{"gene":"DNAJB14","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2012,"finding":"DNAJB14 is an ER-localized, single membrane-spanning J-protein with its J-domain facing the cytosol, as determined by immunofluorescence and protease protection assay. It binds Hsc70 via its J-domain (co-immunoprecipitation), recruits Hsc70 to the ER membrane, and accelerates ERAD of misfolded membrane proteins (e.g., CFTRΔF508) through the ubiquitin-proteasome system, but does not accelerate degradation of misfolded luminal proteins.","method":"Immunofluorescence, protease protection assay, co-immunoprecipitation, overexpression with proteasome inhibitor (MG132) and degradation assay","journal":"Cell structure and function","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in a single study with functional readouts (localization, binding, degradation assay with inhibitor controls)","pmids":["23018488"],"is_preprint":false},{"year":2016,"finding":"DNAJB14 promotes tetrameric assembly of ERG (hERG) and Kv4.2 K+ channel subunits in the ER through an HSP70-independent mechanism. Overexpression of DNAJB14 significantly rescued defective function of hERG mutant channels associated with long QT syndrome by stabilizing the mutated proteins.","method":"Genetic screening in C. elegans and human cells, in vitro assembly assay, electrophysiology, overexpression rescue experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro assembly assay plus genetic and cell-based functional validation across two organisms","pmids":["27916661"],"is_preprint":false},{"year":2014,"finding":"Overexpression of DNAJB14 (or DNAJB12) causes formation of elaborate membranous structures (DJANGOS) within cell nuclei that contain DNAJB14, DNAJB12, Hsc70, and ER lumen/membrane markers; these are connected to the nuclear envelope via a unique nuclear pore configuration. Genetic studies showed that the J-domain chaperone activity of DNAJ/Hsc70 is required for DJANGOS formation.","method":"Immunofluorescence, electron microscopy (cryo-EM), genetic mutation analysis of J-domain chaperone activity, live-cell imaging","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization with functional (genetic) follow-up but single lab study","pmids":["24732912"],"is_preprint":false},{"year":2022,"finding":"Full-length DNAJB14 forms a complex with full-length DNAJB12 (but not with their short isoforms) that substantially protects from mutant FUS aggregation in an HSP70-dependent manner. DNAJB14-FL expression increases the mobility of mutFUS aggregates and restores deteriorated proteostasis in mutFUS aggregate-containing cells and primary neurons.","method":"Co-immunoprecipitation (complex identification), fluorescence recovery after photobleaching (FRAP), proteostasis assays, knockdown/overexpression in primary neurons","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP for complex identification combined with multiple functional readouts including primary neuron experiments","pmids":["35082301"],"is_preprint":false},{"year":2023,"finding":"DNAJB14 and DNAJB12 are non-redundant ER transmembrane chaperones involved in ER protein reflux (ER-to-cytosol translocation of PDI). Knockdown of DNAJB14 (and DNAJB12) in ER-stressed cells significantly impairs the amount of PDI in cytosolic-enriched fractions. DNAJB14 protein levels are degraded by the proteasome upon acute reductive challenge, and their ER-lumen DUF1977 domains are dissimilar between B12 and B14, suggesting functional non-redundancy. DNAJB14 transcripts are upregulated during UPR activation.","method":"Knockdown, subcellular fractionation, proteasome inhibitor assay, sulfenic-acid trapping (dimedone), interactome analysis","journal":"Biochimica et biophysica acta. General subjects","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods (fractionation, knockdown, chemical biology) but single lab study","pmids":["37925033"],"is_preprint":false},{"year":2023,"finding":"DNAJB14 (JB14) overexpression affects PINK1 protein levels under CCCP-mediated mitochondrial stress, and JB14 knockout leads to prolonged stabilization of PINK1 during chronic CCCP exposure. Cells depleted of JB14 also exhibit increased mitochondrial count and branching, and an altered kinetics of phosphorylated Drp1 in response to CCCP stress.","method":"Genetic knockout, overexpression, western blot for PINK1 and p-Drp1, mitochondrial morphology imaging","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, but single lab and limited mechanistic follow-up","pmids":["37851175"],"is_preprint":false},{"year":2025,"finding":"DNAJB14 (together with DNAJB12) facilitates ER-protein reflux (ERCYS) by binding HSC70 and the cochaperone SGTA through their