{"gene":"DNAJC7","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2003,"finding":"Tpr2 (DNAJC7) contains two TPR domains that bind Hsp70 and Hsp90 simultaneously, and a J domain that stimulates Hsp70 ATPase activity and polypeptide binding. Unlike other co-chaperones, Tpr2 induces ATP-independent dissociation of Hsp90 (but not Hsp70) from chaperone-substrate complexes, mediating retrograde transfer of substrates from Hsp90 back onto Hsp70. Excess Tpr2 inhibits Hsp90-dependent folding of the glucocorticoid receptor (GR) in cell lysates.","method":"In vitro biochemical assays (ATPase stimulation, polypeptide binding), cell lysate GR folding assays, domain-binding studies, overexpression/knockdown in vivo","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with ATPase assay and polypeptide binding, combined with cell lysate folding assay and in vivo GR activation; multiple orthogonal methods in one rigorous study","pmids":["12853476"],"is_preprint":false},{"year":2008,"finding":"Tpr2 (DNAJC7) associates with Hsp90 and Hsp70 complexes that also contain the progesterone receptor (PR); it can bind Hsp70 and Hsp90 simultaneously, but unlike Hop, its binding to Hsp70 in the presence of Hsp90 is ATP-dependent. Tpr2 cannot replace Hop in Hsp90 chaperoning in vitro or in vivo. Tpr2 replaces type I and II J proteins in Hsp90-dependent chaperoning of the PR and Chk1 kinase and promotes accumulation of Hsp70 in PR heterocomplexes in the presence of Hsp90.","method":"Immunoprecipitation, pulldown, in vitro and in vivo chaperoning assays, knockdown/overexpression in HeLa cells","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reciprocal Co-IP, in vitro chaperoning assays, KD/OE with defined PR activity readout; multiple orthogonal methods, single lab","pmids":["18620420"],"is_preprint":false},{"year":2001,"finding":"Tpr2 (DNAJC7) binds Rad9, Rad1, and Hus1 (checkpoint clamp proteins) through its N-terminal TPR region. The J domain of Tpr2 negatively regulates its interaction with Rad9: deletion of the J domain or mutation of the conserved HPD motif greatly enhances Tpr2-Rad9 binding. Following heat-shock or UV treatment, Rad9 transiently dissociates from Tpr2 in a J-domain-dependent manner. The J domain also modulates the cellular localization of both Tpr2 and Rad9.","method":"Yeast two-hybrid screening, in vivo and in vitro binding assays, J-domain point mutation (HPD motif), cellular localization analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal in vivo/in vitro binding with mutagenesis of HPD motif, multiple substrates tested, single lab","pmids":["11573955"],"is_preprint":false},{"year":2012,"finding":"DnaJC7/TPR2 binds p53 through its central DNA-binding domain (identified by yeast two-hybrid), confirmed by co-immunoprecipitation in mammalian cells. DnaJC7 enhances p53-dependent transcriptional and growth-suppressive activity, extends p53 half-life, and reduces the amount of p53/MDM2 complex, suggesting DnaJC7 dissociates MDM2 from p53 to stabilize p53.","method":"Yeast two-hybrid screening, co-immunoprecipitation, luciferase reporter assay, colony formation assay, pulse-chase/half-life analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmed yeast two-hybrid; functional readouts (reporter, growth suppression, p53 half-life); single lab, multiple orthogonal methods","pmids":["23261415"],"is_preprint":false},{"year":2014,"finding":"CCRP/DNAJC7 interacts with HSP70 (co-immunoprecipitation in HepG2 cells) and retains nuclear receptor CAR in the cytoplasm. DNAJC7 is ubiquitinated and degraded by the proteasome upon CAR activation; this ubiquitination of DNAJC7 (but not CAR itself) is increased by TCPOBOP in the presence of MG132. HSP70 induction by heat shock also increases cytoplasmic CAR levels and attenuates CAR transcriptional activation, phenocopying proteasome inhibition.","method":"Co-immunoprecipitation, proteasome inhibitor (MG132) treatment, ubiquitination assay, luciferase reporter assay, heat shock experiments in HepG2 cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, functional reporter; single lab, multiple methods","pmids":["24789201"],"is_preprint":false},{"year":2014,"finding":"CCRP/DNAJC7 knockout mice show increased nuclear CAR accumulation after phenobarbital treatment but paradoxically attenuated Cyp2b10 gene activation. ChIP assays reveal that DNAJC7 is required for phenobarbital-induced de-methylation of H3K27 on the Cyp2b10 promoter and for RNA polymerase II recruitment, but not for CAR/RXRα binding to the promoter. DNAJC7 KO males also develop steatotic livers and altered cholesterol levels upon fasting.","method":"Knockout mouse model, ChIP assays (H3K27 methylation, RNA Pol II, CAR/RXRα), immunoblotting, gene expression analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO mouse with ChIP demonstrating specific epigenetic and transcriptional mechanism; multiple orthogonal assays, defines pathway position","pmids":["25542016"],"is_preprint":false},{"year":2016,"finding":"Mass spectrometric and pulldown analysis identified DNAJC7 as a substrate of cytosolic carboxypeptidase 6 (CCP6). When CCP6 is reduced (as in RCC), DNAJC7 accumulates in a polyglutamylated form (polyE-DNAJC7) detectable in serum.","method":"Mass spectrometry, pulldown assay, immunohistochemistry, Western blot, electrochemiluminescence immunoassay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification and pulldown confirm CCP6-DNAJC7 substrate relationship; single lab","pmids":["26993597"],"is_preprint":false},{"year":2021,"finding":"DnaJC7 binds preferentially to natively folded wild-type tau (not aggregated conformers) using a single TPR domain that recognizes a β-turn structural element containing the 275VQIINK280 amyloid motif. Disease-associated tau mutants that disrupt this β-turn reduce DnaJC7 binding affinity. DnaJC7 efficiently suppresses tau aggregation in vitro and in cells.","method":"In vitro aggregation assays, binding affinity measurements, domain mapping (single TPR domain), peptide competition assays, cell-based aggregation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of binding and inhibition of aggregation, domain-level mechanistic dissection with multiple tau variants, validated in cells; single lab but multiple