claim":"Positioned DNAJC10 upstream of PERK in disease cells, where its loss selectively triggers PERK-eIF2α-ATF4 driven apoptosis of leukemia stem cells.","evidence":"shRNA/CRISPR in AML lines and LSCs, MLL-AF9 model in knockout mice, PERK inhibitor epistasis rescue","pmids":["37496439"],"confidence":"Medium","gaps":["Why LSCs are selectively dependent unclear","Direct ER substrate driving PERK activation unknown"]},{"year":2025,"claim":"Linked DNAJC10 to UPR-controlled transcription, showing it suppresses EGFR in glioblastoma by inhibiting the IRE1α-XBP-1s axis and downstream SET7/9-mediated promoter methylation.","evidence":"Overexpression/knockdown with XBP-1s rescue, ChIP for XBP-1s and H3K4 marks, histone methylation inhibition, xenograft assays","pmids":["41191192"],"confidence":"Medium","gaps":["How an ER reductase modulates IRE1α activity mechanistically unresolved","Single-lab, single tumor context"]},{"year":null,"claim":"How ERdj5 redox state, BiP-regulated oligomerization, and conformational dynamics are integrated to differentially route a given client toward productive folding, ERAD, or Ca2+ pump activation — and which clients drive its disease phenotypes — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Decision logic between folding vs degradation reduction unknown","Endogenous clients driving autoimmunity and UPR phenotypes unidentified","No structure of active SERCA2b-engaged or oligomeric inactive states"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[1,3,13,21]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,7,13]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,2,20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[13]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,10]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,3,21]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[5,22,23]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[13]}],"complexes":["EDEM1-BiP-ERdj5 ERAD complex","Hrd1/Sel1L ERAD complex"],"partners":["HSPA5","EDEM1","SEL1L","ATP2A2","LDLR","ERO1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IXB1","full_name":"Endoplasmic reticulum disulfide reductase DNAJC10","aliases":["DnaJ homolog subfamily C member 10","Endoplasmic reticulum DNA J domain-containing protein 5","ER-resident protein ERdj5","Macrothioredoxin","MTHr"],"length_aa":793,"mass_kda":91.1,"function":"Endoplasmic reticulum disulfide reductase that collaborates directly with the chaperone BIP/HSPA5 (GRP78) to maintain protein quality control by facilitating either the correct folding or the targeted degradation of misfolded proteins (PubMed:12411443, PubMed:23769672, PubMed:37739037). Essential for efficient maturation of newly synthesized polypeptides in the endoplasmic reticulum, binds to substrate proteins and specifically catalyzes the reduction and removal of improper (non-native) disulfide bonds during the folding process (PubMed:23769672, PubMed:37739037). In endoplasmic reticulum-associated degradation (ERAD), 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 (PubMed:18400946). Promotes apoptotic signaling pathway in response to endoplasmic reticulum stress (PubMed:19122239)","subcellular_location":"Endoplasmic reticulum lumen","url":"https://www.uniprot.org/uniprotkb/Q8IXB1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DNAJC10","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DNAJC10","total_profiled":1310},"omim":[{"mim_id":"613777","title":"FAD-DEPENDENT OXIDOREDUCTASE DOMAIN-CONTAINING PROTEIN 2; FOXRED2","url":"https://www.omim.org/entry/613777"},{"mim_id":"607987","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 10; DNAJC10","url":"https://www.omim.org/entry/607987"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in 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ER-resident protein disulfide reductase ERdj5.","date":"2011","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/21329881","citation_count":117,"is_preprint":false},{"pmid":"23769672","id":"PMC_23769672","title":"ERdj5 is the ER reductase that catalyzes the removal of non-native disulfides and correct folding of the LDL receptor.","date":"2013","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/23769672","citation_count":110,"is_preprint":false},{"pmid":"17353921","id":"PMC_17353921","title":"Targeting homeostatic mechanisms of endoplasmic reticulum stress to increase susceptibility of cancer cells to fenretinide-induced apoptosis: the role of stress proteins ERdj5 and ERp57.","date":"2007","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/17353921","citation_count":104,"is_preprint":false},{"pmid":"27694578","id":"PMC_27694578","title":"Redox-assisted regulation of Ca2+ homeostasis in the endoplasmic reticulum by disulfide 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gland.","date":"2009","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/19788412","citation_count":39,"is_preprint":false},{"pmid":"23363602","id":"PMC_23363602","title":"The ERdj5-Sel1L complex facilitates cholera toxin retrotranslocation.","date":"2013","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/23363602","citation_count":36,"is_preprint":false},{"pmid":"19122239","id":"PMC_19122239","title":"ERdj5 sensitizes neuroblastoma cells to endoplasmic reticulum stress-induced apoptosis.