{"gene":"ZDHHC7","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2016,"finding":"ZDHHC7 is the major palmitoyl acyltransferase that S-palmitoylates Scribble (SCRIB) at conserved cysteine residues, which is required for SCRIB membrane targeting to cell-cell junctions, maintenance of epithelial cell polarity, and tumor suppression. Knockout of ZDHHC7 causes SCRIB mislocalization and YAP activation, and disrupts SCRIB's suppressive activities in HRas(V12)-induced cell invasion.","method":"Chemical reporter palmitoylation assay, ZDHHC7 knockout, palmitoylation-deficient SCRIB mutants, cell polarity assays, invasion assays","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (chemical reporters, KO, site-specific mutants, functional readouts), single lab with rigorous controls","pmids":["27380321"],"is_preprint":false},{"year":2024,"finding":"ZDHHC7 palmitoylates NLRP3 at Cys126, promoting NLRP3 localization on the trans-Golgi network (TGN) at rest and on dispersed TGN upon activation, which is required for recruitment and oligomerization of the adaptor ASC and full inflammasome activation in macrophages and in vivo.","method":"ZDHHC7 knockout, pharmacological inhibition, Cys126 site mutation, palmitoylation assay, subcellular localization imaging, ASC oligomerization assay, in vivo inflammasome activation","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (KO, inhibitor, mutagenesis, localization, in vivo), mechanistic pathway placement established","pmids":["38583156"],"is_preprint":false},{"year":2024,"finding":"ZDHHC7 S-palmitoylates ATG16L1 at Cys153; this palmitoylation enhances formation of the ATG16L1-WIPI2B and ATG16L1-RAB33B complexes on the phagophore, facilitating LC3 lipidation and autophagosome formation.","method":"Acyl-biotin exchange assay, ATG16L1-KO HeLa cell rescue with wild-type vs. C153S mutant, ZDHHC7 overexpression/deletion, LC3-II immunoblot, co-immunoprecipitation, transmission electron microscopy","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis of palmitoylation site, KO rescue, multiple orthogonal readouts (lipidation, autophagosome formation, complex formation), single lab","pmids":["39087410"],"is_preprint":false},{"year":2023,"finding":"ZDHHC7 inhibits androgen receptor (AR) gene transcription, thereby reducing AR protein levels and abolishing AR signaling in prostate cancer cells; ZDHHC7 depletion increases oncogenic properties while ZDHHC7 restoration suppresses proliferation and invasion in vitro and tumor growth in vivo.","method":"RNA-seq, ZDHHC7 knockdown/overexpression, AR transcription and protein level assays, xenograft tumor model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO/OE with defined molecular phenotype (AR transcription), in vivo validation, but mechanism of AR transcriptional suppression by ZDHHC7 not fully resolved at molecular level","pmids":["37198397"],"is_preprint":false},{"year":2022,"finding":"The transcription factor KLF10 transcriptionally activates ZDHHC7 expression, which then palmitoylates CD36, promoting its plasma membrane localization and driving hepatic lipid accumulation and inflammation in NASH pathogenesis.","method":"Transcriptomic analysis, gain/loss-of-function in hepatocyte-specific mouse models, CD36 palmitoylation assay, membrane fractionation, diet-induced NASH model","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model with mechanistic epistasis (KLF10→ZDHHC7→CD36 palmitoylation→membrane localization), single lab, multiple functional readouts","pmids":["35492028"],"is_preprint":false},{"year":2019,"finding":"ZDHHC7 deficiency in mice impairs excitatory transmission, synaptic plasticity at hippocampal Schaffer collateral CA1 synapses, and hippocampal structural connectivity in both sexes; it also causes sex-specific effects on medial prefrontal cortical synaptic transmission and anxiety-related behavior (females only), consistent with a role in palmitoylation of sex steroid receptors linking them to membrane microdomains.","method":"Constitutive Zdhhc7 knockout mouse, behavioral tests, electrophysiology, protein