orthogonal methods","pmids":["34504072"],"is_preprint":false},{"year":2023,"finding":"DnaJC7 co-purifies with insoluble tau and colocalizes with intracellular tau aggregates. Knockout of DnaJC7 (but not other JDPs) specifically decreases aggregate clearance and increases intracellular tau seeding. This protective activity depends on the ability of the DnaJC7 J domain to stimulate Hsp70 ATPase activity; J-domain mutations blocking Hsp70 interaction abolish protection. Disease-associated mutations in both the J domain and the substrate-binding site of DnaJC7 also abolish protective activity.","method":"Proteomics (co-purification with insoluble tau), CRISPR knockout of all JDPs individually, tau seeding assay, co-localization imaging, J-domain mutagenesis (HPD motif and ALS variants)","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic KO screen of all JDPs with functional seeding assay, mechanistic dissection via mutagenesis, proteomics; multiple orthogonal methods, defines specificity","pmids":["37387473"],"is_preprint":false},{"year":2022,"finding":"DnaJC7 acts as a bridge between Hsp70 and viral Hexon protein: the J domain of DnaJC7 is required for inhibiting FAdV-4 replication, and DnaJC7 mediates the indirect interaction between Hsp70 and Hexon. Hsp70 subsequently suppresses Hexon through the autophagy pathway to restrict viral replication.","method":"LC-MS/MS protein interaction screen, Co-IP, domain deletion analysis (J domain of DnaJC7, NBD of Hsp70), overexpression and autophagy inhibitor (chloroquine) experiments","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain dissection, functional viral replication assay, autophagy pathway involvement confirmed; single lab","pmids":["35852354"],"is_preprint":false},{"year":2025,"finding":"DNAJC7 knockdown impairs disassembly of TDP-43 condensates following arsenite-induced stress, while DNAJC7 overexpression suppresses assembly and promotes disassembly of arsenite-induced TDP-43 condensates. In a zebrafish ALS model, dnajc7 knockdown increases TDP-43 aggregation in motor neurons and reduces survival.","method":"Cell-based TDP-43 condensate assay with arsenite stress, DNAJC7 KD and OE, zebrafish dnajc7 morpholino knockdown, immunohistochemistry, RNA sequencing","journal":"Acta neuropathologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD/OE with specific TDP-43 condensate phenotype, validated in zebrafish model; single lab, two orthogonal systems","pmids":["40802071"],"is_preprint":false},{"year":2026,"finding":"The ALS-associated E425K mutation in the DNAJC7 J domain does not alter protein structure (confirmed by NMR) but specifically disrupts J-domain–Hsp70 interaction, uncoupling DNAJC7 from Hsp70 activation. A second Hsp70-binding interface exists in the TPR domains (binding the C-terminal EEVD motif of Hsp70), which is preserved in E425K but cannot compensate for loss of J-domain function. The TPR domains of DNAJC7 directly bind TDP-43 and prevent its aggregation (holdase activity retained in E425K), but the mutant fails to support client transfer to Hsp70 and subsequent Hsp70-mediated substrate refolding.","method":"NMR spectroscopy (structural and interaction analysis), in vitro binding assays, Hsp70 ATPase activation assay, TDP-43 aggregation assay","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural validation combined with in vitro ATPase and aggregation assays and mutagenesis; single lab with multiple orthogonal methods in one rigorous study","pmids":["41531269"],"is_preprint":false},{"year":2024,"finding":"The DNAJC7 interactome in human motor neurons (iPSC-derived) is enriched for RNA-binding proteins (RBPs) and stress-response chaperones (mass spectrometry). The ALS-associated R156X loss-of-function mutation causes increased insolubility of client RBP HNRNPU and associated RNA metabolism alterations. DNAJC7 haploinsufficiency renders motor neurons susceptible to proteotoxic stress and cell death through an ablated HSF1 stress-response pathway; exogenous HSF1 expression rescues sensitivity to proteotoxic stress in DNAJC7-mutant motor neurons.","method":"Mass spectrometry interactome, iPSC-derived motor neurons with ALS mutation (R156X), protein solubility fractionation, HSF1 rescue experiment, RNA sequencing","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS interactome plus mechanistic rescue experiment in disease-relevant cell type; preprint, single lab","pmids":["39651147"],"is_preprint":true},{"year":2025,"finding":"USP19 deubiquitinates DnaJC7, increasing its protein stability. Upregulation of both USP19 and DnaJC7 disrupts the p53-MDM2 interaction; knockdown of USP19 and DnaJC7 decreases p53 expression following cisplatin treatment, indicating that the USP19-DnaJC7 axis stabilizes p53.","method":"Co-immunoprecipitation (USP19-DnaJC7 interaction), deubiquitination assay, knockdown experiments, p53 stability and MDM2 interaction assays in cisplatin-treated cells","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and deubiquitination assay confirm USP19 as eraser of DnaJC7 ubiquitination, KD experiments link to p53; single lab, multiple methods","pmids":["42193933"],"is_preprint":false},{"year":2026,"finding":"DNAJC7 is a potent suppressor of polyglutamine (polyQ) aggregation, identified in a genome-wide CRISPRi screen of all chaperones. Physical interaction between DNAJC7 and polyQ-expanded protein was established. DNAJC7 knockdown specifically increased polyQ aggregation, while overexpressed DNAJC7 colocalized with both polyQ and polyG aggregates and reduced their aggregation. Direct knockdown of DNAJC7 did not affect polyG aggregation in the baseline model (negative result for polyG).","method":"FRET-based aggregation reporter, CRISPRi screen (all chaperones), KD validation, overexpression colocalization in human cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide CRISPRi screen with functional validation including KD and OE; single lab, multiple orthogonal assays","pmids":["41708002"],"is_preprint":false}],"current_model":"DNAJC7 (TPR2) is an HSP40/J-domain co-chaperone that bridges the Hsp70 and Hsp90 chaperone machines: its two TPR domains bind simultaneously to the EEVD motifs of Hsp70 and Hsp90, while its J domain stimulates Hsp70 ATPase activity to drive substrate processing; it mediates retrograde transfer of substrates from Hsp90 back to Hsp70, regulates steroid receptor (GR, PR) and nuclear receptor (CAR) chaperoning, stabilizes p53 by disrupting the p53–MDM2 interaction (itself regulated by USP19-mediated deubiquitination), binds natively folded tau via a single TPR domain to prevent conversion to amyloids in an Hsp70-dependent manner, suppresses TDP-43 and polyQ protein aggregation, and ALS-associated mutations in its J domain (e.g., E425K) structurally preserve the protein but selectively uncouple it from Hsp70 activation, abolishing client refolding while retaining holdase activity."