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19122239","citation_count":34,"is_preprint":false},{"pmid":"25055872","id":"PMC_25055872","title":"The co-chaperone and reductase ERdj5 facilitates rod opsin biogenesis and quality control.","date":"2014","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25055872","citation_count":25,"is_preprint":false},{"pmid":"28479060","id":"PMC_28479060","title":"The Highly Dynamic Nature of ERdj5 Is Key to Efficient Elimination of Aberrant Protein Oligomers through ER-Associated Degradation.","date":"2017","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/28479060","citation_count":25,"is_preprint":false},{"pmid":"30967862","id":"PMC_30967862","title":"Ablation of the Chaperone Protein ERdj5 Results in a Sjögren's Syndrome-Like Phenotype in Mice, Consistent With an Upregulated Unfolded Protein Response in Human Patients.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30967862","citation_count":18,"is_preprint":false},{"pmid":"31276733","id":"PMC_31276733","title":"Upregulation of JHDM1D-AS1 protects PDLSCs from H2O2-induced apoptosis by decreasing DNAJC10 via phosphorylation of 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population.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29088834","citation_count":11,"is_preprint":false},{"pmid":"37496439","id":"PMC_37496439","title":"DNAJC10 maintains survival and self-renewal of leukemia stem cells through PERK branch of the unfolded protein response.","date":"2024","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/37496439","citation_count":10,"is_preprint":false},{"pmid":"32196553","id":"PMC_32196553","title":"AAV-mediated ERdj5 overexpression protects against P23H rhodopsin toxicity.","date":"2020","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32196553","citation_count":10,"is_preprint":false},{"pmid":"36759578","id":"PMC_36759578","title":"ERdj5 protects goblet cells from endoplasmic reticulum stress-mediated apoptosis under inflammatory conditions.","date":"2023","source":"Experimental & molecular 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34305928","citation_count":9,"is_preprint":false},{"pmid":"31275300","id":"PMC_31275300","title":"ERdj5 in Innate Immune Cells Is a Crucial Factor for the Mucosal Adjuvanticity of Cholera Toxin.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31275300","citation_count":7,"is_preprint":false},{"pmid":"34728782","id":"PMC_34728782","title":"Ca2+ imbalance caused by ERdj5 deletion affects mitochondrial fragmentation.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34728782","citation_count":6,"is_preprint":false},{"pmid":"39031896","id":"PMC_39031896","title":"MCM8 promotes lung cancer progression through upregulating DNAJC10.","date":"2024","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39031896","citation_count":1,"is_preprint":false},{"pmid":"41191192","id":"PMC_41191192","title":"Endoplasmic reticulum-resident 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(DnaJ domain-BiP interaction), immunofluorescence/subcellular fractionation for ER localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro interaction demonstrated, ER localization confirmed, single lab with two orthogonal methods\",\n      \"pmids\": [\"12411443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ERdj5 functions as a disulfide reductase that cleaves disulfide bonds of misfolded proteins in the ER, physically associates with EDEM and BiP as part of a supramolecular ERAD complex, and accelerates retrotranslocation of ERAD substrates.\",\n      \"method\": \"In vitro reductase assay, co-immunoprecipitation (ERdj5-EDEM and ERdj5-BiP), siRNA knockdown with ERAD substrate degradation readout\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro enzymatic assay plus reciprocal co-IP plus functional knockdown, replicated across multiple approaches in the same study\",\n      \"pmids\": [\"18653895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ERdj5 and ERdj4 associate with misfolded surfactant protein C (SP-C) and coprecipitate with p97/VCP, remaining associated until substrate dislocation to the cytosol; HPD motif mutations abolishing BiP ATPase stimulation prevent ERdj5-mediated ERAD of misfolded SP-C.