analyses, diffusion tensor-based fiber tractography neuroimaging","journal":"Brain structure & function","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with multiple defined electrophysiological and behavioral phenotypes, single lab, multiple orthogonal methods","pmids":["31183559"],"is_preprint":false},{"year":2024,"finding":"zDHHC7 expression and protein S-palmitoylation are elevated in hippocampi of 3×Tg-AD mice and post-mortem AD patients; hippocampal silencing of zDHHC7 prevents cognitive deficits in 3×Tg-AD mice; a FoxO1-mediated epigenetic mechanism drives zDHHC7 expression in response to brain insulin resistance; and S-palmitoylation of BACE1 (Beta-Secretase 1) by zDHHC7 is associated with Aβ1-42 load.","method":"zDHHC7 hippocampal silencing (knockdown) in 3×Tg-AD mice, cognitive behavior tests, 2-bromopalmitate pharmacological inhibition, palmitoylation assays, human post-mortem tissue analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD with cognitive phenotype and molecular readouts (Aβ deposition, BACE1 palmitoylation), single lab, multiple methods","pmids":["39589870"],"is_preprint":false},{"year":2025,"finding":"ZDHHC7 palmitoylates Sprouty 4 (SPRY4), and this modification is reversed by palmitoyl-protein thioesterase 1 (PPT1); the dynamic palmitoylation-depalmitoylation cycle of SPRY4 modulates MAPK signaling and affects tumor cell proliferation, migration, apoptosis, and cisplatin resistance in osteosarcoma cells.","method":"In vitro and in vivo experiments, single-cell analysis, palmitoylation assays, MAPK signaling readouts, drug resistance assays","journal":"Research (Washington, D.C.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — abstract describes mechanism but method details are limited; single lab, no mutagenesis or reconstitution explicitly described","pmids":["40416361"],"is_preprint":false},{"year":2026,"finding":"ZDHHC7 and ZDHHC3 (both Golgi-localized S-acyltransferases) mediate triple S-acylation of the small GTPase ARL15 at Cys17, Cys22, and Cys23; loss of S-acylation disrupts ARL15 membrane association, redistributing it from membranes to the cytosol.","method":"Acyl-PEGyl exchange gel-shift assay, siRNA knockdown, CRISPR/Cas9 gene disruption, confocal imaging, subcellular fractionation, cysteine-to-serine mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — site-specific mutagenesis, dual-enzyme CRISPR KO, acylation stoichiometry assay, and localization by fractionation and imaging; multiple orthogonal methods in single rigorous study","pmids":["41999893"],"is_preprint":false},{"year":2026,"finding":"ZDHHC7 S-palmitoylates the PRRSV nonstructural protein Nsp10 in an acyltransferase-dependent manner, weakening Nsp10 binding to viral RNA and restricting PRRSV replication; PRRSV counteracts this by having Nsp4 cleave ZDHHC7 at E226 (abolishing palmitoylation of Nsp10, STING, and MAVS), and by Nsp2/GP5 inducing APT1 (depalmitoylase) via NFATC3 to reverse Nsp10 palmitoylation.","method":"Palmitoylation assays, ZDHHC7 overexpression/mutation (E226A cleavage-resistant), viral replication assays, RNA-protein binding assays, transcription factor analysis","journal":"Research in veterinary science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — acyltransferase-dependent antiviral mechanism with cleavage-site mutagenesis and multiple viral protein interactions identified, single lab","pmids":["41671757"],"is_preprint":false},{"year":2021,"finding":"ZDHHC7 deficiency impairs synaptic plasticity in mice of both sexes; after acute stress, male Zdhhc7-KO mice show reduced mean fiber lengths of the medioventral hippocampus, while acute stress improves synaptic plasticity in female (but not male) mice; estrogen receptor α and β mRNA levels are reduced by acute stress in male mice regardless of genotype, consistent with ZDHHC7 modulating stress responses partly via estrogen receptor-mediated pathways.","method":"Zdhhc7 knockout mouse, electrophysiology, diffusion tensor imaging, mRNA expression analysis (qPCR), behavioral tests","journal":"Brain structure & function","confidence":"Low","confidence_rationale":"Tier 3 / Weak — KO mouse with electrophysiology and neuroimaging, but molecular mechanism linking ZDHHC7 to estrogen receptor pathway in stress context is inferred rather than directly demonstrated","pmids":["33880616"],"is_preprint":false}],"current_model":"ZDHHC7 is a Golgi-localized DHHC-family palmitoyl acyltransferase that catalyzes S-palmitoylation of multiple substrates—including Scribble (SCRIB), NLRP3, ATG16L1, CD36, SPRY4, ARL15, estrogen receptors, BACE1, and viral Nsp10—to regulate their membrane targeting and downstream signaling, thereby controlling epithelial cell polarity and tumor suppression, NLRP3 inflammasome activation via TGN localization, autophagosome formation, hepatic lipid metabolism, androgen receptor transcription, synaptic plasticity, and antiviral immunity."},"narrative":{"mechanistic_narrative":"ZDHHC7 is a Golgi-localized DHHC-family palmitoyl acyltransferase that S-palmitoylates a diverse set of substrate proteins to control their membrane targeting and downstream signaling across epithelial polarity, innate immunity, autophagy, and metabolism [PMID:27380321, PMID:38583156, PMID:39087410]. Mechanistically, ZDHHC7 attaches palmitate to specific cysteines on its substrates: it palmitoylates Scribble to drive its targeting to cell-cell junctions, sustaining epithelial polarity and tumor suppression, such that its loss causes SCRIB mislocalization, YAP activation, and HRas(V12)-driven invasion [PMID:27380321]; it palmitoylates NLRP3 at Cys126 to position the sensor on the trans-Golgi network and enable ASC recruitment and inflammasome activation [PMID:38583156]; and it palmitoylates ATG16L1 at Cys153 to promote ATG16L1-WIPI2B and ATG16L1-RAB33B complex assembly, LC3 lipidation, and autophagosome formation [PMID:39087410]. The same enzymatic logic extends to the small GTPase ARL15, which ZDHHC7 (together with ZDHHC3) triple-acylates at Cys17/Cys22/Cys23 to maintain its membrane association [PMID:41999893]. Through substrate-specific palmitoylation ZDHHC7 also governs hepatic CD36 plasma-membrane delivery in NASH downstream of KLF10 [PMID:35492028], antiviral restriction by palmitoylating the PRRSV protein Nsp10 to weaken its RNA binding [PMID:41671757], and hippocampal synaptic plasticity and stress-related behavior [PMID:31183559]. In prostate cancer cells ZDHHC7 suppresses androgen receptor transcription and tumor growth [PMID:37198397], and in models of Alzheimer's disease elevated hippocampal zDHHC7 driven by a FoxO1 epigenetic mechanism palmitoylates BACE1 and contributes to cognitive deficits [PMID:39589870].","teleology":[{"year":2016,"claim":"Established ZDHHC7 as the major acyltransferase for Scribble, answering how a polarity scaffold is targeted to junctions and linking ZDHHC7 to tumor suppression.","evidence":"Chemical reporter palmitoylation assay, ZDHHC7 knockout, palmitoylation-deficient SCRIB mutants, and cell polarity/invasion assays","pmids":["27380321"],"confidence":"High","gaps":["Does not define the structural basis of substrate selection","Other ZDHHC7 substrates not addressed"]},{"year":2019,"claim":"Showed ZDHHC7 is required for hippocampal excitatory transmission and synaptic plasticity in vivo, with sex-specific behavioral effects, placing palmitoylation in neuronal circuit function.","evidence":"Constitutive Zdhhc7 knockout mouse with electrophysiology, behavior, and fiber tractography","pmids":["31183559"],"confidence":"Medium","gaps":["Direct neuronal substrate not identified","Link to sex steroid receptors inferred, not demonstrated"]},{"year":2021,"claim":"Extended the neuronal role by linking ZDHHC7 to stress-dependent plasticity and estrogen receptor expression, but the molecular connection remained inferential.","evidence":"Zdhhc7-KO mouse with electrophysiology, diffusion tensor imaging, and ER mRNA quantification under acute stress","pmids":["33880616"],"confidence":"Low","gaps":["Estrogen receptor pathway link inferred rather than shown by palmitoylation assay","No identified palmitoylated