},"narrative":{"mechanistic_narrative":"DNAJC7 (Tpr2) is an HSP40/J-domain co-chaperone that physically bridges the Hsp70 and Hsp90 chaperone machines, using two TPR domains to bind Hsp70 and Hsp90 simultaneously while its J domain stimulates Hsp70 ATPase activity and polypeptide binding [PMID:12853476]. Unlike other co-chaperones, it induces ATP-independent dissociation of Hsp90 from chaperone-substrate complexes, mediating retrograde transfer of substrates from Hsp90 back onto Hsp70 [PMID:12853476], and it substitutes for J proteins in Hsp90-dependent maturation of clients such as the progesterone receptor and Chk1 [PMID:18620420]. Through this co-chaperone activity DNAJC7 regulates the chaperoning and signaling of steroid and nuclear receptors, retaining the constitutive androstane receptor (CAR) in the cytoplasm and being itself degraded by the proteasome upon CAR activation [PMID:12853476, PMID:24789201], and acting in the nucleus where it is required for phenobarbital-induced H3K27 demethylation and RNA polymerase II recruitment at the Cyp2b10 promoter [PMID:25542016]. A second major function is suppression of pathological protein aggregation: DNAJC7 binds natively folded tau via a single TPR domain recognizing a β-turn around the 275VQIINK280 amyloid motif and blocks tau aggregation and seeding in an Hsp70 ATPase-dependent manner [PMID:34504072, PMID:37387473], and it likewise suppresses TDP-43 condensate assembly and polyglutamine aggregation while promoting their disassembly/clearance [PMID:40802071, PMID:41708002]. ALS-associated J-domain mutations (e.g., E425K) leave the protein structurally intact and preserve TPR-mediated holdase binding to clients, but selectively uncouple DNAJC7 from Hsp70 activation, abolishing client transfer and refolding [PMID:41531269], consistent with loss-of-function ALS mutations that increase client RBP insolubility and ablate the HSF1 stress-response pathway in motor neurons [PMID:39651147]. DNAJC7 additionally stabilizes p53 by disrupting the p53–MDM2 interaction, an activity reinforced by USP19-mediated deubiquitination of DNAJC7 [PMID:23261415, PMID:42193933].","teleology":[{"year":2001,"claim":"Established that DNAJC7's TPR region engages specific clients and that its J domain actively gates these interactions, hinting the protein is more than a passive scaffold.","evidence":"Yeast two-hybrid and in vitro/in vivo binding with HPD-motif mutagenesis against Rad9/Rad1/Hus1 checkpoint proteins","pmids":["11573955"],"confidence":"Medium","gaps":["Functional consequence for the checkpoint clamp not resolved","Link to Hsp70/Hsp90 machinery not yet drawn"]},{"year":2003,"claim":"Defined the core biochemical mechanism: DNAJC7 bridges Hsp70 and Hsp90, stimulates Hsp70 ATPase, and uniquely drives retrograde substrate transfer from Hsp90 to Hsp70.","evidence":"In vitro ATPase and polypeptide-binding assays, cell-lysate GR folding assays, domain-binding studies","pmids":["12853476"],"confidence":"High","gaps":["Physiological clients of retrograde transfer not enumerated","Structural basis of dual TPR/EEVD engagement not resolved"]},{"year":2008,"claim":"Showed DNAJC7 can replace J proteins in Hsp90-dependent client maturation but is distinct from Hop, clarifying its non-redundant role in steroid receptor chaperoning.","evidence":"Reciprocal Co-IP and in vitro/in vivo chaperoning assays for PR and Chk1 in HeLa cells","pmids":["18620420"],"confidence":"High","gaps":["ATP-dependence of Hsp70 binding mechanistically unexplained","Range of clients beyond PR/Chk1 unknown"]},{"year":2012,"claim":"Identified a chaperone-independent role in tumor suppression, with DNAJC7 stabilizing p53 by displacing MDM2.","evidence":"Yeast two-hybrid, Co-IP, luciferase reporter, colony formation, and p53 half-life analysis","pmids":["23261415"],"confidence":"Medium","gaps":["Direct vs chaperone-mediated mechanism of MDM2 displacement unclear","Whether Hsp70/Hsp90 participate not addressed"]},{"year":2014,"claim":"Connected DNAJC7 to nuclear receptor regulation, showing it retains CAR in the cytoplasm and is itself degraded upon CAR activation; in vivo it controls promoter epigenetics rather than receptor binding.","evidence":"Co-IP, ubiquitination/MG132 assays and reporters in HepG2 cells; knockout mice with ChIP at the Cyp2b10 promoter","pmids":["24789201","25542016"],"confidence":"High","gaps":["How a cytoplasmic co-chaperone influences promoter H3K27 demethylation is mechanistically undefined","Identity of the ubiquitin ligase for DNAJC7 unknown"]},{"year":2016,"claim":"Revealed DNAJC7 as a substrate of polyglutamylation regulated by CCP6, a post-translational modification with potential as a cancer biomarker.","evidence":"Mass spectrometry, pulldown, immunohistochemistry and immunoassay in renal cell carcinoma","pmids":["26993597"],"confidence":"Medium","gaps":["Functional effect of polyglutamylation on chaperone activity unknown","Single-lab biomarker observation"]},{"year":2021,"claim":"Defined the structural logic of DNAJC7 anti-aggregation activity: a single TPR domain recognizes the tau β-turn/amyloid motif to keep tau natively folded.","evidence":"In vitro aggregation and binding assays, domain mapping, peptide competition, cell-based aggregation","pmids":["34504072"],"confidence":"High","gaps":["Dependence on Hsp70 not yet tested in this study","Whether TPR recognition generalizes to other amyloid clients unknown"]},{"year":2022,"claim":"Extended the bridging mechanism to antiviral defense, with DNAJC7 linking Hsp70 to a viral Hexon protein for autophagic degradation.","evidence":"LC-MS/MS interaction