{"gene":"DNAJC14","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2011,"finding":"DNAJC14 is a mammalian Hsp40 chaperone that, when overexpressed, inhibits yellow fever virus (YFV) replication at the step of viral RNA replication. Both the J-domain and the C-terminal self-interaction domain are required for anti-YFV activity. Endogenous DNAJC14 redistributes to viral replication complexes (identified by dsRNA staining) during infection, and silencing of endogenous DNAJC14 impairs YFV replication, indicating a requirement for DNAJC14 in replication complex assembly. The antiviral effect of overexpressed DNAJC14 is stoichiometric — excess DNAJC14 disrupts proper assembly, which can be overcome as viral nonstructural proteins accumulate.","method":"cDNA library screen, siRNA knockdown, overexpression with mutagenesis, immunofluorescence co-localization with dsRNA, antiviral activity assays across multiple Flaviviridae members","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD, OE, mutagenesis, IF), replicated across multiple virus species, moderate–strong evidence","pmids":["21249176"],"is_preprint":false},{"year":2012,"finding":"DNAJC14 redistributes and clusters with YFV nonstructural proteins via a transmembrane domain and a newly identified membrane-binding domain (MBD), both of which mediate targeting to detergent-resistant membranes. The C-terminal self-interaction domain is required for entry into the viral replication complex (RC) protein interaction network that persists after 1% Triton solubilization. Fusion of the DNAJC14 MBD and self-interaction domain onto another Hsp40 is sufficient to confer YFV-inhibitory activity, supporting a model in which DNAJC14 acts as a membrane-targeted chaperone scaffold that mediates RC formation.","method":"Mutagenesis of DNAJC14 domains, detergent-resistant membrane fractionation, co-immunoprecipitation, domain-fusion rescue experiments","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 — reconstitution-level domain-swap experiment with mutagenesis and fractionation, single lab but multiple orthogonal methods","pmids":["22915803"],"is_preprint":false},{"year":2016,"finding":"DNAJC14 and Hsc70 are required for unconventional (Golgi-independent) cell-surface trafficking of misfolded H723R-pendrin (encoded by SLC26A4). Blockade of ER-to-Golgi transport or ER stress activation induced Golgi-independent surface expression of H723R-pendrin, restoring its Cl⁻/HCO₃⁻ exchange activity. Proteomic and siRNA screening identified Hsc70 and DNAJC14 as essential factors; DNAJC14 upregulation alone was sufficient to induce unconventional surface expression of H723R-pendrin.","method":"Proteomic screening, siRNA knockdown, pharmacological blockade of ER-to-Golgi transport, functional ion-transport assay, overexpression rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — proteomic screen validated by siRNA and functional assay, gain-of-function rescue, moderate–strong evidence","pmids":["27109633"],"is_preprint":false},{"year":2019,"finding":"CRISPR/Cas9 knockout of DNAJC14 in bovine and porcine cells demonstrated that DNAJC14 is an essential cellular cofactor specifically for RNA replication of noncytopathogenic (noncp) pestiviruses (6 distinct species: A–D, F, G), but not for cytopathogenic (cp) pestiviruses. The pestiviral replicase NS3-5B can assemble into functional complexes in the absence of DNAJC14, indicating DNAJC14's role is specifically in NS2 autoprotease activation (which releases NS3) rather than in downstream replicase assembly.","method":"CRISPR/Cas9 knockout of DNAJC14, viral replication assays across multiple pestivirus species, complementation experiments","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 — clean genetic KO with defined molecular phenotype, replicated across 6 virus species in two host cell backgrounds","pmids":["30518653"],"is_preprint":false}],"current_model":"DNAJC14 is a mammalian Hsp40/DnaJ-family co-chaperone that serves as a cellular cofactor for Flaviviridae RNA replication: it is recruited to viral replication complexes via its transmembrane domain and membrane-binding domain, requires its J-domain and C-terminal self-interaction domain for activity, acts stoichiometrically in replication complex assembly, is essential for noncytopathogenic pestivirus replication by activating the NS2 autoprotease to release NS3, and additionally mediates Hsc70-dependent unconventional (Golgi-independent) trafficking of misfolded client proteins such as H723R-pendrin to the cell surface."