{"gene":"ZDHHC1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2014,"finding":"ZDHHC1 is an ER-associated protein that constitutively associates with MITA/STING and mediates dimerization/aggregation of MITA/STING as well as recruitment of downstream signaling components TBK1 and IRF3, acting as a positive regulator of DNA virus-triggered, MITA/STING-dependent innate immune signaling. Zdhhc1-knockout cells failed to produce IFNs and cytokines in response to DNA (but not RNA) viruses.","method":"Expression screen for IFNB1 promoter activation, Zdhhc1 knockout cells and mice, co-immunoprecipitation, cytokine measurement, HSV-1 infection model","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, KO cells and KO mice with defined phenotype, multiple orthogonal methods across in vitro and in vivo systems","pmids":["25299331"],"is_preprint":false},{"year":2013,"finding":"ZDHHC1 (zDHHC1/z1, DHHC1) acts as a palmitoylating enzyme for neurochondrin (Ncdn), palmitoylating it at Cys-3 and Cys-4, and this palmitoylation is required for targeting Ncdn to Rab5-positive early endosomes. ZDHHC1 itself co-localizes with Rab5-positive endosomes, and knockdown of DHHC1 causes loss of Ncdn from these endosomes.","method":"In silico substrate prediction, DHHC enzyme library screening, palmitoylation assay, STED microscopy, siRNA knockdown, subcellular localization by fluorescence imaging","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzyme-substrate palmitoylation assay with mutagenesis of palmitoylation sites, knockdown with defined localization phenotype, single lab","pmids":["23687301"],"is_preprint":false},{"year":2017,"finding":"In teleost (grass carp), ZDHHC1 and STING each interact directly with IRF3 (demonstrated by co-immunoprecipitation and GST pull-down), promote IRF3 dimerization and nuclear translocation, and activate IFN-β expression. STING knockdown inhibits IFN expression and ZDHHC1-mediated IFN activation, indicating STING is required upstream of ZDHHC1 in this pathway. ZDHHC1 knockdown inhibits IFN expression but does not affect STING levels.","method":"Co-immunoprecipitation, GST pull-down, siRNA knockdown, IFN promoter reporter assay, overexpression in Ctenopharyngodon idella kidney cells","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and GST pull-down with knockdown epistasis, single lab, teleost ortholog","pmids":["29046345"],"is_preprint":false},{"year":2020,"finding":"ZDHHC1 is transcriptionally upregulated by p53, and the resulting ZDHHC1 protein interacts with IFITM3 to promote its S-palmitoylation and protein stability, thereby inhibiting Japanese encephalitis virus (JEV) replication. Knockdown of IFITM3 impaired the anti-JEV effect of ZDHHC1, and knockdown of either ZDHHC1 or IFITM3 compromised p53-mediated anti-JEV activity. JEV reduces p53 expression to impair ZDHHC1-mediated IFITM3 palmitoylation as a viral evasion mechanism.","method":"Palmitoyltransferase screening, siRNA knockdown, Co-IP, palmitoylation assay, viral replication assay, protein stability assay","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzyme-substrate interaction by Co-IP, palmitoylation assay, epistasis via multiple knockdowns, single lab","pmids":["33108395"],"is_preprint":false},{"year":2021,"finding":"ZDHHC1 acts as an S-palmitoyltransferase that palmitoylates p53 at Cys-135, Cys-176, and Cys-275. This palmitoylation is required for nuclear translocation of p53. In a feedback loop, p53 recruits DNMT3A to the ZDHHC1 promoter, causing hypermethylation and silencing of ZDHHC1, thereby limiting its own nuclear import.","method":"Palmitoylation assay with site-directed mutagenesis (C135, C176, C275), nuclear translocation assay, chromatin immunoprecipitation, methylation analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — palmitoylation assay with mutagenesis of specific sites, nuclear translocation readout, ChIP for feedback mechanism, single lab","pmids":["34282274"],"is_preprint":false},{"year":2020,"finding":"Restoration of ZDHHC1 expression in cancer cells inhibits glucose metabolism in a CYGB-dependent manner, suppresses the pentose phosphate pathway, and induces oxidative stress and ER stress leading to pyroptosis and apoptosis. Proteomic and metabolomic analyses identified these pathway alterations as ZDHHC1-dependent.","method":"iTRAQ proteomics, GC-MS metabolomics, Western blot, oxidative/ER stress indicator assays, xenograft mouse model, indirect immunofluorescence","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal omics and functional assays, in vivo validation, single lab","pmids":["32863941"],"is_preprint":false},{"year":2024,"finding":"ZDHHC1 palmitoylates IGF2BP1 at Cys-337; this S-palmitoylation results in downregulation of LIPG mRNA stability via m6A modification, inhibiting CRC cell proliferation and invasion. The