substrate"]},{"year":2022,"claim":"Defined a KLF10→ZDHHC7→CD36 axis explaining how ZDHHC7 promotes hepatic lipid uptake, connecting the enzyme to NASH pathogenesis.","evidence":"Hepatocyte-specific gain/loss-of-function mouse models, CD36 palmitoylation assay, membrane fractionation, diet-induced NASH","pmids":["35492028"],"confidence":"Medium","gaps":["CD36 palmitoylation site not mapped","Single lab"]},{"year":2023,"claim":"Revealed an unexpected non-canonical role for ZDHHC7 in suppressing androgen receptor transcription and prostate tumor growth.","evidence":"RNA-seq, knockdown/overexpression, AR transcription/protein assays, xenograft model","pmids":["37198397"],"confidence":"Medium","gaps":["Molecular mechanism of AR transcriptional repression unresolved","Unclear whether this depends on acyltransferase activity"]},{"year":2024,"claim":"Mapped substrate-specific palmitoylation events placing ZDHHC7 in inflammasome activation (NLRP3 Cys126/TGN), autophagosome formation (ATG16L1 Cys153), and AD-associated BACE1 modification.","evidence":"Site-directed mutagenesis, KO/rescue, acyl-biotin exchange, localization imaging, in vivo inflammasome and cognitive readouts","pmids":["38583156","39087410","39589870"],"confidence":"High","gaps":["How ZDHHC7 selects between these substrates is unknown","BACE1 study links palmitoylation to Aβ association but not causation"]},{"year":2025,"claim":"Identified a dynamic SPRY4 palmitoylation-depalmitoylation cycle (ZDHHC7/PPT1) modulating MAPK signaling and chemoresistance in osteosarcoma.","evidence":"Palmitoylation assays, MAPK readouts, drug resistance assays, single-cell analysis","pmids":["40416361"],"confidence":"Low","gaps":["No mutagenesis or reconstitution explicitly described","Palmitoylation site on SPRY4 not defined"]},{"year":2026,"claim":"Demonstrated ZDHHC7 (with ZDHHC3) triple-acylates ARL15 to maintain membrane association, and that ZDHHC7 restricts PRRSV by palmitoylating Nsp10 to weaken RNA binding, with the virus encoding countermeasures.","evidence":"Acyl-PEGyl exchange, dual-enzyme CRISPR KO, cysteine-to-serine mutagenesis, fractionation, and antiviral replication/RNA-binding assays with cleavage-resistant mutants","pmids":["41999893","41671757"],"confidence":"High","gaps":["Functional consequence of ARL15 acylation downstream of membrane targeting not defined","PRRSV mechanism in non-veterinary contexts untested"]},{"year":null,"claim":"What determines ZDHHC7 substrate specificity across this broad and functionally divergent substrate set, and how its activity is regulated in different tissues, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate recognition in the corpus","Regulation of ZDHHC7 expression/activity across tissues incompletely defined","Acyltransferase-dependence of some phenotypes (e.g., AR suppression) unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,8]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,8]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,8]}],"pathway":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2]}],"complexes":[],"partners":["SCRIB","NLRP3","ATG16L1","CD36","ARL15","SPRY4","BACE1","ZDHHC3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NXF8","full_name":"Palmitoyltransferase ZDHHC7","aliases":["Acyltransferase ZDHHC7","Zinc finger DHHC domain-containing protein 7","DHHC-7"],"length_aa":308,"mass_kda":35.1,"function":"Golgi-localized palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates and therefore functions in several unrelated biological processes (PubMed:22031296, PubMed:27380321, PubMed:28196865). Has no stringent fatty acid selectivity and in addition to palmitate can also transfer onto target proteins myristate from tetradecanoyl-CoA and stearate from octadecanoyl-CoA (By similarity). Palmitoylates sex steroid hormone receptors, including ESR1, PGR and AR, thereby regulating their targeting to the plasma membrane and their function in rapid intracellular signaling upon binding of sex hormones (PubMed:22031296). Palmitoylates GNAQ, a heterotrimeric G protein, regulating its dynamic localization