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown with ERAD readout, dominant-negative HPD mutant rescue experiment in XBP1−/− MEFs\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional knockdown, mutagenesis rescue, two independent orthogonal approaches in same study\",\n      \"pmids\": [\"18400946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of full-length ERdj5 revealed an N-terminal J domain followed by six tandem thioredoxin domains organized into N- and C-terminal clusters; the C-terminal cluster forms the highly reducing platform that interacts with EDEM1 and reduces EDEM1-recruited ERAD substrates; pulse-chase experiments showed sequential substrate movement from calnexin → EDEM1-ERdj5 complex → retrotranslocation channel via BiP.\",\n      \"method\": \"X-ray crystallography, systematic biochemical analyses (reductase activity, binding assays), pulse-chase experiment\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with biochemical functional validation and pulse-chase, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"21329881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Knockdown of ERdj5 by RNA interference in neuroectodermal tumour cells increased the apoptotic response to fenretinide, indicating ERdj5 normally protects against ER stress-induced apoptosis in these cells.\",\n      \"method\": \"siRNA knockdown with apoptosis readout (cell viability, apoptosis assays) following fenretinide treatment\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional knockdown with specific phenotypic readout, single lab, limited mechanistic depth\",\n      \"pmids\": [\"17353921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ERdj5 overexpression sensitizes neuroblastoma cells to ER stress-induced apoptosis by abolishing eIF2α phosphorylation and inactivating PERK, thereby compromising the integrated stress response; ER-targeted Bcl-2 prevented this apoptosis, confirming ER-stress-regulated apoptosis pathway.\",\n      \"method\": \"Overexpression with ER stress inducers, phosphorylation assays (eIF2α), ER-targeted Bcl-2 rescue experiment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression with pathway readout and genetic rescue, single lab, two orthogonal methods\",\n      \"pmids\": [\"19122239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ERdj5 knockout mice show activated ER stress responses specifically in salivary glands; re-expression of ERdj5 (but not thioredoxin-like motif mutants) mitigated ER stress caused by overproduction of alpha-amylase, demonstrating that ERdj5's reductase activity is required for ER quality control in secretory cells in vivo.\",\n      \"method\": \"ERdj5 knockout mouse generation and analysis, ER stress markers (qPCR/western), rescue with wild-type vs thioredoxin-motif mutant ERdj5\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout mouse with defined phenotype, functional rescue with domain mutants demonstrating mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"19788412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ERdj5 forms mixed disulfides with multiple endogenous ER client proteins including the LDL receptor (LDLR); for LDLR, ERdj5 reduces non-native disulfides formed during productive folding (not only for ERAD), and this function requires ERdj5's interaction with BiP.\",\n      \"method\": \"Trapping of mixed disulfides (substrate trapping mutant), co-immunoprecipitation, LDLR folding assay, BiP interaction analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — substrate trapping combined with functional folding assays and interaction studies, multiple orthogonal methods, extends substrate repertoire beyond ERAD\",\n      \"pmids\": [\"23769672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ERdj5 interacts directly with the Sel1L N-terminal lumenal domain, linking it to the Hrd1 ERAD complex; ERdj5 promotes CTA1 retrotranslocation partly via its J domain by regulating BiP-CTA interaction proximal to the Hrd1 complex.\",\n      \"method\": \"Co-immunoprecipitation (ERdj5-Sel1L interaction), loss-of-function and gain-of-function approaches, retrotranslocation assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional assays (loss/gain of function), single lab, two orthogonal methods\",\n      \"pmids\": [\"23363602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Redox partners of ERdj5 were identified from mouse epididymis tissue by combining acid quenching and thiol-alkylation to capture disulfide-linked complexes; two identified proteins were confirmed to interact with ERdj5 via intermolecular disulfide bonds in vivo.