cytosolically localized J-domains. Mutations in the DNAJB14 J-domain prevent the inhibitory interaction between refluxed AGR2 and wt-p53. DNAJB14 and DNAJB12 knockdown rescues wt-p53 and caspase-3 activity in cancer cells.","method":"J-domain mutagenesis, co-immunoprecipitation, knockdown, subcellular fractionation, functional p53/caspase-3 activity assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 — J-domain mutagenesis combined with co-IP, KD rescue, and functional enzymatic readouts in same study","pmids":["40202782"],"is_preprint":false},{"year":2025,"finding":"DNAJB14 knockdown selectively impairs morphogenesis of HBV virions (but not subviral particles), and knockdown of DNAJB14 (and DNAJB12) hinders production of infectious HDV, identifying DNAJB14 as required for HBV virion and HDV morphogenesis.","method":"siRNA knockdown, virion/SVP secretion assay, HDV infectivity assay","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — clean knockdown with specific viral phenotypic readouts, but single lab and no mechanistic follow-up of how DNAJB14 acts on HBV assembly","pmids":["41684842"],"is_preprint":false},{"year":2025,"finding":"DNAJB14 (with DNAJB12) facilitates redistribution of PDIA4 from the ER to the cytosol during ER stress; in the cytosol, PDIA4 inhibits caspase-3 and wt-p53. Silencing DNAJB14/DNAJB12 or SGTA rescues wt-p53 and caspase-3 activity and reduces chemoresistance.","method":"siRNA knockdown, subcellular fractionation, co-immunoprecipitation, caspase-3 and p53 activity assays, cisplatin/doxorubicin cytotoxicity assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal functional assays but single lab, and mechanistic distinction from PMID:40202782 is partial","pmids":["41120732"],"is_preprint":false}],"current_model":"DNAJB14 is an ER-resident, single-pass transmembrane co-chaperone (J-protein) whose cytosol-facing J-domain recruits Hsc70/HSC70 and SGTA to the ER membrane, enabling: (1) ERAD of misfolded transmembrane proteins via the ubiquitin-proteasome system; (2) HSP70-independent tetrameric assembly of K+ channel subunits (e.g., hERG, Kv4.2); (3) HSP70-dependent protection against mutant FUS aggregation as part of a DNAJB14-FL/DNAJB12-FL complex; (4) ER-to-cytosol protein reflux (ERCYS) that can inhibit apoptotic factors (caspase-3, wt-p53) in cancer cells; and (5) roles in mitochondrial dynamics and in HBV/HDV virion morphogenesis."},"narrative":{"teleology":[{"year":2012,"claim":"Establishing DNAJB14 as an ER-anchored co-chaperone resolved how a J-protein could act specifically at the ER membrane to accelerate degradation of misfolded transmembrane — but not luminal — substrates via Hsc70 and the proteasome.","evidence":"Immunofluorescence, protease protection, co-IP with Hsc70, and CFTRΔF508 degradation assays with MG132 in mammalian cells","pmids":["23018488"],"confidence":"High","gaps":["Identity of endogenous ERAD substrates beyond CFTRΔF508 not determined","How DNAJB14 discriminates transmembrane versus luminal misfolded clients is unclear","Relationship to other ER-resident J-proteins such as DNAJB12 not yet defined"]},{"year":2014,"claim":"Overexpression-induced formation of nuclear membranous structures (DJANGOS) containing DNAJB14, DNAJB12, Hsc70, and ER markers revealed that DNAJB14's chaperone activity can remodel ER-nuclear envelope connections.","evidence":"Immunofluorescence, cryo-EM, J-domain mutation analysis, and live-cell imaging","pmids":["24732912"],"confidence":"Medium","gaps":["DJANGOS observed only upon overexpression; physiological relevance at endogenous levels unestablished","Mechanism by which J-domain activity drives membrane reorganization unknown"]},{"year":2016,"claim":"Demonstrating that DNAJB14 promotes tetrameric assembly of hERG and Kv4.2 K⁺ channels via an HSP70-independent mechanism established a chaperone-independent scaffolding function and linked DNAJB14 to cardiac ion channelopathies.","evidence":"C. elegans genetic screen, in vitro assembly assay, electrophysiology, and hERG mutant rescue in human cells","pmids":["27916661"],"confidence":"High","gaps":["Structural basis for HSP70-independent assembly promotion unknown","Whether DNAJB14 acts on other multimeric membrane protein complexes beyond K⁺ channels not tested"]},{"year":2022,"claim":"Identifying a full-length DNAJB14–DNAJB12 complex that suppresses mutant FUS aggregation in an HSP70-dependent manner showed that DNAJB14 functions as part of a heteromeric ER-tethered disaggregation system relevant to ALS-linked proteotoxicity.","evidence":"Reciprocal co-IP, FRAP on mutFUS aggregates, proteostasis reporters, and knockdown/overexpression in primary neurons","pmids":["35082301"],"confidence":"High","gaps":["Whether