ZDHHC1/IGF2BP1/LIPG signaling axis was defined by functional rescue and mechanistic experiments.","method":"Palmitoylation assay with site mutagenesis (C337), Co-IP, m6A modification analysis, in vitro and in vivo cell growth assays","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — palmitoylation with specific site mutagenesis, downstream m6A/mRNA stability mechanistic follow-up, single lab","pmids":["39069526"],"is_preprint":false},{"year":2024,"finding":"ZDHHC1 palmitoylates p110α (the catalytic subunit of PI3K) in macrophages; loss of Zdhhc1 reduces p110α palmitoylation, promotes nuclear translocation of p110α, and significantly decreases downstream phosphorylation of Akt (Ser473) and mTOR (Ser2448), thereby reducing foam cell formation and atherosclerotic plaque development.","method":"Zdhhc1 knockout in THP-1 cells and ApoE−/− mice, mass spectrometry palmitoylation analysis, bioinformatic pathway analysis, Western blot for PI3K-Akt-mTOR phosphorylation, nuclear fractionation, ox-LDL uptake assay","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined molecular mechanism (palmitoylation + nuclear translocation + kinase signaling), in vivo atherosclerosis model, single lab","pmids":["39566590"],"is_preprint":false},{"year":2024,"finding":"Zdhhc1 and Zdhhc2 co-operatively palmitoylate Gpm6a at Cys17, Cys18, and Cys246, which is required for lipid raft formation mediated by Gpm6a, thereby stabilizing Procr protein and maintaining mammary stem cell (aMaSC) activity and postnatal mammary development.","method":"Gpm6a knockout mouse model, Zdhhc1/2 palmitoylation assay with site mutagenesis, lipid raft fractionation, Procr protein stability assay, mammary reconstitution assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — palmitoylation assay with mutagenesis of specific sites, KO mouse model, defined functional readout in aMaSCs, single lab","pmids":["39321020"],"is_preprint":false},{"year":2025,"finding":"ZDHHC1 physically interacts with GSDMD (gasdermin D) and mediates its palmitoylation; ZDHHC1 overexpression enhances GSDMD palmitoylation-mediated membrane translocation and pyroptosis in prostate cancer cells, and this effect is partially reversed by the palmitoylation inhibitor 2-BP.","method":"Co-IP, palmitoylation assay, 2-BP palmitoylation inhibitor, GSDMD membrane translocation assay, pyroptosis markers (IL-1β, IL-18, LDH, HMGB1), in vivo xenograft model","journal":"Naunyn-Schmiedeberg's archives of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for interaction, palmitoylation-dependent membrane translocation with pharmacological inhibitor confirmation, in vivo model, single lab","pmids":["40237800"],"is_preprint":false},{"year":2022,"finding":"In Chinese perch (Siniperca chuatsi), ZDHHC1 interacts with MITA (the fish ortholog of STING) by co-immunoprecipitation, and overexpression of ZDHHC1 upregulates ISGs (Mx, RSAD2, IRF3) and type I IFNs, consistent with an antiviral adaptor role conserved from fish to mammals.","method":"Co-immunoprecipitation, overexpression, qRT-PCR for ISG/IFN expression, in vivo infection with ISKNV","journal":"Fish & shellfish immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP in a teleost ortholog, no mutagenesis or epistasis, single lab","pmids":["36122636"],"is_preprint":false}],"current_model":"ZDHHC1 is an ER-localized DHHC-domain S-palmitoyltransferase that palmitoylates multiple substrates—including MITA/STING (promoting its dimerization and downstream TBK1/IRF3 recruitment for antiviral innate immunity), p53 (required for its nuclear translocation), IFITM3 (stabilizing it against lysosomal degradation and enabling antiviral activity), IGF2BP1 (suppressing LIPG via m6A-dependent mRNA destabilization), p110α/PI3K (regulating Akt-mTOR signaling and foam cell formation), Gpm6a (enabling lipid raft formation and Procr stability in mammary stem cells), neurochondrin (directing it to Rab5-positive early endosomes), and GSDMD (promoting its membrane translocation and pyroptosis); ZDHHC1 expression is frequently silenced by promoter methylation in cancers, and a p53–ZDHHC1 epigenetic feedback loop—wherein p53 recruits DNMT3A to silence ZDHHC1, thereby limiting its own palmitoylation and nuclear import—represents a mechanism of p53 inactivation independent of mutation."