},"narrative":{"teleology":[],"mechanism_profile":null,"mechanistic_narrative":"Parse failed — see logs"},"prefetch_data":{"uniprot":{"accession":"Q6Y2X3","full_name":"DnaJ homolog subfamily C member 14","aliases":["DnaJ protein homolog 3","Dopamine receptor-interacting protein of 78 kDa","DRIP78","Human DnaJ protein 3","hDj-3"],"length_aa":702,"mass_kda":78.6,"function":"Regulates the export of target proteins, such as DRD1, from the endoplasmic reticulum to the cell surface","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q6Y2X3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DNAJC14","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DNAJC14","total_profiled":1310},"omim":[{"mim_id":"606092","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 14; DNAJC14","url":"https://www.omim.org/entry/606092"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DNAJC14"},"hgnc":{"alias_symbol":["DNAJ","DRIP78","HDJ3","LIP6","FLJ32792"],"prev_symbol":[]},"alphafold":{"accession":"Q6Y2X3","domains":[{"cath_id":"1.10.287.110","chopping":"422-516","consensus_level":"medium","plddt":90.2063,"start":422,"end":516},{"cath_id":"-","chopping":"537-617","consensus_level":"high","plddt":91.4495,"start":537,"end":617},{"cath_id":"1.20.5","chopping":"378-408","consensus_level":"medium","plddt":58.7252,"start":378,"end":408}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6Y2X3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6Y2X3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6Y2X3-F1-predicted_aligned_error_v6.png","plddt_mean":59.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DNAJC14","jax_strain_url":"https://www.jax.org/strain/search?query=DNAJC14"},"sequence":{"accession":"Q6Y2X3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6Y2X3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6Y2X3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6Y2X3"}},"corpus_meta":[{"pmid":"1826368","id":"PMC_1826368","title":"Escherichia coli DnaJ and GrpE heat shock proteins jointly stimulate ATPase activity of DnaK.","date":"1991","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1826368","citation_count":744,"is_preprint":false},{"pmid":"16952052","id":"PMC_16952052","title":"The diversity of the DnaJ/Hsp40 family, the crucial partners for Hsp70 chaperones.","date":"2006","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/16952052","citation_count":684,"is_preprint":false},{"pmid":"7900997","id":"PMC_7900997","title":"DnaK, DnaJ and GrpE form a cellular chaperone machinery capable of repairing heat-induced protein damage.","date":"1993","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/7900997","citation_count":531,"is_preprint":false},{"pmid":"8016869","id":"PMC_8016869","title":"DnaJ-like proteins: molecular chaperones and specific regulators of Hsp70.","date":"1994","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/8016869","citation_count":409,"is_preprint":false},{"pmid":"9572938","id":"PMC_9572938","title":"Chaperone coexpression plasmids: differential and synergistic roles of DnaK-DnaJ-GrpE and GroEL-GroES in assisting folding of an allergen of Japanese cedar pollen, Cryj2, in Escherichia coli.","date":"1998","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/9572938","citation_count":346,"is_preprint":false},{"pmid":"14752510","id":"PMC_14752510","title":"hsp70-DnaJ chaperone pair prevents nitric oxide- and CHOP-induced apoptosis by inhibiting translocation of Bax to mitochondria.","date":"2004","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/14752510","citation_count":302,"is_preprint":false},{"pmid":"18557634","id":"PMC_18557634","title":"Structural and functional diversities between members of the human HSPB, HSPH, HSPA, and DNAJ chaperone families.","date":"2008","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18557634","citation_count":291,"is_preprint":false},{"pmid":"10497158","id":"PMC_10497158","title":"ClpB cooperates with DnaK, DnaJ, and GrpE in suppressing protein aggregation. 