at the plasma membrane and is thereby involved in GNAQ-dependent G protein-coupled receptor signaling pathways (PubMed:19001095). Also functions in ligand-induced cell death by regulating the FAS signaling pathway through the palmitoylation and stabilization of the receptor at the plasma membrane (PubMed:25301068). In epithelial cells, palmitoylates SCRIB and regulates its localization to the plasma membrane, regulating indirectly cell polarity and differentiation (PubMed:27380321). Also palmitoylates JAM3 and promotes its expression at tight junctions and regulates its function in cell migration (PubMed:28196865). Palmitoylates the glucose transporter GLUT4/SLC2A4 and controls the insulin-dependent translocation of GLUT4 to the plasma membrane (By similarity). In brain, could also palmitoylate SNAP25 and DLG4/PSD95 (By similarity). Could also palmitoylate DNAJC5 and regulate its localization to the Golgi membrane (By similarity). Could also palmitoylate NCDN (By similarity). May play a role in follicle stimulation hormone (FSH) activation of testicular Sertoli cells (By similarity). Activates pyroptosis by catalyzing palmitoylation of gasdermin-D (GSDMD) (By similarity)","subcellular_location":"Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q9NXF8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZDHHC7","classification":"Not Classified","n_dependent_lines":20,"n_total_lines":1208,"dependency_fraction":0.016556291390728478},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZDHHC7","total_profiled":1310},"omim":[{"mim_id":"616143","title":"LYSOPHOSPHOLIPASE II; LYPLA2","url":"https://www.omim.org/entry/616143"},{"mim_id":"614604","title":"ZDHHC PALMITOYLTRANSFERASE 7; ZDHHC7","url":"https://www.omim.org/entry/614604"},{"mim_id":"102582","title":"SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3; STAT3","url":"https://www.omim.org/entry/102582"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Golgi apparatus","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZDHHC7"},"hgnc":{"alias_symbol":["FLJ10792","ZNF370","FLJ20279","SERZ-B","SERZ1","DHHC7"],"prev_symbol":[]},"alphafold":{"accession":"Q9NXF8","domains":[{"cath_id":"1.20.140","chopping":"40-106_157-283","consensus_level":"high","plddt":94.8143,"start":40,"end":283}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NXF8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NXF8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NXF8-F1-predicted_aligned_error_v6.png","plddt_mean":83.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZDHHC7","jax_strain_url":"https://www.jax.org/strain/search?query=ZDHHC7"},"sequence":{"accession":"Q9NXF8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NXF8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NXF8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NXF8"}},"corpus_meta":[{"pmid":"27380321","id":"PMC_27380321","title":"ZDHHC7-mediated S-palmitoylation of Scribble regulates cell polarity.","date":"2016","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/27380321","citation_count":97,"is_preprint":false},{"pmid":"38583156","id":"PMC_38583156","title":"NLRP3 Cys126 palmitoylation by ZDHHC7 promotes inflammasome activation.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38583156","citation_count":78,"is_preprint":false},{"pmid":"39087410","id":"PMC_39087410","title":"ZDHHC7-mediated S-palmitoylation of ATG16L1 facilitates LC3 lipidation and autophagosome formation.","date":"2024","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/39087410","citation_count":35,"is_preprint":false},{"pmid":"37198397","id":"PMC_37198397","title":"Palmitoyl acyltransferase ZDHHC7 inhibits androgen receptor and suppresses prostate cancer.","date":"2023","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/37198397","citation_count":26,"is_preprint":false},{"pmid":"35492028","id":"PMC_35492028","title":"KLF10 promotes nonalcoholic steatohepatitis progression through transcriptional activation of zDHHC7.","date":"2022","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/35492028","citation_count":26,"is_preprint":false},{"pmid":"39589870","id":"PMC_39589870","title":"Inhibition of zDHHC7-driven protein S-palmitoylation prevents cognitive deficits in an experimental model of Alzheimer's disease.