},"narrative":{"mechanistic_narrative":"ZDHHC1 is an ER-localized DHHC-domain S-palmitoyltransferase that modifies a diverse set of substrates to control innate antiviral immunity, tumor suppression, and lipid-associated signaling [PMID:25299331, PMID:34282274]. In antiviral signaling it constitutively associates with MITA/STING, drives its dimerization/aggregation, and recruits TBK1 and IRF3, so that loss of ZDHHC1 abolishes type I interferon and cytokine responses to DNA but not RNA viruses [PMID:25299331]; a conserved STING-dependent adaptor role acting through IRF3 dimerization and nuclear translocation is also seen in teleost orthologs [PMID:29046345]. ZDHHC1 palmitoylates IFITM3 to stabilize it against degradation and restrict viral replication, an activity placed downstream of p53 transcriptional control [PMID:33108395]. As an enzyme it palmitoylates p53 itself at Cys-135/176/275 to enable p53 nuclear translocation, and is in turn silenced by a p53-DNMT3A promoter-methylation feedback loop that limits p53 nuclear import [PMID:34282274]. Additional defined substrates link ZDHHC1 to membrane targeting and disease processes: neurochondrin (palmitoylated at Cys-3/Cys-4 for delivery to Rab5-positive early endosomes) [PMID:23687301], IGF2BP1 (Cys-337, destabilizing LIPG mRNA via m6A to suppress colorectal cancer growth) [PMID:39069526], the PI3K catalytic subunit p110α (controlling Akt-mTOR signaling and macrophage foam-cell formation) [PMID:39566590], Gpm6a (co-palmitoylated with ZDHHC2 to promote lipid raft formation and Procr stability in mammary stem cells) [PMID:39321020], and gasdermin D (promoting membrane translocation and pyroptosis) [PMID:40237800]. Re-expression of ZDHHC1 in cancer cells, where it is frequently silenced, suppresses glucose metabolism and the pentose phosphate pathway and induces oxidative/ER stress-driven cell death [PMID:32863941].","teleology":[{"year":2013,"claim":"Established ZDHHC1 as a bona fide palmitoyltransferase with a defined substrate and a membrane-targeting consequence, the first direct enzymatic characterization.","evidence":"DHHC enzyme library screening, palmitoylation assay with site mutagenesis (Cys-3/Cys-4), STED imaging and siRNA knockdown of neurochondrin localization","pmids":["23687301"],"confidence":"Medium","gaps":["Single substrate in one lab","Endosomal targeting mechanism of ZDHHC1 itself not resolved"]},{"year":2014,"claim":"Defined a non-enzyme adaptor role for ZDHHC1 in DNA-virus innate immunity by linking it to MITA/STING signaling and downstream IRF3/TBK1 recruitment.","evidence":"IFNB1 promoter screen, reciprocal Co-IP, Zdhhc1 knockout cells and mice, HSV-1 infection","pmids":["25299331"],"confidence":"High","gaps":["Whether catalytic palmitoyltransferase activity is required for STING regulation not dissected","No palmitoylated residue on STING defined"]},{"year":2017,"claim":"Showed the STING-IRF3 antiviral axis through ZDHHC1 is evolutionarily conserved and ordered, with STING acting upstream.","evidence":"Co-IP, GST pull-down, knockdown epistasis and IFN reporter assays in grass carp kidney cells","pmids":["29046345"],"confidence":"Medium","gaps":["Teleost ortholog only","Catalytic requirement not tested"]},{"year":2020,"claim":"Connected ZDHHC1 to p53-driven antiviral defense by identifying IFITM3 as a substrate whose palmitoylation-dependent stability mediates restriction.","evidence":"Palmitoyltransferase screen, Co-IP, palmitoylation and protein-stability assays, JEV replication assay with knockdown epistasis","pmids":["33108395"],"confidence":"Medium","gaps":["IFITM3 palmitoylation site not mapped here","Single lab"]},{"year":2020,"claim":"Established a tumor-suppressive metabolic role for ZDHHC1, showing its re-expression rewires glucose metabolism and triggers stress-induced death.","evidence":"iTRAQ proteomics, GC-MS metabolomics, stress assays and xenograft model","pmids":["32863941"],"confidence":"Medium","gaps":["Direct palmitoylation substrate driving the metabolic effect not identified","CYGB-dependence mechanistically incomplete"]},{"year":2021,"claim":"Identified p53 as a direct ZDHHC1 substrate and uncovered a p53-DNMT3A feedback loop silencing ZDHHC1, defining a mutation-independent route to p53 inactivation.","evidence":"Palmitoylation assay with Cys-135/176/275 mutagenesis, nuclear translocation assay, ChIP and methylation analysis","pmids":["34282274"],"confidence":"Medium","gaps":["Mechanism by which palmitoylation drives nuclear import not structurally defined","Single lab"]},{"year":2024,"claim":"Extended ZDHHC1 substrate repertoire to IGF2BP1, linking palmitoylation to m6A-dependent mRNA destabilization of LIPG and CRC suppression.","evidence":"Palmitoylation assay with Cys-337 mutagenesis, Co-IP, m6A analysis, in vitro/in vivo growth assays","pmids":["39069526"],"confidence":"Medium","gaps":["How palmitoylation alters IGF2BP1 m6A reader function unclear","Single lab"]},{"year":2024,"claim":"Implicated ZDHHC1 in lipid-signaling and cardiovascular disease by showing it palmitoylates PI3K p110α to control its localization and Akt-mTOR output.","evidence":"Zdhhc1 knockout in THP-1 cells and ApoE−/− mice, MS palmitoylation analysis, nuclear fractionation, ox-LDL uptake assay","pmids":["39566590"],"confidence":"Medium","gaps":["p110α palmitoylation site not mapped","Single lab"]},{"year":2024,"claim":"Showed ZDHHC1 cooperates