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Both the J-domain and the C-terminal self-interaction domain are required for anti-YFV activity. Endogenous DNAJC14 redistributes to viral replication complexes (identified by dsRNA staining) during infection, and silencing of endogenous DNAJC14 impairs YFV replication, indicating a requirement for DNAJC14 in replication complex assembly. The antiviral effect of overexpressed DNAJC14 is stoichiometric — excess DNAJC14 disrupts proper assembly, which can be overcome as viral nonstructural proteins accumulate.\",\n      \"method\": \"cDNA library screen, siRNA knockdown, overexpression with mutagenesis, immunofluorescence co-localization with dsRNA, antiviral activity assays across multiple Flaviviridae members\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD, OE, mutagenesis, IF), replicated across multiple virus species, moderate–strong evidence\",\n      \"pmids\": [\"21249176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DNAJC14 redistributes and clusters with YFV nonstructural proteins via a transmembrane domain and a newly identified membrane-binding domain (MBD), both of which mediate targeting to detergent-resistant membranes. The C-terminal self-interaction domain is required for entry into the viral replication complex (RC) protein interaction network that persists after 1% Triton solubilization. Fusion of the DNAJC14 MBD and self-interaction domain onto another Hsp40 is sufficient to confer YFV-inhibitory activity, supporting a model in which DNAJC14 acts as a membrane-targeted chaperone scaffold that mediates RC formation.\",\n      \"method\": \"Mutagenesis of DNAJC14 domains, detergent-resistant membrane fractionation, co-immunoprecipitation, domain-fusion rescue experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution-level domain-swap experiment with mutagenesis and fractionation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22915803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DNAJC14 and Hsc70 are required for unconventional (Golgi-independent) cell-surface trafficking of misfolded H723R-pendrin (encoded by SLC26A4). Blockade of ER-to-Golgi transport or ER stress activation induced Golgi-independent surface expression of H723R-pendrin, restoring its Cl⁻/HCO₃⁻ exchange activity. Proteomic and siRNA screening identified Hsc70 and DNAJC14 as essential factors; DNAJC14 upregulation alone was sufficient to induce unconventional surface expression of H723R-pendrin.\",\n      \"method\": \"Proteomic screening, siRNA knockdown, pharmacological blockade of ER-to-Golgi transport, functional ion-transport assay, overexpression rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — proteomic screen validated by siRNA and functional assay, gain-of-function rescue, moderate–strong evidence\",\n      \"pmids\": [\"27109633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CRISPR/Cas9 knockout of DNAJC14 in bovine and porcine cells demonstrated that DNAJC14 is an essential cellular cofactor specifically for RNA replication of noncytopathogenic (noncp) pestiviruses (6 distinct species: A–D, F, G), but not for cytopathogenic (cp) pestiviruses. The pestiviral replicase NS3-5B can assemble into functional complexes in the absence of DNAJC14, indicating DNAJC14's role is specifically in NS2 autoprotease activation (which releases NS3) rather than in downstream replicase assembly.\",\n      \"method\": \"CRISPR/Cas9 knockout of DNAJC14, viral replication assays across multiple pestivirus species, complementation experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — clean genetic KO with defined molecular phenotype, replicated across 6 virus species in two host cell backgrounds\",\n      \"pmids\": [\"30518653\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DNAJC14 is a mammalian Hsp40/DnaJ-family co-chaperone that serves as a cellular cofactor for Flaviviridae RNA replication: it is recruited to viral replication complexes via its transmembrane domain and membrane-binding domain, requires its J-domain and C-terminal self-interaction domain for activity, acts stoichiometrically in replication complex assembly, is essential for noncytopathogenic pestivirus replication by activating the NS2 autoprotease to release NS3, and additionally mediates Hsc70-dependent unconventional (Golgi-independent) trafficking of misfolded client proteins such as H723R-pendrin to the cell surface.\"\n}\n```","stage2_raw":""}