\",\n      \"method\": \"Acid quenching, thiol-alkylation, affinity purification followed by mass spectrometry, validation by western blot of disulfide-linked complexes\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo tissue trapping method with MS identification plus biochemical validation, single lab\",\n      \"pmids\": [\"24055038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In C. elegans, dnj-27/ERdj5 ortholog is an ER luminal protein whose expression is induced by ER stress via IRE-1/XBP-1; its knockdown increases aggregation and pathological phenotypes of Aβ, α-synuclein, and polyQ proteins, and causes mitochondrial fragmentation.\",\n      \"method\": \"RNAi knockdown in C. elegans disease models, fluorescence microscopy of protein aggregation, motility/paralysis assays, mitochondrial morphology analysis\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined phenotypic readouts, multiple disease models, C. elegans ortholog study\",\n      \"pmids\": [\"23641861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ERdj5 (DNAJC10) regulates P23H rod opsin biogenesis; overexpression promoted degradation and prevented aggregation of P23H rod opsin, while shRNA knockdown delayed degradation and promoted aggregation; both reductase and co-chaperone activities of ERdj5 were required, and mutations in these domains acted as dominant negatives affecting wild-type rod opsin biogenesis.\",\n      \"method\": \"Overexpression and shRNA knockdown with fluorescence microscopy (FRAP, aggregation), domain mutant analysis including dominant negative effects, ER retention assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with domain mutants demonstrating mechanistic requirements, single lab\",\n      \"pmids\": [\"25055872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ERdj5 reduces disulfide bonds of SV40 virus in the ER lumen, a reaction required for ER membrane transport and infection; ERdj5 cooperates with PDI to induce structural rearrangements in SV40 enabling engagement of BAP31 for membrane penetration; ERdj5 also mediates BK PyV infection.\",\n      \"method\": \"Loss-of-function (siRNA), infection assays, negative-stain electron microscopy of ER-localized SV40, co-immunoprecipitation (SV40-BAP31)\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with EM structural evidence and infection readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"26085143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ERdj5 activates SERCA2b calcium pump function by reducing its luminal disulfide bond; at lower ER luminal Ca2+ concentrations ERdj5 is active, while higher Ca2+ induces ERdj5 oligomerization preventing SERCA2b interaction; BiP binding to the J domain of ERdj5 regulates this oligomerization, providing Ca2+-dependent feedback regulation of ER Ca2+ homeostasis.\",\n      \"method\": \"In vitro reductase activity assay, SERCA2b activity assay, co-immunoprecipitation, Ca2+ measurement, oligomerization analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro enzymatic reconstitution of SERCA2b activation, mechanistic dissection of oligomerization regulation by Ca2+ and BiP, multiple orthogonal methods in one study\",\n      \"pmids\": [\"27694578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A new crystal structure of ERdj5 revealed a largely different cluster arrangement relative to the original structure; high-speed atomic force microscopy showed rapid cluster movement around the flexible linker loop; ERdj5 mutants with fixed-cluster orientation compromised ERAD enhancement activity, indicating that conformational dynamics are required for efficient reduction of aberrantly formed disulfide bonds and substrate transfer.\",\n      \"method\": \"X-ray crystallography, high-speed atomic force microscopy (single-molecule observation), ERAD activity assays with fixed-cluster mutants\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus single-molecule imaging plus functional mutagenesis, multiple orthogonal high-quality methods in one study\",\n      \"pmids\": [\"28479060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ERdj5 ablation in mice produces a Sjögren's syndrome-like phenotype including spontaneous inflammation in salivary glands with T and B lymphocyte infiltration, reduced saliva flow, production of anti-SSA/Ro and anti-SSB/La autoantibodies, and a distinct cytokine signature, demonstrating ERdj5 is required for salivary gland homeostasis and prevention of autoimmune inflammatory responses.\",\n      \"method\": \"ERdj5 knockout mouse model, histopathology, serological assays (ANA, cytokine profiling), saliva flow rate measurement\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with multiple defined phenotypic readouts, single lab\",\n      \"pmids\": [\"30967862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ERdj5 in innate immune cells (particularly dendritic cells) is required for full immune activation by cholera toxin; ERdj5-knockout DCs show decreased costimulatory molecule expression (MHC II, CD80, CD86) and reduced pro-inflammatory cytokine secretion (IL-1β, TNF-α, IL-6), and ERdj5 KO mice show impaired antigen-specific IgG/IgA responses after CT immunization, specifically through CTA1 retro-translocation.