with ZDHHC2 to palmitoylate Gpm6a, coupling palmitoylation to lipid raft formation and stem-cell maintenance.","evidence":"Gpm6a knockout mice, palmitoylation assay with Cys-17/18/246 mutagenesis, lipid raft fractionation, mammary reconstitution","pmids":["39321020"],"confidence":"Medium","gaps":["Relative contributions of ZDHHC1 vs ZDHHC2 not separated","Single lab"]},{"year":2025,"claim":"Linked ZDHHC1 to programmed cell death by showing it palmitoylates gasdermin D to promote membrane translocation and pyroptosis.","evidence":"Co-IP, palmitoylation assay, 2-BP inhibition, membrane translocation and pyroptosis marker assays, xenograft model","pmids":["40237800"],"confidence":"Medium","gaps":["GSDMD palmitoylation site not mapped","Single lab, pharmacological inhibitor not fully specific"]},{"year":null,"claim":"Whether ZDHHC1 catalytic palmitoyltransferase activity is required across all its reported roles (notably STING/MITA antiviral signaling) and how substrate selectivity is governed remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ZDHHC1 substrate recognition","Catalytic-dead vs adaptor functions not systematically separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,3,4,6,7,8,9]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,4,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,4,6,7,8,9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7]}],"complexes":[],"partners":["STING1","MITA","IRF3","TBK1","IFITM3","TP53","IGF2BP1","GSDMD"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WTX9","full_name":"Palmitoyltransferase ZDHHC1","aliases":["DHHC domain-containing cysteine-rich protein 1","Zinc finger DHHC domain-containing protein 1","DHHC-1","Zinc finger protein 377"],"length_aa":485,"mass_kda":54.8,"function":"Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates, such as NCDN and NLRP3 (PubMed:39173637). Has a palmitoyltransferase activity toward NCDN and regulates NCDN association with endosome membranes through this palmitoylation (By similarity). Acts as an activator of the NLRP3 inflammasome by mediating palmitoylation of 'Cys-130' and 'Cys-958' of NLRP3, thereby promoting NLRP3 phosphorylation and activation by NEK7 (PubMed:39173637) Also has a palmitoyltransferase activity-independent function in DNA virus-triggered and CGAS-mediated innate immune response (PubMed:25299331). Functions as an activator of STING1 by promoting its cGAMP-induced oligomerization and the recruitment of downstream signaling components (PubMed:25299331)","subcellular_location":"Endosome membrane; Endoplasmic reticulum membrane; Golgi apparatus","url":"https://www.uniprot.org/uniprotkb/Q8WTX9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZDHHC1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZDHHC1","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZDHHC1"},"hgnc":{"alias_symbol":["HSU90653","ZNF377"],"prev_symbol":["C16orf1"]},"alphafold":{"accession":"Q8WTX9","domains":[{"cath_id":"-","chopping":"58-106_167-286","consensus_level":"high","plddt":95.4518,"start":58,"end":286}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WTX9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WTX9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WTX9-F1-predicted_aligned_error_v6.png","plddt_mean":67.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZDHHC1","jax_strain_url":"https://www.jax.org/strain/search?query=ZDHHC1"},"sequence":{"accession":"Q8WTX9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WTX9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WTX9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WTX9"}},"corpus_meta":[{"pmid":"25299331","id":"PMC_25299331","title":"The ER-associated protein ZDHHC1 is a positive regulator of DNA virus-triggered, MITA/STING-dependent innate immune signaling.","date":"2014","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/25299331","citation_count":139,"is_preprint":false},{"pmid":"32863941","id":"PMC_32863941","title":"DNA methylation downregulated ZDHHC1 suppresses tumor growth by altering cellular metabolism and inducing oxidative/ER stress-mediated apoptosis and pyroptosis.","date":"2020","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/32863941","citation_count":102,"is_preprint":false},{"pmid":"34282274","id":"PMC_34282274","title":"Cancer cells escape p53's tumor suppression through ablation of ZDHHC1-mediated p53 palmitoylation.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34282274","citation_count":47,"is_preprint":false},{"pmid":"23687301","id":"PMC_23687301","title":"In silico screening for palmitoyl substrates reveals a role for DHHC1/3/10 (zDHHC1/3/11)-mediated neurochondrin palmitoylation in its targeting to Rab5-positive endosomes.