screen, Co-IP, domain deletion, autophagy inhibitor experiments","pmids":["35852354"],"confidence":"Medium","gaps":["Generality beyond FAdV-4 unknown","Mechanism of Hsp70-to-autophagy handoff not detailed"]},{"year":2023,"claim":"Demonstrated that tau protection is specifically Hsp70-dependent: among all JDPs, only DNAJC7 loss impairs aggregate clearance, and both J-domain and substrate-binding mutations abolish protection.","evidence":"Proteomics, CRISPR knockout of all JDPs, tau seeding assays, colocalization imaging, J-domain mutagenesis","pmids":["37387473"],"confidence":"High","gaps":["In vivo relevance in neurons not established here","Quantitative contribution of holdase vs Hsp70-coupled clearance unresolved"]},{"year":2024,"claim":"Linked DNAJC7 loss-of-function to ALS pathology in human motor neurons, showing client RBP insolubility and an ablated HSF1 stress response rescuable by exogenous HSF1.","evidence":"MS interactome, iPSC-derived motor neurons (R156X), solubility fractionation, HSF1 rescue, RNA-seq (preprint)","pmids":["39651147"],"confidence":"Medium","gaps":["Preprint, single lab","Mechanism by which DNAJC7 haploinsufficiency disables HSF1 signaling unclear"]},{"year":2025,"claim":"Broadened the anti-aggregation role to TDP-43 condensate dynamics and identified a USP19 deubiquitination axis that stabilizes DNAJC7 to support p53.","evidence":"TDP-43 condensate assays with arsenite stress and zebrafish dnajc7 knockdown; USP19-DnaJC7 Co-IP, deubiquitination and p53 stability assays","pmids":["40802071","42193933"],"confidence":"Medium","gaps":["Direct vs Hsp70-mediated control of TDP-43 condensates not separated","How USP19 regulation intersects with chaperone activity unknown"]},{"year":2026,"claim":"Resolved the molecular defect of ALS mutation E425K and confirmed broad anti-aggregation function: the mutant preserves structure and TPR-mediated holdase activity but selectively uncouples from Hsp70, while DNAJC7 also suppresses polyQ aggregation.","evidence":"NMR, in vitro binding and Hsp70 ATPase assays, TDP-43 aggregation assays; genome-wide CRISPRi chaperone screen with KD/OE polyQ aggregation validation","pmids":["41531269","41708002"],"confidence":"High","gaps":["In vivo demonstration that holdase activity alone is insufficient in neurons lacking","Whether other ALS mutations act by the same uncoupling mechanism not exhaustively tested"]},{"year":null,"claim":"How DNAJC7's cytoplasmic co-chaperone activity is mechanistically coupled to its nuclear functions (Cyp2b10 promoter epigenetics, p53 stabilization) and how client specificity is partitioned between TPR holdase and Hsp70-coupled refolding across its many clients remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking chaperone bridging to transcriptional/epigenetic roles","Structural basis of differential client recognition by TPR domains incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,8,11]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,8,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[7,11,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,4,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,5]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,7,8]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[10,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,5]}],"complexes":["Hsp70-Hsp90 chaperone complex"],"partners":["HSPA1A","HSP90","TP53","MDM2","USP19","MAPT","TARDBP","NR1I3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99615","full_name":"DnaJ homolog subfamily C member 7","aliases":["Tetratricopeptide repeat protein 2","TPR repeat protein 2"],"length_aa":494,"mass_kda":56.4,"function":"Acts as a co-chaperone regulating the molecular chaperones HSP70 and HSP90 in folding of steroid receptors, such as the glucocorticoid receptor and the progesterone receptor. Proposed to act as a recycling chaperone by facilitating the return of chaperone substrates to early stages of chaperoning if further folding is required. In vitro, induces ATP-independent dissociation of HSP90 but not of HSP70 from the chaperone-substrate complexes. Recruits NR1I3 to the cytoplasm (By similarity)","subcellular_location":"Cytoplasm; Nucleus; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q99615/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DNAJC7","classification":"Not Classified","n_dependent_lines":25,"n_total_lines":1208,"dependency_fraction":0.020695364238410598},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000168259","cell_line_id":"CID000036","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"big_aggregates","grade":2}],"interactors":[{"gene":"BAG2","stoichiometry":10.0},{"gene":"BRD2","stoichiometry":4.0},{"gene":"TUBA1A;TUBA3E","stoichiometry":4.0},{"gene":"TUBB4B","stoichiometry":4.0},{"gene":"BAG5","stoichiometry":4.0},{"gene":"HSPA5","stoichiometry":4.0},{"gene":"CXORF57","stoichiometry":0.2},{"gene":"RNF219","stoichiometry":0.2},{"gene":"MLK4","stoichiometry":0.2},{"gene":"HSP90AB2P","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000036","total_profiled":1310},"omim":[{"mim_id":"601964","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 7; DNAJC7","url":"https://www.omim.org/entry/601964"},{"mim_id":"123830","title":"CYCLIC NUCLEOTIDE PHOSPHODIESTERASE; CNP","url":"https://www.omim.org/entry/123830"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DNAJC7"},"hgnc":{"alias_symbol":["TPR2"],"prev_symbol":["TTC2"]},"alphafold":{"accession":"Q99615","domains":[{"cath_id":"1.25.40.10","chopping":"21-144","consensus_level":"medium","plddt":96.8888,"start":21,"end":144},{"cath_id":"1.25.40.10","chopping":"189-242","consensus_level":"medium","plddt":96.1426,"start":189,"end":242},{"cath_id":"1.25.40.10","chopping":"283-377","consensus_level":"high","plddt":96.6073,"start":283,"end":377},{"cath_id":"1.10.287.110","chopping":"381-447","consensus_level":"high","plddt":91.65,"start":381,"end":447}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99615","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99615-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99615-F1-predicted_aligned_error_v6.png","plddt_mean":90.