\",\n      \"method\": \"ERdj5 knockout mouse model, DC activation assays (flow cytometry, ELISA), intranasal immunization with CT, cytokine profiling\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with multiple immune readouts, single lab\",\n      \"pmids\": [\"31275300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AAV-mediated overexpression of ERdj5 in P23H-3 rats reduced visual function loss and preserved photoreceptor cells, correlating with reduced rhodopsin retention in the outer nuclear layer, demonstrating in vivo therapeutic benefit of ERdj5 overexpression for P23H rhodopsin-mediated retinal degeneration.\",\n      \"method\": \"AAV subretinal injection, electroretinogram (ERG), optical coherence tomography, outer nuclear layer morphometry, rhodopsin immunolocalization\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gene augmentation with multiple functional and structural readouts, single lab\",\n      \"pmids\": [\"32196553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ERdj5 deletion causes intracellular Ca2+ imbalance, which activates Drp1 (a cytosolic GTPase involved in mitochondrial fission), leading to aberrant mitochondrial fragmentation and a cellular senescence phenotype, demonstrating that ERdj5-mediated Ca2+ regulation is essential for mitochondrial homeostasis.\",\n      \"method\": \"ERdj5 knockout cell lines, Ca2+ measurement, Drp1 activation assays (phosphorylation), mitochondrial morphology (fluorescence microscopy), senescence markers\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic deletion with mechanistic pathway readout (Ca2+→Drp1→mitochondrial fission), single lab, multiple assays\",\n      \"pmids\": [\"34728782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ERdj5 (Dnajc10) loss in mice exacerbates alcohol-induced liver injury and promotes oxidative stress; mechanistically, ERdj5 deficiency reduces nuclear Nrf2 and downstream antioxidant gene expression, and decreases hepatic glutathione content, placing ERdj5 upstream of the Nrf2 antioxidant pathway.\",\n      \"method\": \"Dnajc10 knockout mouse (chronic-binge ethanol model), H2O2 measurement, Nrf2 nuclear fractionation/western blot, antioxidant gene expression (qRT-PCR), glutathione assay\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with mechanistic pathway readout (Nrf2 nuclear translocation), single lab, multiple orthogonal assays\",\n      \"pmids\": [\"35390453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ERdj5 and BiP cooperate in a reconstituted in vitro system to reduce disulfide-linked J-chain oligomers in a stepwise manner (large oligomers → trimers → dimers → monomers); BiP synergistically enhances ERdj5-mediated reduction in an ATP-dependent manner; single-molecule AFM showed stochastic release of small oligomers through repeated ERdj5 actions on peripheral/flexible regions of aggregates; systematic mutagenesis dissected the molecular requirements.\",\n      \"method\": \"In vitro reconstitution with purified proteins, biochemical reduction assays, high-speed atomic force microscopy (single-molecule), systematic mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified proteins plus single-molecule imaging plus mutagenesis, multiple rigorous orthogonal methods in one study\",\n      \"pmids\": [\"37739037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ERdj5 (DNAJC10) functions specifically as a reductase (not isomerase) in ER disulfide bond processing; ERp57 is required for isomerisation of non-native disulfides in glycoproteins; ERdj5 is required to provide the reductive pathway that enables alternative PDIs to compensate for absence of ERp57, indicating ERdj5's essential cellular function is reduction of non-native disulfides.\",\n      \"method\": \"Knockout cell lines (ERdj5 and ERp57), disulfide bond formation/isomerization assays, metabolic labeling, substrate folding analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout cells with defined biochemical readouts distinguishing reduction vs isomerization, replication of ERdj5 reductase role, multiple orthogonal approaches\",\n      \"pmids\": [\"36655611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DNAJC10 deficiency in AML specifically induces ER stress and activates the PERK-EIF2α-ATF4 branch of the UPR, leading to apoptosis of leukemia stem cells; blocking PERK (with GSK2606414 or shRNA) rescued the DNAJC10 loss-of-function phenotype both in vitro and in vivo, placing DNAJC10 upstream of PERK in the UPR.