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23687301","citation_count":44,"is_preprint":false},{"pmid":"29046345","id":"PMC_29046345","title":"Endoplasmic Reticulum Transmembrane Proteins ZDHHC1 and STING Both Act as Direct Adaptors for IRF3 Activation in Teleost.","date":"2017","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/29046345","citation_count":40,"is_preprint":false},{"pmid":"39069526","id":"PMC_39069526","title":"ZDHHC1 downregulates LIPG and inhibits colorectal cancer growth via IGF2BP1 Palmitoylation.","date":"2024","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39069526","citation_count":20,"is_preprint":false},{"pmid":"33108395","id":"PMC_33108395","title":"p53 promotes ZDHHC1-mediated IFITM3 palmitoylation to inhibit Japanese encephalitis virus replication.","date":"2020","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/33108395","citation_count":18,"is_preprint":false},{"pmid":"36589680","id":"PMC_36589680","title":"Identification of ZDHHC1 as a Pyroptosis Inducer and Potential Target in the Establishment of Pyroptosis-Related Signature in Localized Prostate Cancer.","date":"2022","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/36589680","citation_count":17,"is_preprint":false},{"pmid":"39566590","id":"PMC_39566590","title":"Zdhhc1 deficiency mitigates foam cell formation and atherosclerosis by inhibiting PI3K-Akt-mTOR signaling pathway through facilitating the nuclear translocation of p110α.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/39566590","citation_count":9,"is_preprint":false},{"pmid":"39321020","id":"PMC_39321020","title":"Zdhhc1- and Zdhhc2-mediated Gpm6a palmitoylation is essential for maintenance of mammary stem cell activity.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39321020","citation_count":8,"is_preprint":false},{"pmid":"36122636","id":"PMC_36122636","title":"Molecular and functional characterization of zinc finger aspartate-histidine-histidine-cysteine (DHHC)-type containing 1, ZDHHC1 in Chinese perch Siniperca chuatsi.","date":"2022","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36122636","citation_count":6,"is_preprint":false},{"pmid":"40237800","id":"PMC_40237800","title":"Astragaloside IV-PESV facilitates pyroptosis by enhancing palmitoylation of GSDMD protein mediated by ZDHHC1.","date":"2025","source":"Naunyn-Schmiedeberg's archives of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40237800","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8532,"output_tokens":3325,"usd":0.037735,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10785,"output_tokens":3544,"usd":0.071263,"stage2_stop_reason":"end_turn"},"total_usd":0.108998,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"ZDHHC1 is an ER-associated protein that constitutively associates with MITA/STING and mediates dimerization/aggregation of MITA/STING as well as recruitment of downstream signaling components TBK1 and IRF3, acting as a positive regulator of DNA virus-triggered, MITA/STING-dependent innate immune signaling. Zdhhc1-knockout cells failed to produce IFNs and cytokines in response to DNA (but not RNA) viruses.\",\n      \"method\": \"Expression screen for IFNB1 promoter activation, Zdhhc1 knockout cells and mice, co-immunoprecipitation, cytokine measurement, HSV-1 infection model\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, KO cells and KO mice with defined phenotype, multiple orthogonal methods across in vitro and in vivo systems\",\n      \"pmids\": [\"25299331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ZDHHC1 (zDHHC1/z1, DHHC1) acts as a palmitoylating enzyme for neurochondrin (Ncdn), palmitoylating it at Cys-3 and Cys-4, and this palmitoylation is required for targeting Ncdn to Rab5-positive early endosomes. ZDHHC1 itself co-localizes with Rab5-positive endosomes, and knockdown of DHHC1 causes loss of Ncdn from these endosomes.\",\n      \"method\": \"In silico substrate prediction, DHHC enzyme library screening, palmitoylation assay, STED microscopy, siRNA knockdown, subcellular localization by fluorescence imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzyme-substrate palmitoylation assay with mutagenesis of palmitoylation sites, knockdown with defined localization phenotype, single lab\",\n      \"pmids\": [\"23687301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In teleost (grass carp), ZDHHC1 and STING each interact directly with IRF3 (demonstrated by co-immunoprecipitation and GST pull-down), promote IRF3 dimerization and nuclear translocation, and activate IFN-β expression. STING knockdown inhibits IFN expression and ZDHHC1-mediated IFN activation, indicating STING is required upstream of ZDHHC1 in this pathway. ZDHHC1 knockdown inhibits IFN expression but does not affect STING levels.