the DNAJB14–DNAJB12 complex acts on other cytosolic aggregate-prone proteins not explored","How an ER-tethered complex accesses cytosolic/nuclear aggregates mechanistically unresolved"]},{"year":2023,"claim":"Showing that DNAJB14 knockdown impairs ER-to-cytosol translocation of PDI under ER stress, and that DNAJB14 is itself degraded by the proteasome upon reductive challenge, established DNAJB14 as a regulated component of the ERCYS pathway with non-redundant function relative to DNAJB12.","evidence":"Knockdown, subcellular fractionation, proteasome inhibitor treatment, sulfenic-acid trapping, and UPR activation in mammalian cells","pmids":["37925033"],"confidence":"Medium","gaps":["Cargo selectivity of DNAJB14-dependent ER reflux beyond PDI not defined","How DNAJB14's DUF1977 luminal domain contributes to non-redundancy with DNAJB12 unclear","Mechanism of DNAJB14 redox-dependent proteasomal turnover not elucidated"]},{"year":2023,"claim":"DNAJB14 knockout alters PINK1 stabilization kinetics and mitochondrial morphology under mitochondrial stress, linking DNAJB14 to ER–mitochondria crosstalk and mitophagy regulation.","evidence":"CRISPR knockout, PINK1/p-Drp1 western blot, and mitochondrial morphology imaging under CCCP treatment","pmids":["37851175"],"confidence":"Medium","gaps":["Direct physical interaction between DNAJB14 and PINK1 or Drp1 not demonstrated","Whether mitochondrial phenotype is secondary to general ER chaperone dysfunction not excluded","Mechanism connecting ER-localized DNAJB14 to mitochondrial fission/fusion machinery unknown"]},{"year":2025,"claim":"J-domain mutagenesis and SGTA interaction studies established the molecular mechanism by which DNAJB14 drives ERCYS: its J-domain recruits HSC70 and SGTA to translocate ER-resident proteins (AGR2, PDIA4) to the cytosol, where they inhibit caspase-3 and wt-p53, conferring chemoresistance in cancer cells.","evidence":"J-domain point mutations, co-IP, siRNA knockdown of DNAJB14/DNAJB12/SGTA, subcellular fractionation, p53 and caspase-3 activity assays, and cisplatin/doxorubicin cytotoxicity in cancer cell lines","pmids":["40202782","41120732"],"confidence":"High","gaps":["Whether ERCYS operates in non-cancer cell contexts at physiological expression levels is unresolved","Structural basis of the DNAJB14–SGTA interaction not determined","Full repertoire of ERCYS cargoes beyond AGR2 and PDIA4 not mapped"]},{"year":2025,"claim":"DNAJB14 knockdown selectively impaired HBV virion morphogenesis without affecting subviral particle secretion, and also reduced infectious HDV production, revealing an unexpected role in hepatitis virus assembly.","evidence":"siRNA knockdown, virion and subviral particle secretion assays, HDV infectivity assay","pmids":["41684842"],"confidence":"Medium","gaps":["Direct interaction between DNAJB14 and HBV envelope or core proteins not shown","Whether this role involves DNAJB14's co-chaperone, scaffolding, or ERCYS activity is unknown","Not independently confirmed by a second laboratory"]},{"year":null,"claim":"The structural basis for DNAJB14's dual HSP70-dependent and HSP70-independent activities, the full client/cargo repertoire of ERCYS, and the mechanism linking ER-tethered DNAJB14 to mitochondrial dynamics and viral assembly remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No atomic-resolution structure of DNAJB14 or its complexes available","Comprehensive substrate identification (e.g., proximity labeling) not reported","In vivo phenotype of DNAJB14 knockout in animal models not described"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,3,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,6]}],"pathway":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[4,6,8]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,8]}],"complexes":["DNAJB14–DNAJB12 complex","DNAJB14–HSC70–SGTA complex"],"partners":["DNAJB12","HSPA8","SGTA","KCNH2","KCND2","PINK1"],"other_free_text":[]},"mechanistic_narrative":"DNAJB14 is an ER-resident, single-pass transmembrane J-domain co-chaperone that recruits cytosolic Hsc70 and SGTA to the ER membrane to regulate transmembrane protein quality control, ion channel assembly, aggregate clearance, and ER-to-cytosol protein reflux. Its cytosol-facing J-domain binds Hsc70 and accelerates ERAD of misfolded transmembrane substrates such as CFTRΔF508 via the ubiquitin–proteasome system, and it forms a complex with DNAJB12 that protects against mutant FUS aggregation in an HSP70-dependent manner [PMID:23018488, PMID:35082301]. Through an HSP70-independent mechanism, DNAJB14 promotes tetrameric assembly of K⁺ channel subunits (hERG, Kv4.2) and can rescue trafficking-defective hERG mutants linked to long QT syndrome [PMID:27916661]. DNAJB14 also drives ER-to-cytosol reflux (ERCYS) of ER-resident proteins including PDI family members, and its J-domain-dependent recruitment of SGTA enables cytosolic accumulation of factors that inhibit caspase-3 and wt-p53, thereby conferring chemoresistance in cancer cells [PMID:40202782, PMID:41120732]."