\",\n      \"method\": \"shRNA knockdown and CRISPR knockout in human AML lines and LSC-enriched populations, MLL-AF9 murine leukemia model in Dnajc10 knockout mice, PERK inhibitor rescue (GSK2606414), apoptosis assays, UPR pathway analysis\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (PERK inhibitor rescues DNAJC10 KO phenotype) in vitro and in vivo, single lab, two orthogonal approaches\",\n      \"pmids\": [\"37496439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DNAJC10 overexpression suppresses EGFR transcription in glioblastoma by inhibiting the IRE1α-XBP-1s axis of the UPR; XBP-1s binds the EGFR promoter and recruits SET7/9 methyltransferase, promoting H3K4me3 and H3K4me1 marks; XBP-1s overexpression reverses DNAJC10-mediated EGFR downregulation; pharmacological histone methylation inhibition attenuates XBP-1s-induced EGFR transcription.\",\n      \"method\": \"Overexpression and knockdown of DNAJC10, XBP-1s overexpression rescue, ChIP (XBP-1s binding to EGFR promoter, H3K4me3/me1), pharmacological inhibition of histone methylation, in vitro and xenograft invasion assays\",\n      \"journal\": \"Molecular biomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue (XBP-1s reverses DNAJC10 effect), ChIP evidence, pharmacological validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41191192\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DNAJC10 (ERdj5) is an ER-resident protein disulfide reductase and BiP co-chaperone that, through its N-terminal J domain and six tandem thioredoxin domains, accelerates ERAD by reducing incorrect disulfide bonds in misfolded glycoproteins recognized by EDEM1, promotes productive folding of clients such as the LDL receptor, activates the ER calcium pump SERCA2b by reducing its luminal disulfide bond (with activity regulated by ER Ca2+ levels and BiP-dependent oligomerization), and facilitates retrotranslocation of bacterial toxins and viruses; its conformational dynamics are essential for substrate disaggregation, and loss of ERdj5 function disrupts Ca2+ homeostasis, activates Drp1-mediated mitochondrial fragmentation, sensitizes cells to PERK-dependent ER stress, and in vivo causes salivary gland dysfunction and Sjögren's syndrome-like autoimmunity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DNAJC10 (ERdj5) is an ER-resident protein disulfide reductase and BiP co-chaperone that couples disulfide reduction to ER quality control, secretory homeostasis, and Ca2+ regulation [#1, #6]. It is organized as an N-terminal J domain that binds BiP in an ATP-dependent manner followed by six tandem thioredoxin domains arranged into N- and C-terminal clusters, with the C-terminal cluster forming a highly reducing platform that engages EDEM1 and reduces EDEM1-recruited misfolded substrates [#0, #3]. Through this activity ERdj5 acts within a supramolecular ERAD complex with EDEM, BiP, and the Hrd1 component Sel1L, cleaving non-native disulfide bonds in misfolded glycoproteins and accelerating their retrotranslocation from the calnexin cycle to the dislocation channel [#1, #3, #8]. Its physiological role is reduction rather than isomerization of non-native disulfides, providing the reductive pathway that lets alternative PDIs compensate when ERp57 is absent [#21]. Beyond ERAD, ERdj5 reduces non-native disulfides during productive folding of clients including the LDL receptor and P23H rod opsin, and activates the SERCA2b calcium pump by reducing its luminal disulfide bond, with this activity switched off at high luminal Ca2+ through BiP-regulated oligomerization to provide feedback control of ER Ca2+ homeostasis [#7, #11, #13]. Conformational dynamics of the thioredoxin clusters around a flexible linker are required for efficient substrate reduction and for stepwise disaggregation of disulfide-linked oligomers in cooperation with BiP [#14, #20]. Loss of ERdj5 disrupts Ca2+ balance and triggers Drp1-mediated mitochondrial fragmentation and senescence, sensitizes cells to PERK-dependent ER stress, and in mice causes salivary gland ER stress and a Sjögren's syndrome-like autoimmune phenotype [#6, #15, #18, #22]. ERdj5 also reduces disulfide bonds of SV40 and facilitates retrotranslocation of cholera toxin CTA1, linking it to viral infection and toxin-driven immune activation [#12, #16].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that ERdj5 is an ER luminal protein and a bona fide BiP co-chaperone, defining its domain architecture and placing it in the Hsp70 chaperone cycle.\",\n      \"evidence\": \"In vitro DnaJ domain-BiP binding assay plus immunofluorescence/fractionation in cells\",\n      \"pmids\": [\"12411443\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzymatic activity of the thioredoxin domains undefined\", \"No substrate identified\", \"BiP interaction shown in vitro only\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"First functional context: ERdj5 protects cells against ER stress-induced apoptosis, linking it to cell survival under proteostatic stress.