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, siRNA knockdown, IFN promoter reporter assay, overexpression in Ctenopharyngodon idella kidney cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and GST pull-down with knockdown epistasis, single lab, teleost ortholog\",\n      \"pmids\": [\"29046345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZDHHC1 is transcriptionally upregulated by p53, and the resulting ZDHHC1 protein interacts with IFITM3 to promote its S-palmitoylation and protein stability, thereby inhibiting Japanese encephalitis virus (JEV) replication. Knockdown of IFITM3 impaired the anti-JEV effect of ZDHHC1, and knockdown of either ZDHHC1 or IFITM3 compromised p53-mediated anti-JEV activity. JEV reduces p53 expression to impair ZDHHC1-mediated IFITM3 palmitoylation as a viral evasion mechanism.\",\n      \"method\": \"Palmitoyltransferase screening, siRNA knockdown, Co-IP, palmitoylation assay, viral replication assay, protein stability assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzyme-substrate interaction by Co-IP, palmitoylation assay, epistasis via multiple knockdowns, single lab\",\n      \"pmids\": [\"33108395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZDHHC1 acts as an S-palmitoyltransferase that palmitoylates p53 at Cys-135, Cys-176, and Cys-275. This palmitoylation is required for nuclear translocation of p53. In a feedback loop, p53 recruits DNMT3A to the ZDHHC1 promoter, causing hypermethylation and silencing of ZDHHC1, thereby limiting its own nuclear import.\",\n      \"method\": \"Palmitoylation assay with site-directed mutagenesis (C135, C176, C275), nuclear translocation assay, chromatin immunoprecipitation, methylation analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — palmitoylation assay with mutagenesis of specific sites, nuclear translocation readout, ChIP for feedback mechanism, single lab\",\n      \"pmids\": [\"34282274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Restoration of ZDHHC1 expression in cancer cells inhibits glucose metabolism in a CYGB-dependent manner, suppresses the pentose phosphate pathway, and induces oxidative stress and ER stress leading to pyroptosis and apoptosis. Proteomic and metabolomic analyses identified these pathway alterations as ZDHHC1-dependent.\",\n      \"method\": \"iTRAQ proteomics, GC-MS metabolomics, Western blot, oxidative/ER stress indicator assays, xenograft mouse model, indirect immunofluorescence\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal omics and functional assays, in vivo validation, single lab\",\n      \"pmids\": [\"32863941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZDHHC1 palmitoylates IGF2BP1 at Cys-337; this S-palmitoylation results in downregulation of LIPG mRNA stability via m6A modification, inhibiting CRC cell proliferation and invasion. The ZDHHC1/IGF2BP1/LIPG signaling axis was defined by functional rescue and mechanistic experiments.\",\n      \"method\": \"Palmitoylation assay with site mutagenesis (C337), Co-IP, m6A modification analysis, in vitro and in vivo cell growth assays\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — palmitoylation with specific site mutagenesis, downstream m6A/mRNA stability mechanistic follow-up, single lab\",\n      \"pmids\": [\"39069526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZDHHC1 palmitoylates p110α (the catalytic subunit of PI3K) in macrophages; loss of Zdhhc1 reduces p110α palmitoylation, promotes nuclear translocation of p110α, and significantly decreases downstream phosphorylation of Akt (Ser473) and mTOR (Ser2448), thereby reducing foam cell formation and atherosclerotic plaque development.\",\n      \"method\": \"Zdhhc1 knockout in THP-1 cells and ApoE−/− mice, mass spectrometry palmitoylation analysis, bioinformatic pathway analysis, Western blot for PI3K-Akt-mTOR phosphorylation, nuclear fractionation, ox-LDL uptake assay\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined molecular mechanism (palmitoylation + nuclear translocation + kinase signaling), in vivo atherosclerosis model, single lab\",\n      \"pmids\": [\"39566590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Zdhhc1 and Zdhhc2 co-operatively palmitoylate Gpm6a at Cys17, Cys18, and Cys246, which is required for lipid raft formation mediated by Gpm6a, thereby stabilizing Procr protein and maintaining mammary stem cell (aMaSC) activity and postnatal mammary development.\",\n      \"method\": \"Gpm6a knockout mouse model, Zdhhc1/2 palmitoylation assay with site mutagenesis, lipid raft fractionation, Procr protein stability assay, mammary reconstitution assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — palmitoylation assay with mutagenesis of specific sites, KO mouse model, defined functional readout in aMaSCs, single lab\",\n      \"pmids\": [\"39321020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZDHHC1 physically interacts with GSDMD (gasdermin D) and mediates its palmitoylation; ZDHHC1 overexpression enhances GSDMD palmitoylation-mediated membrane translocation and pyroptosis in prostate cancer cells, and this effect is partially reversed by the palmitoylation inhibitor 2-BP.