},"prefetch_data":{"uniprot":{"accession":"Q8TBM8","full_name":"DnaJ homolog subfamily B member 14","aliases":[],"length_aa":379,"mass_kda":42.5,"function":"Acts as a co-chaperone with HSPA8/Hsc70; required to promote protein folding and trafficking, prevent aggregation of client proteins, and promote unfolded proteins to endoplasmic reticulum-associated degradation (ERAD) pathway (PubMed:24732912). Acts by determining HSPA8/Hsc70's ATPase and polypeptide-binding activities (PubMed:24732912). Can also act independently of HSPA8/Hsc70: together with DNAJB12, acts as a chaperone that promotes maturation of potassium channels KCND2 and KCNH2 by stabilizing nascent channel subunits and assembling them into tetramers (PubMed:27916661). While stabilization of nascent channel proteins is dependent on HSPA8/Hsc70, the process of oligomerization of channel subunits is independent of HSPA8/Hsc70 (PubMed:27916661). When overexpressed, forms membranous structures together with DNAJB12 and HSPA8/Hsc70 within the nucleus; the role of these structures, named DJANGOs, is still unclear (PubMed:24732912) (Microbial infection) In case of infection by polyomavirus, involved in the virus endoplasmic reticulum membrane penetration and infection (PubMed:21673190, PubMed:24675744)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q8TBM8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DNAJB14","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DNAJB14","total_profiled":1310},"omim":[{"mim_id":"621108","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 18; DNAJC2","url":"https://www.omim.org/entry/621108"},{"mim_id":"617487","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY B, MEMBER 14; DNAJB14","url":"https://www.omim.org/entry/617487"},{"mim_id":"608376","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY B, MEMBER 12; DNAJB12","url":"https://www.omim.org/entry/608376"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DNAJB14"},"hgnc":{"alias_symbol":["FLJ14281"],"prev_symbol":[]},"alphafold":{"accession":"Q8TBM8","domains":[{"cath_id":"-","chopping":"1-53","consensus_level":"high","plddt":88.7649,"start":1,"end":53},{"cath_id":"1.10.287.110","chopping":"93-174","consensus_level":"high","plddt":86.6094,"start":93,"end":174},{"cath_id":"1.10.287","chopping":"305-376","consensus_level":"high","plddt":93.7931,"start":305,"end":376}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TBM8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TBM8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TBM8-F1-predicted_aligned_error_v6.png","plddt_mean":75.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DNAJB14","jax_strain_url":"https://www.jax.org/strain/search?query=DNAJB14"},"sequence":{"accession":"Q8TBM8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TBM8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TBM8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TBM8"}},"corpus_meta":[{"pmid":"25973848","id":"PMC_25973848","title":"Differential Genes Expression between Fertile and Infertile Spermatozoa Revealed by Transcriptome Analysis.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25973848","citation_count":120,"is_preprint":false},{"pmid":"27916661","id":"PMC_27916661","title":"Tetrameric Assembly of K+ Channels Requires ER-Located Chaperone Proteins.","date":"2016","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/27916661","citation_count":61,"is_preprint":false},{"pmid":"23018488","id":"PMC_23018488","title":"A novel mammalian ER-located J-protein, DNAJB14, can accelerate ERAD of misfolded membrane proteins.","date":"2012","source":"Cell structure and function","url":"https://pubmed.ncbi.nlm.nih.gov/23018488","citation_count":32,"is_preprint":false},{"pmid":"35082301","id":"PMC_35082301","title":"Differential roles for DNAJ isoforms in HTT-polyQ and FUS aggregation modulation revealed by chaperone screens.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35082301","citation_count":32,"is_preprint":false},{"pmid":"33049985","id":"PMC_33049985","title":"Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington's Disease Status Based on Omics Data.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33049985","citation_count":26,"is_preprint":false},{"pmid":"24732912","id":"PMC_24732912","title":"Expression of DNAJB12 or DNAJB14 causes coordinate invasion of the nucleus by membranes associated with a novel nuclear pore structure.