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DNAJC7","jax_strain_url":"https://www.jax.org/strain/search?query=DNAJC7"},"sequence":{"accession":"Q99615","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99615.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99615/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99615"}},"corpus_meta":[{"pmid":"31768050","id":"PMC_31768050","title":"Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7, encoding a heat-shock protein.","date":"2019","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31768050","citation_count":110,"is_preprint":false},{"pmid":"12853476","id":"PMC_12853476","title":"Cofactor Tpr2 combines two TPR domains and a J domain to regulate the Hsp70/Hsp90 chaperone system.","date":"2003","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/12853476","citation_count":107,"is_preprint":false},{"pmid":"30514725","id":"PMC_30514725","title":"ABI5-BINDING PROTEIN2 Coordinates CONSTANS to Delay Flowering by Recruiting the Transcriptional Corepressor TPR2.","date":"2018","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30514725","citation_count":42,"is_preprint":false},{"pmid":"18620420","id":"PMC_18620420","title":"Role of the cochaperone Tpr2 in Hsp90 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of co-chaperone CCRP/DNAJC7 in Cyp2b10 gene activation and steatosis development in mouse livers.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25542016","citation_count":21,"is_preprint":false},{"pmid":"37387473","id":"PMC_37387473","title":"DnaJC7 specifically regulates tau seeding.","date":"2023","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/37387473","citation_count":18,"is_preprint":false},{"pmid":"23261415","id":"PMC_23261415","title":"Co-chaperon DnaJC7/TPR2 enhances p53 stability and activity through blocking the complex formation between p53 and MDM2.","date":"2012","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/23261415","citation_count":16,"is_preprint":false},{"pmid":"11573955","id":"PMC_11573955","title":"The J domain of Tpr2 regulates its interaction with the proapoptotic and cell-cycle checkpoint protein, Rad9.","date":"2001","source":"Biochemical and biophysical research 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Unlike other co-chaperones, Tpr2 induces ATP-independent dissociation of Hsp90 (but not Hsp70) from chaperone-substrate complexes, mediating retrograde transfer of substrates from Hsp90 back onto Hsp70. Excess Tpr2 inhibits Hsp90-dependent folding of the glucocorticoid receptor (GR) in cell lysates.\",\n      \"method\": \"In vitro biochemical assays (ATPase stimulation, polypeptide binding), cell lysate GR folding assays, domain-binding studies, overexpression/knockdown in vivo\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with ATPase assay and polypeptide binding, combined with cell lysate folding assay and in vivo GR activation; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"12853476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Tpr2 (DNAJC7) associates with Hsp90 and Hsp70 complexes that also contain the progesterone receptor (PR); it can bind Hsp70 and Hsp90 simultaneously, but unlike Hop, its binding to Hsp70 in the presence of Hsp90 is ATP-dependent. Tpr2 cannot replace Hop in Hsp90 chaperoning in vitro or in vivo. Tpr2 replaces type I and II J proteins in Hsp90-dependent chaperoning of the PR and Chk1 kinase and promotes accumulation of Hsp70 in PR heterocomplexes in the presence of Hsp90.\",\n      \"method\": \"Immunoprecipitation, pulldown, in vitro and in vivo chaperoning assays, knockdown/overexpression in HeLa cells\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reciprocal Co-IP, in vitro chaperoning assays, KD/OE with defined PR activity readout; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"18620420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Tpr2 (DNAJC7) binds Rad9, Rad1, and Hus1 (checkpoint clamp proteins) through its N-terminal TPR region. The J domain of Tpr2 negatively regulates its interaction with Rad9: deletion of the J domain or mutation of the conserved HPD motif greatly enhances Tpr2-Rad9 binding. Following heat-shock or UV treatment, Rad9 transiently dissociates from Tpr2 in a J-domain-dependent manner. The J domain also modulates the cellular localization of both Tpr2 and Rad9.\",\n      \"method\": \"Yeast two-hybrid screening, in vivo and in vitro binding assays, J-domain point mutation (HPD motif), cellular localization analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal in vivo/in vitro binding with mutagenesis of HPD motif, multiple substrates tested, single lab\",\n      \"pmids\": [\"11573955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DnaJC7/TPR2 binds p53 through its central DNA-binding domain (identified by yeast two-hybrid), confirmed by co-immunoprecipitation in mammalian cells. DnaJC7 enhances p53-dependent transcriptional and growth-suppressive activity, extends p53 half-life, and reduces the amount of p53/MDM2 complex, suggesting DnaJC7 dissociates MDM2 from p53 to stabilize p53.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, luciferase reporter assay, colony formation assay, pulse-chase/half-life analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmed yeast two-hybrid; functional readouts (reporter, growth suppression, p53 half-life); single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23261415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CCRP/DNAJC7 interacts with HSP70 (co-immunoprecipitation in HepG2 cells) and retains nuclear receptor CAR in the cytoplasm. DNAJC7 is ubiquitinated and degraded by the proteasome upon CAR activation; this ubiquitination of DNAJC7 (but not CAR itself) is increased by TCPOBOP in the presence of MG132. HSP70 induction by heat shock also increases cytoplasmic CAR levels and attenuates CAR transcriptional activation, phenocopying proteasome inhibition.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor (MG132) treatment, ubiquitination assay, luciferase reporter assay, heat shock experiments in HepG2 cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, functional reporter; single lab, multiple methods\",\n      \"pmids\": [\"24789201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CCRP/DNAJC7 knockout mice show increased nuclear CAR accumulation after phenobarbital treatment but paradoxically attenuated Cyp2b10 gene activation. ChIP assays reveal that DNAJC7 is required for phenobarbital-induced de-methylation of H3K27 on the Cyp2b10 promoter and for RNA polymerase II recruitment, but not for CAR/RXRα binding to the promoter. DNAJC7 KO males also develop steatotic livers and altered cholesterol levels upon fasting.