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39589870","citation_count":19,"is_preprint":false},{"pmid":"31183559","id":"PMC_31183559","title":"Deficiency of the palmitoyl acyltransferase ZDHHC7 impacts brain and behavior of mice in a sex-specific manner.","date":"2019","source":"Brain structure & function","url":"https://pubmed.ncbi.nlm.nih.gov/31183559","citation_count":16,"is_preprint":false},{"pmid":"34355442","id":"PMC_34355442","title":"Brain microstructural changes in mice persist in adulthood and are modulated by the palmitoyl acyltransferase ZDHHC7.","date":"2021","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34355442","citation_count":14,"is_preprint":false},{"pmid":"40416361","id":"PMC_40416361","title":"Dual Regulation of Sprouty 4 Palmitoylation by ZDHHC7 and Palmitoyl-Protein Thioesterase 1: A Potential Therapeutic Strategy for Cisplatin-Resistant Osteosarcoma.","date":"2025","source":"Research (Washington, D.C.)","url":"https://pubmed.ncbi.nlm.nih.gov/40416361","citation_count":11,"is_preprint":false},{"pmid":"33880616","id":"PMC_33880616","title":"Acute stress reveals different impacts in male and female Zdhhc7-deficient mice.","date":"2021","source":"Brain structure & function","url":"https://pubmed.ncbi.nlm.nih.gov/33880616","citation_count":8,"is_preprint":false},{"pmid":"39856044","id":"PMC_39856044","title":"Deficiency of the palmitoyl acyltransferase ZDHHC7 modulates depression-like behaviour in female mice after a mild chronic stress paradigm.","date":"2025","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/39856044","citation_count":1,"is_preprint":false},{"pmid":"41999893","id":"PMC_41999893","title":"S-acylation and membrane localization of the small GTPase ARL15 are mediated by the Golgi S-acyltransferases ZDHHC7 and ZDHHC3.","date":"2026","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41999893","citation_count":0,"is_preprint":false},{"pmid":"41671757","id":"PMC_41671757","title":"S-palmitoylation of the viral Nsp10 by ZDHHC7 restricts PRRSV replication but is counteracted by Nsp2, Nsp4 and GP5.","date":"2026","source":"Research in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/41671757","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9720,"output_tokens":3158,"usd":0.038265,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10615,"output_tokens":3042,"usd":0.064562,"stage2_stop_reason":"end_turn"},"total_usd":0.102827,"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\": 2016,\n      \"finding\": \"ZDHHC7 is the major palmitoyl acyltransferase that S-palmitoylates Scribble (SCRIB) at conserved cysteine residues, which is required for SCRIB membrane targeting to cell-cell junctions, maintenance of epithelial cell polarity, and tumor suppression. Knockout of ZDHHC7 causes SCRIB mislocalization and YAP activation, and disrupts SCRIB's suppressive activities in HRas(V12)-induced cell invasion.\",\n      \"method\": \"Chemical reporter palmitoylation assay, ZDHHC7 knockout, palmitoylation-deficient SCRIB mutants, cell polarity assays, invasion assays\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (chemical reporters, KO, site-specific mutants, functional readouts), single lab with rigorous controls\",\n      \"pmids\": [\"27380321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZDHHC7 palmitoylates NLRP3 at Cys126, promoting NLRP3 localization on the trans-Golgi network (TGN) at rest and on dispersed TGN upon activation, which is required for recruitment and oligomerization of the adaptor ASC and full inflammasome activation in macrophages and in vivo.