\",\n      \"evidence\": \"siRNA knockdown with apoptosis readout after fenretinide in neuroectodermal tumour cells\",\n      \"pmids\": [\"17353921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of protection not defined\", \"Single cell type\", \"Does not connect to disulfide chemistry\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined ERdj5's core biochemical activity as a disulfide reductase acting within an EDEM-BiP ERAD complex to accelerate retrotranslocation of misfolded substrates.\",\n      \"evidence\": \"In vitro reductase assay, reciprocal Co-IP (EDEM, BiP), siRNA with ERAD degradation readout; parallel SP-C/p97 study with HPD-motif mutant rescue\",\n      \"pmids\": [\"18653895\", \"18400946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of substrate selection unknown\", \"How reduction is coordinated with dislocation channel unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established physiological requirement in vivo and a dose-dependent influence on the UPR: reductase activity is needed for ER quality control in secretory cells, while overexpression compromises PERK/eIF2α-mediated stress signaling.\",\n      \"evidence\": \"ERdj5 knockout mice (salivary gland ER stress, mutant rescue) and overexpression studies with eIF2α phosphorylation and ER-targeted Bcl-2 rescue\",\n      \"pmids\": [\"19788412\", \"19122239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue specificity of salivary gland phenotype unexplained\", \"Mechanistic link between ERdj5 levels and PERK not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Solved the full-length structure and ordered the ERAD pathway, showing the C-terminal thioredoxin cluster as the reducing platform receiving EDEM1-recruited substrates en route from calnexin to BiP-mediated retrotranslocation.\",\n      \"evidence\": \"X-ray crystallography, reductase/binding assays, pulse-chase substrate tracking\",\n      \"pmids\": [\"21329881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational behavior in solution not addressed\", \"Dynamics of substrate handoff not captured by static structure\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Broadened ERdj5 function beyond ERAD to productive folding and connected it to the Hrd1 complex and toxin retrotranslocation, while in-vivo trapping mapped endogenous disulfide partners.\",\n      \"evidence\": \"Mixed-disulfide trapping with LDLR folding assays; Sel1L Co-IP with CTA1 retrotranslocation; tissue disulfide-partner capture with MS validation\",\n      \"pmids\": [\"23769672\", \"23363602\", \"24055038\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full client repertoire still incomplete\", \"How ERdj5 distinguishes folding from degradative reduction unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated conserved cytoprotective function of the ERdj5 ortholog and an early link to mitochondrial integrity and proteotoxicity.\",\n      \"evidence\": \"RNAi in C. elegans dnj-27 disease models with aggregation, motility, and mitochondrial morphology readouts\",\n      \"pmids\": [\"23641861\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of mitochondrial fragmentation not defined in this model\", \"Ortholog findings not yet mapped to mammalian biochemistry\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed ERdj5 controls biogenesis of a disease-relevant client (P23H rod opsin) requiring both reductase and co-chaperone activities, with domain mutants acting as dominant negatives.\",\n      \"evidence\": \"Overexpression/shRNA with FRAP, aggregation, ER retention, and domain-mutant analysis\",\n      \"pmids\": [\"25055872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell system\", \"Whether effect translates in vivo not addressed here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended ERdj5 reductase activity to non-self substrates, reducing SV40 disulfides to enable ER-to-cytosol penetration and viral infection.\",\n      \"evidence\": \"siRNA, infection assays, negative-stain EM of ER-localized SV40, SV40-BAP31 Co-IP\",\n      \"pmids\": [\"26085143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality across other viruses limited\", \"Cooperation with PDI not fully reconstituted\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a non-folding role in Ca2+ homeostasis: ERdj5 activates SERCA2b by reducing its luminal disulfide, with BiP- and Ca2+-dependent oligomerization providing feedback regulation.\",\n      \"evidence\": \"In vitro reductase and SERCA2b activity assays, Co-IP, Ca2+ measurement, oligomerization analysis\",\n      \"pmids\": [\"27694578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the oligomeric inactive state not solved\", \"Quantitative thresholds in living cells not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that conformational dynamics of the thioredoxin clusters, not a static arrangement, drive efficient reduction and substrate transfer.