\",\n      \"method\": \"Co-IP, palmitoylation assay, 2-BP palmitoylation inhibitor, GSDMD membrane translocation assay, pyroptosis markers (IL-1β, IL-18, LDH, HMGB1), in vivo xenograft model\",\n      \"journal\": \"Naunyn-Schmiedeberg's archives of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for interaction, palmitoylation-dependent membrane translocation with pharmacological inhibitor confirmation, in vivo model, single lab\",\n      \"pmids\": [\"40237800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Chinese perch (Siniperca chuatsi), ZDHHC1 interacts with MITA (the fish ortholog of STING) by co-immunoprecipitation, and overexpression of ZDHHC1 upregulates ISGs (Mx, RSAD2, IRF3) and type I IFNs, consistent with an antiviral adaptor role conserved from fish to mammals.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, qRT-PCR for ISG/IFN expression, in vivo infection with ISKNV\",\n      \"journal\": \"Fish & shellfish immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP in a teleost ortholog, no mutagenesis or epistasis, single lab\",\n      \"pmids\": [\"36122636\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZDHHC1 is an ER-localized DHHC-domain S-palmitoyltransferase that palmitoylates multiple substrates—including MITA/STING (promoting its dimerization and downstream TBK1/IRF3 recruitment for antiviral innate immunity), p53 (required for its nuclear translocation), IFITM3 (stabilizing it against lysosomal degradation and enabling antiviral activity), IGF2BP1 (suppressing LIPG via m6A-dependent mRNA destabilization), p110α/PI3K (regulating Akt-mTOR signaling and foam cell formation), Gpm6a (enabling lipid raft formation and Procr stability in mammary stem cells), neurochondrin (directing it to Rab5-positive early endosomes), and GSDMD (promoting its membrane translocation and pyroptosis); ZDHHC1 expression is frequently silenced by promoter methylation in cancers, and a p53–ZDHHC1 epigenetic feedback loop—wherein p53 recruits DNMT3A to silence ZDHHC1, thereby limiting its own palmitoylation and nuclear import—represents a mechanism of p53 inactivation independent of mutation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZDHHC1 is an ER-localized DHHC-domain S-palmitoyltransferase that modifies a diverse set of substrates to control innate antiviral immunity, tumor suppression, and lipid-associated signaling [#0, #4]. In antiviral signaling it constitutively associates with MITA/STING, drives its dimerization/aggregation, and recruits TBK1 and IRF3, so that loss of ZDHHC1 abolishes type I interferon and cytokine responses to DNA but not RNA viruses [#0]; a conserved STING-dependent adaptor role acting through IRF3 dimerization and nuclear translocation is also seen in teleost orthologs [#2]. ZDHHC1 palmitoylates IFITM3 to stabilize it against degradation and restrict viral replication, an activity placed downstream of p53 transcriptional control [#3]. As an enzyme it palmitoylates p53 itself at Cys-135/176/275 to enable p53 nuclear translocation, and is in turn silenced by a p53-DNMT3A promoter-methylation feedback loop that limits p53 nuclear import [#4]. Additional defined substrates link ZDHHC1 to membrane targeting and disease processes: neurochondrin (palmitoylated at Cys-3/Cys-4 for delivery to Rab5-positive early endosomes) [#1], IGF2BP1 (Cys-337, destabilizing LIPG mRNA via m6A to suppress colorectal cancer growth) [#6], the PI3K catalytic subunit p110\\u03b1 (controlling Akt-mTOR signaling and macrophage foam-cell formation) [#7], Gpm6a (co-palmitoylated with ZDHHC2 to promote lipid raft formation and Procr stability in mammary stem cells) [#8], and gasdermin D (promoting membrane translocation and pyroptosis) [#9]. Re-expression of ZDHHC1 in cancer cells, where it is frequently silenced, suppresses glucose metabolism and the pentose phosphate pathway and induces oxidative/ER stress-driven cell death [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established ZDHHC1 as a bona fide palmitoyltransferase with a defined substrate and a membrane-targeting consequence, the first direct enzymatic characterization.\",\n      \"evidence\": \"DHHC enzyme library screening, palmitoylation assay with site mutagenesis (Cys-3/Cys-4), STED imaging and siRNA knockdown of neurochondrin localization\",\n      \"pmids\": [\"23687301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single substrate in one lab\", \"Endosomal targeting mechanism of ZDHHC1 itself not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a non-enzyme adaptor role for ZDHHC1 in DNA-virus innate immunity by linking it to MITA/STING signaling and downstream IRF3/TBK1 recruitment.