\",\n      \"method\": \"Knockout mouse model, ChIP assays (H3K27 methylation, RNA Pol II, CAR/RXRα), immunoblotting, gene expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO mouse with ChIP demonstrating specific epigenetic and transcriptional mechanism; multiple orthogonal assays, defines pathway position\",\n      \"pmids\": [\"25542016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mass spectrometric and pulldown analysis identified DNAJC7 as a substrate of cytosolic carboxypeptidase 6 (CCP6). When CCP6 is reduced (as in RCC), DNAJC7 accumulates in a polyglutamylated form (polyE-DNAJC7) detectable in serum.\",\n      \"method\": \"Mass spectrometry, pulldown assay, immunohistochemistry, Western blot, electrochemiluminescence immunoassay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification and pulldown confirm CCP6-DNAJC7 substrate relationship; single lab\",\n      \"pmids\": [\"26993597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DnaJC7 binds preferentially to natively folded wild-type tau (not aggregated conformers) using a single TPR domain that recognizes a β-turn structural element containing the 275VQIINK280 amyloid motif. Disease-associated tau mutants that disrupt this β-turn reduce DnaJC7 binding affinity. DnaJC7 efficiently suppresses tau aggregation in vitro and in cells.\",\n      \"method\": \"In vitro aggregation assays, binding affinity measurements, domain mapping (single TPR domain), peptide competition assays, cell-based aggregation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of binding and inhibition of aggregation, domain-level mechanistic dissection with multiple tau variants, validated in cells; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"34504072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DnaJC7 co-purifies with insoluble tau and colocalizes with intracellular tau aggregates. Knockout of DnaJC7 (but not other JDPs) specifically decreases aggregate clearance and increases intracellular tau seeding. This protective activity depends on the ability of the DnaJC7 J domain to stimulate Hsp70 ATPase activity; J-domain mutations blocking Hsp70 interaction abolish protection. Disease-associated mutations in both the J domain and the substrate-binding site of DnaJC7 also abolish protective activity.\",\n      \"method\": \"Proteomics (co-purification with insoluble tau), CRISPR knockout of all JDPs individually, tau seeding assay, co-localization imaging, J-domain mutagenesis (HPD motif and ALS variants)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic KO screen of all JDPs with functional seeding assay, mechanistic dissection via mutagenesis, proteomics; multiple orthogonal methods, defines specificity\",\n      \"pmids\": [\"37387473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DnaJC7 acts as a bridge between Hsp70 and viral Hexon protein: the J domain of DnaJC7 is required for inhibiting FAdV-4 replication, and DnaJC7 mediates the indirect interaction between Hsp70 and Hexon. Hsp70 subsequently suppresses Hexon through the autophagy pathway to restrict viral replication.\",\n      \"method\": \"LC-MS/MS protein interaction screen, Co-IP, domain deletion analysis (J domain of DnaJC7, NBD of Hsp70), overexpression and autophagy inhibitor (chloroquine) experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain dissection, functional viral replication assay, autophagy pathway involvement confirmed; single lab\",\n      \"pmids\": [\"35852354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DNAJC7 knockdown impairs disassembly of TDP-43 condensates following arsenite-induced stress, while DNAJC7 overexpression suppresses assembly and promotes disassembly of arsenite-induced TDP-43 condensates. In a zebrafish ALS model, dnajc7 knockdown increases TDP-43 aggregation in motor neurons and reduces survival.\",\n      \"method\": \"Cell-based TDP-43 condensate assay with arsenite stress, DNAJC7 KD and OE, zebrafish dnajc7 morpholino knockdown, immunohistochemistry, RNA sequencing\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD/OE with specific TDP-43 condensate phenotype, validated in zebrafish model; single lab, two orthogonal systems\",\n      \"pmids\": [\"40802071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The ALS-associated E425K mutation in the DNAJC7 J domain does not alter protein structure (confirmed by NMR) but specifically disrupts J-domain–Hsp70 interaction, uncoupling DNAJC7 from Hsp70 activation. A second Hsp70-binding interface exists in the TPR domains (binding the C-terminal EEVD motif of Hsp70), which is preserved in E425K but cannot compensate for loss of J-domain function. The TPR domains of DNAJC7 directly bind TDP-43 and prevent its aggregation (holdase activity retained in E425K), but the mutant fails to support client transfer to Hsp70 and subsequent Hsp70-mediated substrate refolding.\",\n      \"method\": \"NMR spectroscopy (structural and interaction analysis), in vitro binding assays, Hsp70 ATPase activation assay, TDP-43 aggregation assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural validation combined with in vitro ATPase and aggregation assays and mutagenesis; single lab with multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"41531269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The DNAJC7 interactome in human motor neurons (iPSC-derived) is enriched for RNA-binding proteins (RBPs) and stress-response chaperones (mass spectrometry). The ALS-associated R156X loss-of-function mutation causes increased insolubility of client RBP HNRNPU and associated RNA metabolism alterations. DNAJC7 haploinsufficiency renders motor neurons susceptible to proteotoxic stress and cell death through an ablated HSF1 stress-response pathway; exogenous HSF1 expression rescues sensitivity to proteotoxic stress in DNAJC7-mutant motor neurons.