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24732912","citation_count":19,"is_preprint":false},{"pmid":"37925033","id":"PMC_37925033","title":"DNAJB12 and DNJB14 are non-redundant Hsp40 redox chaperones involved in endoplasmic reticulum protein reflux.","date":"2023","source":"Biochimica et biophysica acta. General subjects","url":"https://pubmed.ncbi.nlm.nih.gov/37925033","citation_count":11,"is_preprint":false},{"pmid":"40202782","id":"PMC_40202782","title":"Cytosolic and endoplasmic reticulum chaperones inhibit wt-p53 to increase cancer cells' survival by refluxing ER-proteins to the cytosol.","date":"2025","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/40202782","citation_count":4,"is_preprint":false},{"pmid":"37851175","id":"PMC_37851175","title":"Novel functions of the ER-located Hsp40s DNAJB12 and DNAJB14 on proteins at the outer mitochondrial membrane under stress mediated by CCCP.","date":"2023","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37851175","citation_count":2,"is_preprint":false},{"pmid":"38679420","id":"PMC_38679420","title":"Heat shock protein-related diagnostic signature and molecular subtypes in ankylosing spondylitis: new pathogenesis insights.","date":"2024","source":"International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group","url":"https://pubmed.ncbi.nlm.nih.gov/38679420","citation_count":1,"is_preprint":false},{"pmid":"41120732","id":"PMC_41120732","title":"Non-genetic inactivation of caspase-3 and P53 increases cancer cell fitness by PDIA4 redistribution.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/41120732","citation_count":1,"is_preprint":false},{"pmid":"39548148","id":"PMC_39548148","title":"Genetic variation perspective reveals potential drug targets for subtypes of endometrial cancer.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39548148","citation_count":1,"is_preprint":false},{"pmid":"41684842","id":"PMC_41684842","title":"Unveiling DNAJB12 and DNAJB14 as crucial chaperones in hepatitis B and D virus particle morphogenesis.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/41684842","citation_count":0,"is_preprint":false},{"pmid":"40475163","id":"PMC_40475163","title":"Genetic architecture of the limbic white matter microstructure in aging and Alzheimer's Disease.","date":"2025","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40475163","citation_count":0,"is_preprint":false},{"pmid":"40553479","id":"PMC_40553479","title":"The Effect of Circulating Proteins and Their Role in Mediating Adiposity's Effect on Endometrial Cancer Risk: Mendelian Randomization and Colocalization Analyses.","date":"2025","source":"Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40553479","citation_count":0,"is_preprint":false},{"pmid":"41897962","id":"PMC_41897962","title":"Genetic Structure and Selective Signature Analysis of Xinjiang Local Sheep Populations.","date":"2026","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/41897962","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.19.25327915","title":"Genetic architecture of the limbic white matter microstructure in aging and Alzheimer’s Disease","date":"2025-05-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.19.25327915","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11995,"output_tokens":2513,"usd":0.03684},"stage2":{"model":"claude-opus-4-6","input_tokens":5810,"output_tokens":2763,"usd":0.147187},"total_usd":0.184027,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"DNAJB14 is an ER-localized, single membrane-spanning J-protein with its J-domain facing the cytosol, as determined by immunofluorescence and protease protection assay. It binds Hsc70 via its J-domain (co-immunoprecipitation), recruits Hsc70 to the ER membrane, and accelerates ERAD of misfolded membrane proteins (e.g., CFTRΔF508) through the ubiquitin-proteasome system, but does not accelerate degradation of misfolded luminal proteins.\",\n      \"method\": \"Immunofluorescence, protease protection assay, co-immunoprecipitation, overexpression with proteasome inhibitor (MG132) and degradation assay\",\n      \"journal\": \"Cell structure and function\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in a single study with functional readouts (localization, binding, degradation assay with inhibitor controls)\",\n      \"pmids\": [\"23018488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DNAJB14 promotes tetrameric assembly of ERG (hERG) and Kv4.2 K+ channel subunits in the ER through an HSP70-independent mechanism. Overexpression of DNAJB14 significantly rescued defective function of hERG mutant channels associated with long QT syndrome by stabilizing the mutated proteins.