\",\n      \"evidence\": \"Second crystal structure, high-speed AFM single-molecule imaging, fixed-cluster mutant ERAD assays\",\n      \"pmids\": [\"28479060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Energetics of cluster motion unquantified\", \"Coupling of dynamics to BiP cycle not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected ERdj5 loss to organ-level pathology and immune function: knockout causes Sjögren's-like salivary autoimmunity, and ERdj5 in dendritic cells is required for cholera toxin-driven immune activation via CTA1 retrotranslocation.\",\n      \"evidence\": \"Knockout mice with histopathology/serology/saliva measurements; DC activation, immunization, and cytokine assays\",\n      \"pmids\": [\"30967862\", \"31275300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal client(s) driving autoimmunity unidentified\", \"Single-lab phenotypes\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided in vivo proof-of-concept that restoring ERdj5 is protective, preserving photoreceptors in a P23H rhodopsin retinal degeneration model.\",\n      \"evidence\": \"AAV subretinal ERdj5 overexpression with ERG, OCT, morphometry, and rhodopsin localization\",\n      \"pmids\": [\"32196553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Durability and dosing not optimized\", \"Mechanism inferred from earlier cell work\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mechanistically linked ERdj5 loss to mitochondrial dysfunction, showing Ca2+ imbalance activates Drp1-driven fission and senescence.\",\n      \"evidence\": \"Knockout cells with Ca2+ measurement, Drp1 activation, mitochondrial morphology, and senescence markers\",\n      \"pmids\": [\"34728782\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SERCA2b is the sole upstream node untested\", \"Reversibility of senescence not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Refined ERdj5's essential cellular role as a dedicated reductase and reconstituted its disaggregase-like cooperation with BiP on disulfide-linked oligomers.\",\n      \"evidence\": \"ERdj5/ERp57 knockout cells distinguishing reduction vs isomerization; in vitro reconstitution and single-molecule AFM of stepwise J-chain oligomer reduction with mutagenesis\",\n      \"pmids\": [\"36655611\", \"37739037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of disaggregation activity not established\", \"Substrate specificity rules for oligomer reduction incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Positioned DNAJC10 upstream of PERK in disease cells, where its loss selectively triggers PERK-eIF2α-ATF4 driven apoptosis of leukemia stem cells.\",\n      \"evidence\": \"shRNA/CRISPR in AML lines and LSCs, MLL-AF9 model in knockout mice, PERK inhibitor epistasis rescue\",\n      \"pmids\": [\"37496439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why LSCs are selectively dependent unclear\", \"Direct ER substrate driving PERK activation unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked DNAJC10 to UPR-controlled transcription, showing it suppresses EGFR in glioblastoma by inhibiting the IRE1α-XBP-1s axis and downstream SET7/9-mediated promoter methylation.\",\n      \"evidence\": \"Overexpression/knockdown with XBP-1s rescue, ChIP for XBP-1s and H3K4 marks, histone methylation inhibition, xenograft assays\",\n      \"pmids\": [\"41191192\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How an ER reductase modulates IRE1α activity mechanistically unresolved\", \"Single-lab, single tumor context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ERdj5 redox state, BiP-regulated oligomerization, and conformational dynamics are integrated to differentially route a given client toward productive folding, ERAD, or Ca2+ pump activation — and which clients drive its disease phenotypes — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Decision logic between folding vs degradation reduction unknown\", \"Endogenous clients driving autoimmunity and UPR phenotypes unidentified\", \"No structure of active SERCA2b-engaged or oligomeric inactive states\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [1, 3, 13, 21]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 7, 13]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 2, 20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 3, 21]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [5, 22, 23]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\"EDEM1-BiP-ERdj5 ERAD complex\", \"Hrd1/Sel1L ERAD complex\"],\n    \"partners\": [\"HSPA5\", \"EDEM1\", \"SEL1L\", \"ATP2A2\", \"LDLR\", \"ERO1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}