\",\n      \"method\": \"Mass spectrometry interactome, iPSC-derived motor neurons with ALS mutation (R156X), protein solubility fractionation, HSF1 rescue experiment, RNA sequencing\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS interactome plus mechanistic rescue experiment in disease-relevant cell type; preprint, single lab\",\n      \"pmids\": [\"39651147\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP19 deubiquitinates DnaJC7, increasing its protein stability. Upregulation of both USP19 and DnaJC7 disrupts the p53-MDM2 interaction; knockdown of USP19 and DnaJC7 decreases p53 expression following cisplatin treatment, indicating that the USP19-DnaJC7 axis stabilizes p53.\",\n      \"method\": \"Co-immunoprecipitation (USP19-DnaJC7 interaction), deubiquitination assay, knockdown experiments, p53 stability and MDM2 interaction assays in cisplatin-treated cells\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and deubiquitination assay confirm USP19 as eraser of DnaJC7 ubiquitination, KD experiments link to p53; single lab, multiple methods\",\n      \"pmids\": [\"42193933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DNAJC7 is a potent suppressor of polyglutamine (polyQ) aggregation, identified in a genome-wide CRISPRi screen of all chaperones. Physical interaction between DNAJC7 and polyQ-expanded protein was established. DNAJC7 knockdown specifically increased polyQ aggregation, while overexpressed DNAJC7 colocalized with both polyQ and polyG aggregates and reduced their aggregation. Direct knockdown of DNAJC7 did not affect polyG aggregation in the baseline model (negative result for polyG).\",\n      \"method\": \"FRET-based aggregation reporter, CRISPRi screen (all chaperones), KD validation, overexpression colocalization in human cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide CRISPRi screen with functional validation including KD and OE; single lab, multiple orthogonal assays\",\n      \"pmids\": [\"41708002\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DNAJC7 (TPR2) is an HSP40/J-domain co-chaperone that bridges the Hsp70 and Hsp90 chaperone machines: its two TPR domains bind simultaneously to the EEVD motifs of Hsp70 and Hsp90, while its J domain stimulates Hsp70 ATPase activity to drive substrate processing; it mediates retrograde transfer of substrates from Hsp90 back to Hsp70, regulates steroid receptor (GR, PR) and nuclear receptor (CAR) chaperoning, stabilizes p53 by disrupting the p53–MDM2 interaction (itself regulated by USP19-mediated deubiquitination), binds natively folded tau via a single TPR domain to prevent conversion to amyloids in an Hsp70-dependent manner, suppresses TDP-43 and polyQ protein aggregation, and ALS-associated mutations in its J domain (e.g., E425K) structurally preserve the protein but selectively uncouple it from Hsp70 activation, abolishing client refolding while retaining holdase activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DNAJC7 (Tpr2) is an HSP40/J-domain co-chaperone that physically bridges the Hsp70 and Hsp90 chaperone machines, using two TPR domains to bind Hsp70 and Hsp90 simultaneously while its J domain stimulates Hsp70 ATPase activity and polypeptide binding [#0]. Unlike other co-chaperones, it induces ATP-independent dissociation of Hsp90 from chaperone-substrate complexes, mediating retrograde transfer of substrates from Hsp90 back onto Hsp70 [#0], and it substitutes for J proteins in Hsp90-dependent maturation of clients such as the progesterone receptor and Chk1 [#1]. Through this co-chaperone activity DNAJC7 regulates the chaperoning and signaling of steroid and nuclear receptors, retaining the constitutive androstane receptor (CAR) in the cytoplasm and being itself degraded by the proteasome upon CAR activation [#0, #4], and acting in the nucleus where it is required for phenobarbital-induced H3K27 demethylation and RNA polymerase II recruitment at the Cyp2b10 promoter [#5]. A second major function is suppression of pathological protein aggregation: DNAJC7 binds natively folded tau via a single TPR domain recognizing a \\u03b2-turn around the 275VQIINK280 amyloid motif and blocks tau aggregation and seeding in an Hsp70 ATPase-dependent manner [#7, #8], and it likewise suppresses TDP-43 condensate assembly and polyglutamine aggregation while promoting their disassembly/clearance [#10, #14]. ALS-associated J-domain mutations (e.g., E425K) leave the protein structurally intact and preserve TPR-mediated holdase binding to clients, but selectively uncouple DNAJC7 from Hsp70 activation, abolishing client transfer and refolding [#11], consistent with loss-of-function ALS mutations that increase client RBP insolubility and ablate the HSF1 stress-response pathway in motor neurons [#12]. DNAJC7 additionally stabilizes p53 by disrupting the p53\\u2013MDM2 interaction, an activity reinforced by USP19-mediated deubiquitination of DNAJC7 [#3, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that DNAJC7's TPR region engages specific clients and that its J domain actively gates these interactions, hinting the protein is more than a passive scaffold.\",\n      \"evidence\": \"Yeast two-hybrid and in vitro/in vivo binding with HPD-motif mutagenesis against Rad9/Rad1/Hus1 checkpoint proteins\",\n      \"pmids\": [\"11573955\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence for the checkpoint clamp not resolved\", \"Link to Hsp70/Hsp90 machinery not yet drawn\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the core biochemical mechanism: DNAJC7 bridges Hsp70 and Hsp90, stimulates Hsp70 ATPase, and uniquely drives retrograde substrate transfer from Hsp90 to Hsp70.\",\n      \"evidence\": \"In vitro ATPase and polypeptide-binding assays, cell-lysate GR folding assays, domain-binding studies\",\n      \"pmids\": [\"12853476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological clients of retrograde transfer not enumerated\", \"Structural basis of dual TPR/EEVD engagement not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed DNAJC7 can replace J proteins in Hsp90-dependent client maturation but is distinct from Hop, clarifying its non-redundant role in steroid receptor chaperoning.