\",\n      \"method\": \"Genetic screening in C. elegans and human cells, in vitro assembly assay, electrophysiology, overexpression rescue experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro assembly assay plus genetic and cell-based functional validation across two organisms\",\n      \"pmids\": [\"27916661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Overexpression of DNAJB14 (or DNAJB12) causes formation of elaborate membranous structures (DJANGOS) within cell nuclei that contain DNAJB14, DNAJB12, Hsc70, and ER lumen/membrane markers; these are connected to the nuclear envelope via a unique nuclear pore configuration. Genetic studies showed that the J-domain chaperone activity of DNAJ/Hsc70 is required for DJANGOS formation.\",\n      \"method\": \"Immunofluorescence, electron microscopy (cryo-EM), genetic mutation analysis of J-domain chaperone activity, live-cell imaging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional (genetic) follow-up but single lab study\",\n      \"pmids\": [\"24732912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Full-length DNAJB14 forms a complex with full-length DNAJB12 (but not with their short isoforms) that substantially protects from mutant FUS aggregation in an HSP70-dependent manner. DNAJB14-FL expression increases the mobility of mutFUS aggregates and restores deteriorated proteostasis in mutFUS aggregate-containing cells and primary neurons.\",\n      \"method\": \"Co-immunoprecipitation (complex identification), fluorescence recovery after photobleaching (FRAP), proteostasis assays, knockdown/overexpression in primary neurons\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP for complex identification combined with multiple functional readouts including primary neuron experiments\",\n      \"pmids\": [\"35082301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DNAJB14 and DNAJB12 are non-redundant ER transmembrane chaperones involved in ER protein reflux (ER-to-cytosol translocation of PDI). Knockdown of DNAJB14 (and DNAJB12) in ER-stressed cells significantly impairs the amount of PDI in cytosolic-enriched fractions. DNAJB14 protein levels are degraded by the proteasome upon acute reductive challenge, and their ER-lumen DUF1977 domains are dissimilar between B12 and B14, suggesting functional non-redundancy. DNAJB14 transcripts are upregulated during UPR activation.\",\n      \"method\": \"Knockdown, subcellular fractionation, proteasome inhibitor assay, sulfenic-acid trapping (dimedone), interactome analysis\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (fractionation, knockdown, chemical biology) but single lab study\",\n      \"pmids\": [\"37925033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DNAJB14 (JB14) overexpression affects PINK1 protein levels under CCCP-mediated mitochondrial stress, and JB14 knockout leads to prolonged stabilization of PINK1 during chronic CCCP exposure. Cells depleted of JB14 also exhibit increased mitochondrial count and branching, and an altered kinetics of phosphorylated Drp1 in response to CCCP stress.\",\n      \"method\": \"Genetic knockout, overexpression, western blot for PINK1 and p-Drp1, mitochondrial morphology imaging\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, but single lab and limited mechanistic follow-up\",\n      \"pmids\": [\"37851175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DNAJB14 (together with DNAJB12) facilitates ER-protein reflux (ERCYS) by binding HSC70 and the cochaperone SGTA through their cytosolically localized J-domains. Mutations in the DNAJB14 J-domain prevent the inhibitory interaction between refluxed AGR2 and wt-p53. DNAJB14 and DNAJB12 knockdown rescues wt-p53 and caspase-3 activity in cancer cells.\",\n      \"method\": \"J-domain mutagenesis, co-immunoprecipitation, knockdown, subcellular fractionation, functional p53/caspase-3 activity assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — J-domain mutagenesis combined with co-IP, KD rescue, and functional enzymatic readouts in same study\",\n      \"pmids\": [\"40202782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DNAJB14 knockdown selectively impairs morphogenesis of HBV virions (but not subviral particles), and knockdown of DNAJB14 (and DNAJB12) hinders production of infectious HDV, identifying DNAJB14 as required for HBV virion and HDV morphogenesis.