\",\n      \"evidence\": \"IFNB1 promoter screen, reciprocal Co-IP, Zdhhc1 knockout cells and mice, HSV-1 infection\",\n      \"pmids\": [\"25299331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether catalytic palmitoyltransferase activity is required for STING regulation not dissected\", \"No palmitoylated residue on STING defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed the STING-IRF3 antiviral axis through ZDHHC1 is evolutionarily conserved and ordered, with STING acting upstream.\",\n      \"evidence\": \"Co-IP, GST pull-down, knockdown epistasis and IFN reporter assays in grass carp kidney cells\",\n      \"pmids\": [\"29046345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Teleost ortholog only\", \"Catalytic requirement not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected ZDHHC1 to p53-driven antiviral defense by identifying IFITM3 as a substrate whose palmitoylation-dependent stability mediates restriction.\",\n      \"evidence\": \"Palmitoyltransferase screen, Co-IP, palmitoylation and protein-stability assays, JEV replication assay with knockdown epistasis\",\n      \"pmids\": [\"33108395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IFITM3 palmitoylation site not mapped here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established a tumor-suppressive metabolic role for ZDHHC1, showing its re-expression rewires glucose metabolism and triggers stress-induced death.\",\n      \"evidence\": \"iTRAQ proteomics, GC-MS metabolomics, stress assays and xenograft model\",\n      \"pmids\": [\"32863941\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct palmitoylation substrate driving the metabolic effect not identified\", \"CYGB-dependence mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified p53 as a direct ZDHHC1 substrate and uncovered a p53-DNMT3A feedback loop silencing ZDHHC1, defining a mutation-independent route to p53 inactivation.\",\n      \"evidence\": \"Palmitoylation assay with Cys-135/176/275 mutagenesis, nuclear translocation assay, ChIP and methylation analysis\",\n      \"pmids\": [\"34282274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which palmitoylation drives nuclear import not structurally defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended ZDHHC1 substrate repertoire to IGF2BP1, linking palmitoylation to m6A-dependent mRNA destabilization of LIPG and CRC suppression.\",\n      \"evidence\": \"Palmitoylation assay with Cys-337 mutagenesis, Co-IP, m6A analysis, in vitro/in vivo growth assays\",\n      \"pmids\": [\"39069526\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How palmitoylation alters IGF2BP1 m6A reader function unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated ZDHHC1 in lipid-signaling and cardiovascular disease by showing it palmitoylates PI3K p110\\u03b1 to control its localization and Akt-mTOR output.\",\n      \"evidence\": \"Zdhhc1 knockout in THP-1 cells and ApoE\\u2212/\\u2212 mice, MS palmitoylation analysis, nuclear fractionation, ox-LDL uptake assay\",\n      \"pmids\": [\"39566590\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"p110\\u03b1 palmitoylation site not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed ZDHHC1 cooperates with ZDHHC2 to palmitoylate Gpm6a, coupling palmitoylation to lipid raft formation and stem-cell maintenance.\",\n      \"evidence\": \"Gpm6a knockout mice, palmitoylation assay with Cys-17/18/246 mutagenesis, lipid raft fractionation, mammary reconstitution\",\n      \"pmids\": [\"39321020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contributions of ZDHHC1 vs ZDHHC2 not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked ZDHHC1 to programmed cell death by showing it palmitoylates gasdermin D to promote membrane translocation and pyroptosis.\",\n      \"evidence\": \"Co-IP, palmitoylation assay, 2-BP inhibition, membrane translocation and pyroptosis marker assays, xenograft model\",\n      \"pmids\": [\"40237800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GSDMD palmitoylation site not mapped\", \"Single lab, pharmacological inhibitor not fully specific\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether ZDHHC1 catalytic palmitoyltransferase activity is required across all its reported roles (notably STING/MITA antiviral signaling) and how substrate selectivity is governed remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ZDHHC1 substrate recognition\", \"Catalytic-dead vs adaptor functions not systematically separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 3, 4, 6, 7, 8, 9]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 4, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 4, 6, 7, 8, 9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"STING1\", \"MITA\", \"IRF3\", \"TBK1\", \"IFITM3\", \"TP53\", \"IGF2BP1\", \"GSDMD\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}