\",\n      \"evidence\": \"Reciprocal Co-IP and in vitro/in vivo chaperoning assays for PR and Chk1 in HeLa cells\",\n      \"pmids\": [\"18620420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ATP-dependence of Hsp70 binding mechanistically unexplained\", \"Range of clients beyond PR/Chk1 unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a chaperone-independent role in tumor suppression, with DNAJC7 stabilizing p53 by displacing MDM2.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, luciferase reporter, colony formation, and p53 half-life analysis\",\n      \"pmids\": [\"23261415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs chaperone-mediated mechanism of MDM2 displacement unclear\", \"Whether Hsp70/Hsp90 participate not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected DNAJC7 to nuclear receptor regulation, showing it retains CAR in the cytoplasm and is itself degraded upon CAR activation; in vivo it controls promoter epigenetics rather than receptor binding.\",\n      \"evidence\": \"Co-IP, ubiquitination/MG132 assays and reporters in HepG2 cells; knockout mice with ChIP at the Cyp2b10 promoter\",\n      \"pmids\": [\"24789201\", \"25542016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a cytoplasmic co-chaperone influences promoter H3K27 demethylation is mechanistically undefined\", \"Identity of the ubiquitin ligase for DNAJC7 unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed DNAJC7 as a substrate of polyglutamylation regulated by CCP6, a post-translational modification with potential as a cancer biomarker.\",\n      \"evidence\": \"Mass spectrometry, pulldown, immunohistochemistry and immunoassay in renal cell carcinoma\",\n      \"pmids\": [\"26993597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional effect of polyglutamylation on chaperone activity unknown\", \"Single-lab biomarker observation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the structural logic of DNAJC7 anti-aggregation activity: a single TPR domain recognizes the tau \\u03b2-turn/amyloid motif to keep tau natively folded.\",\n      \"evidence\": \"In vitro aggregation and binding assays, domain mapping, peptide competition, cell-based aggregation\",\n      \"pmids\": [\"34504072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dependence on Hsp70 not yet tested in this study\", \"Whether TPR recognition generalizes to other amyloid clients unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the bridging mechanism to antiviral defense, with DNAJC7 linking Hsp70 to a viral Hexon protein for autophagic degradation.\",\n      \"evidence\": \"LC-MS/MS interaction screen, Co-IP, domain deletion, autophagy inhibitor experiments\",\n      \"pmids\": [\"35852354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality beyond FAdV-4 unknown\", \"Mechanism of Hsp70-to-autophagy handoff not detailed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that tau protection is specifically Hsp70-dependent: among all JDPs, only DNAJC7 loss impairs aggregate clearance, and both J-domain and substrate-binding mutations abolish protection.\",\n      \"evidence\": \"Proteomics, CRISPR knockout of all JDPs, tau seeding assays, colocalization imaging, J-domain mutagenesis\",\n      \"pmids\": [\"37387473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance in neurons not established here\", \"Quantitative contribution of holdase vs Hsp70-coupled clearance unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked DNAJC7 loss-of-function to ALS pathology in human motor neurons, showing client RBP insolubility and an ablated HSF1 stress response rescuable by exogenous HSF1.\",\n      \"evidence\": \"MS interactome, iPSC-derived motor neurons (R156X), solubility fractionation, HSF1 rescue, RNA-seq (preprint)\",\n      \"pmids\": [\"39651147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Mechanism by which DNAJC7 haploinsufficiency disables HSF1 signaling unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Broadened the anti-aggregation role to TDP-43 condensate dynamics and identified a USP19 deubiquitination axis that stabilizes DNAJC7 to support p53.\",\n      \"evidence\": \"TDP-43 condensate assays with arsenite stress and zebrafish dnajc7 knockdown; USP19-DnaJC7 Co-IP, deubiquitination and p53 stability assays\",\n      \"pmids\": [\"40802071\", \"42193933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs Hsp70-mediated control of TDP-43 condensates not separated\", \"How USP19 regulation intersects with chaperone activity unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved the molecular defect of ALS mutation E425K and confirmed broad anti-aggregation function: the mutant preserves structure and TPR-mediated holdase activity but selectively uncouples from Hsp70, while DNAJC7 also suppresses polyQ aggregation.\",\n      \"evidence\": \"NMR, in vitro binding and Hsp70 ATPase assays, TDP-43 aggregation assays; genome-wide CRISPRi chaperone screen with KD/OE polyQ aggregation validation\",\n      \"pmids\": [\"41531269\", \"41708002\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo demonstration that holdase activity alone is insufficient in neurons lacking\", \"Whether other ALS mutations act by the same uncoupling mechanism not exhaustively tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DNAJC7's cytoplasmic co-chaperone activity is mechanistically coupled to its nuclear functions (Cyp2b10 promoter epigenetics, p53 stabilization) and how client specificity is partitioned between TPR holdase and Hsp70-coupled refolding across its many clients remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking chaperone bridging to transcriptional/epigenetic roles\", \"Structural basis of differential client recognition by TPR domains incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 8, 11]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 8, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [7, 11, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 4, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 7, 8]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [10, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [\"Hsp70-Hsp90 chaperone complex\"],\n    \"partners\": [\"HSPA1A\", \"HSP90\", \"TP53\", \"MDM2\", \"USP19\", \"MAPT\", \"TARDBP\", \"NR1I3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}