\",\n      \"method\": \"siRNA knockdown, virion/SVP secretion assay, HDV infectivity assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean knockdown with specific viral phenotypic readouts, but single lab and no mechanistic follow-up of how DNAJB14 acts on HBV assembly\",\n      \"pmids\": [\"41684842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DNAJB14 (with DNAJB12) facilitates redistribution of PDIA4 from the ER to the cytosol during ER stress; in the cytosol, PDIA4 inhibits caspase-3 and wt-p53. Silencing DNAJB14/DNAJB12 or SGTA rescues wt-p53 and caspase-3 activity and reduces chemoresistance.\",\n      \"method\": \"siRNA knockdown, subcellular fractionation, co-immunoprecipitation, caspase-3 and p53 activity assays, cisplatin/doxorubicin cytotoxicity assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays but single lab, and mechanistic distinction from PMID:40202782 is partial\",\n      \"pmids\": [\"41120732\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DNAJB14 is an ER-resident, single-pass transmembrane co-chaperone (J-protein) whose cytosol-facing J-domain recruits Hsc70/HSC70 and SGTA to the ER membrane, enabling: (1) ERAD of misfolded transmembrane proteins via the ubiquitin-proteasome system; (2) HSP70-independent tetrameric assembly of K+ channel subunits (e.g., hERG, Kv4.2); (3) HSP70-dependent protection against mutant FUS aggregation as part of a DNAJB14-FL/DNAJB12-FL complex; (4) ER-to-cytosol protein reflux (ERCYS) that can inhibit apoptotic factors (caspase-3, wt-p53) in cancer cells; and (5) roles in mitochondrial dynamics and in HBV/HDV virion morphogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DNAJB14 is an ER-resident, single-pass transmembrane J-domain co-chaperone that recruits cytosolic Hsc70 and SGTA to the ER membrane to regulate transmembrane protein quality control, ion channel assembly, aggregate clearance, and ER-to-cytosol protein reflux. Its cytosol-facing J-domain binds Hsc70 and accelerates ERAD of misfolded transmembrane substrates such as CFTRΔF508 via the ubiquitin–proteasome system, and it forms a complex with DNAJB12 that protects against mutant FUS aggregation in an HSP70-dependent manner [PMID:23018488, PMID:35082301]. Through an HSP70-independent mechanism, DNAJB14 promotes tetrameric assembly of K⁺ channel subunits (hERG, Kv4.2) and can rescue trafficking-defective hERG mutants linked to long QT syndrome [PMID:27916661]. DNAJB14 also drives ER-to-cytosol reflux (ERCYS) of ER-resident proteins including PDI family members, and its J-domain-dependent recruitment of SGTA enables cytosolic accumulation of factors that inhibit caspase-3 and wt-p53, thereby conferring chemoresistance in cancer cells [PMID:40202782, PMID:41120732].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing DNAJB14 as an ER-anchored co-chaperone resolved how a J-protein could act specifically at the ER membrane to accelerate degradation of misfolded transmembrane — but not luminal — substrates via Hsc70 and the proteasome.\",\n      \"evidence\": \"Immunofluorescence, protease protection, co-IP with Hsc70, and CFTRΔF508 degradation assays with MG132 in mammalian cells\",\n      \"pmids\": [\"23018488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of endogenous ERAD substrates beyond CFTRΔF508 not determined\",\n        \"How DNAJB14 discriminates transmembrane versus luminal misfolded clients is unclear\",\n        \"Relationship to other ER-resident J-proteins such as DNAJB12 not yet defined\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Overexpression-induced formation of nuclear membranous structures (DJANGOS) containing DNAJB14, DNAJB12, Hsc70, and ER markers revealed that DNAJB14's chaperone activity can remodel ER-nuclear envelope connections.\",\n      \"evidence\": \"Immunofluorescence, cryo-EM, J-domain mutation analysis, and live-cell imaging\",\n      \"pmids\": [\"24732912\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"DJANGOS observed only upon overexpression; physiological relevance at endogenous levels unestablished\",\n        \"Mechanism by which J-domain activity drives membrane reorganization unknown\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating that DNAJB14 promotes tetrameric assembly of hERG and Kv4.2 K⁺ channels via an HSP70-independent mechanism established a chaperone-independent scaffolding function and linked DNAJB14 to cardiac ion channelopathies.\",\n      \"evidence\": \"C. elegans genetic screen, in vitro assembly assay, electrophysiology, and hERG mutant rescue in human cells\",\n      \"pmids\": [\"27916661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for HSP70-independent assembly promotion unknown\",\n        \"Whether DNAJB14 acts on other multimeric membrane protein complexes beyond K⁺ channels not tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying a full-length DNAJB14–DNAJB12 complex that suppresses mutant FUS aggregation in an HSP70-dependent manner showed that DNAJB14 functions as part of a heteromeric ER-tethered disaggregation system relevant to ALS-linked proteotoxicity.\",\n      \"evidence\": \"Reciprocal co-IP, FRAP on mutFUS aggregates, proteostasis reporters, and knockdown/overexpression in primary neurons\",\n      \"pmids\": [\"35082301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the DNAJB14–DNAJB12 complex acts on other cytosolic aggregate-prone proteins not explored\",\n        \"How an ER-tethered complex accesses cytosolic/nuclear aggregates mechanistically unresolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing that DNAJB14 knockdown impairs ER-to-cytosol translocation of PDI under ER stress, and that DNAJB14 is itself degraded by the proteasome upon reductive challenge, established DNAJB14 as a regulated component of the ERCYS pathway with non-redundant function relative to DNAJB12.\",\n      \"evidence\": \"Knockdown, subcellular fractionation, proteasome inhibitor treatment, sulfenic-acid trapping, and UPR activation in mammalian cells\",\n      \"pmids\": [\"37925033\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Cargo selectivity of DNAJB14-dependent ER reflux beyond PDI not defined\",\n        \"How DNAJB14's DUF1977 luminal domain contributes to non-redundancy with DNAJB12 unclear\",\n        \"Mechanism of DNAJB14 redox-dependent proteasomal turnover not elucidated\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"DNAJB14 knockout alters PINK1 stabilization kinetics and mitochondrial morphology under mitochondrial stress, linking DNAJB14 to ER–mitochondria crosstalk and mitophagy regulation.\",\n      \"evidence\": \"CRISPR knockout, PINK1/p-Drp1 western blot, and mitochondrial morphology imaging under CCCP treatment\",\n      \"pmids\": [\"37851175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical interaction between DNAJB14 and PINK1 or Drp1 not demonstrated\",\n        \"Whether mitochondrial phenotype is secondary to general ER chaperone dysfunction not excluded\",\n        \"Mechanism connecting ER-localized DNAJB14 to mitochondrial fission/fusion machinery unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"J-domain mutagenesis and SGTA interaction studies established the molecular mechanism by which DNAJB14 drives ERCYS: its J-domain recruits HSC70 and SGTA to translocate ER-resident proteins (AGR2, PDIA4) to the cytosol, where they inhibit caspase-3 and wt-p53, conferring chemoresistance in cancer cells.\",\n      \"evidence\": \"J-domain point mutations, co-IP, siRNA knockdown of DNAJB14/DNAJB12/SGTA, subcellular fractionation, p53 and caspase-3 activity assays, and cisplatin/doxorubicin cytotoxicity in cancer cell lines\",\n      \"pmids\": [\"40202782\", \"41120732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ERCYS operates in non-cancer cell contexts at physiological expression levels is unresolved\",\n        \"Structural basis of the DNAJB14–SGTA interaction not determined\",\n        \"Full repertoire of ERCYS cargoes beyond AGR2 and PDIA4 not mapped\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"DNAJB14 knockdown selectively impaired HBV virion morphogenesis without affecting subviral particle secretion, and also reduced infectious HDV production, revealing an unexpected role in hepatitis virus assembly.\",\n      \"evidence\": \"siRNA knockdown, virion and subviral particle secretion assays, HDV infectivity assay\",\n      \"pmids\": [\"41684842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct interaction between DNAJB14 and HBV envelope or core proteins not shown\",\n        \"Whether this role involves DNAJB14's co-chaperone, scaffolding, or ERCYS activity is unknown\",\n        \"Not independently confirmed by a second laboratory\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for DNAJB14's dual HSP70-dependent and HSP70-independent activities, the full client/cargo repertoire of ERCYS, and the mechanism linking ER-tethered DNAJB14 to mitochondrial dynamics and viral assembly remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No atomic-resolution structure of DNAJB14 or its complexes available\",\n        \"Comprehensive substrate identification (e.g., proximity labeling) not reported\",\n        \"In vivo phenotype of DNAJB14 knockout in animal models not described\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [4, 6, 8]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"complexes\": [\n      \"DNAJB14–DNAJB12 complex\",\n      \"DNAJB14–HSC70–SGTA complex\"\n    ],\n    \"partners\": [\n      \"DNAJB12\",\n      \"HSPA8\",\n      \"SGTA\",\n      \"KCNH2\",\n      \"KCND2\",\n      \"PINK1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}