\",\n      \"method\": \"ZDHHC7 knockout, pharmacological inhibition, Cys126 site mutation, palmitoylation assay, subcellular localization imaging, ASC oligomerization assay, in vivo inflammasome activation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (KO, inhibitor, mutagenesis, localization, in vivo), mechanistic pathway placement established\",\n      \"pmids\": [\"38583156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZDHHC7 S-palmitoylates ATG16L1 at Cys153; this palmitoylation enhances formation of the ATG16L1-WIPI2B and ATG16L1-RAB33B complexes on the phagophore, facilitating LC3 lipidation and autophagosome formation.\",\n      \"method\": \"Acyl-biotin exchange assay, ATG16L1-KO HeLa cell rescue with wild-type vs. C153S mutant, ZDHHC7 overexpression/deletion, LC3-II immunoblot, co-immunoprecipitation, transmission electron microscopy\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis of palmitoylation site, KO rescue, multiple orthogonal readouts (lipidation, autophagosome formation, complex formation), single lab\",\n      \"pmids\": [\"39087410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZDHHC7 inhibits androgen receptor (AR) gene transcription, thereby reducing AR protein levels and abolishing AR signaling in prostate cancer cells; ZDHHC7 depletion increases oncogenic properties while ZDHHC7 restoration suppresses proliferation and invasion in vitro and tumor growth in vivo.\",\n      \"method\": \"RNA-seq, ZDHHC7 knockdown/overexpression, AR transcription and protein level assays, xenograft tumor model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO/OE with defined molecular phenotype (AR transcription), in vivo validation, but mechanism of AR transcriptional suppression by ZDHHC7 not fully resolved at molecular level\",\n      \"pmids\": [\"37198397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The transcription factor KLF10 transcriptionally activates ZDHHC7 expression, which then palmitoylates CD36, promoting its plasma membrane localization and driving hepatic lipid accumulation and inflammation in NASH pathogenesis.\",\n      \"method\": \"Transcriptomic analysis, gain/loss-of-function in hepatocyte-specific mouse models, CD36 palmitoylation assay, membrane fractionation, diet-induced NASH model\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model with mechanistic epistasis (KLF10→ZDHHC7→CD36 palmitoylation→membrane localization), single lab, multiple functional readouts\",\n      \"pmids\": [\"35492028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZDHHC7 deficiency in mice impairs excitatory transmission, synaptic plasticity at hippocampal Schaffer collateral CA1 synapses, and hippocampal structural connectivity in both sexes; it also causes sex-specific effects on medial prefrontal cortical synaptic transmission and anxiety-related behavior (females only), consistent with a role in palmitoylation of sex steroid receptors linking them to membrane microdomains.\",\n      \"method\": \"Constitutive Zdhhc7 knockout mouse, behavioral tests, electrophysiology, protein analyses, diffusion tensor-based fiber tractography neuroimaging\",\n      \"journal\": \"Brain structure & function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with multiple defined electrophysiological and behavioral phenotypes, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31183559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"zDHHC7 expression and protein S-palmitoylation are elevated in hippocampi of 3×Tg-AD mice and post-mortem AD patients; hippocampal silencing of zDHHC7 prevents cognitive deficits in 3×Tg-AD mice; a FoxO1-mediated epigenetic mechanism drives zDHHC7 expression in response to brain insulin resistance; and S-palmitoylation of BACE1 (Beta-Secretase 1) by zDHHC7 is associated with Aβ1-42 load.\",\n      \"method\": \"zDHHC7 hippocampal silencing (knockdown) in 3×Tg-AD mice, cognitive behavior tests, 2-bromopalmitate pharmacological inhibition, palmitoylation assays, human post-mortem tissue analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD with cognitive phenotype and molecular readouts (Aβ deposition, BACE1 palmitoylation), single lab, multiple methods\",\n      \"pmids\": [\"39589870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZDHHC7 palmitoylates Sprouty 4 (SPRY4), and this modification is reversed by palmitoyl-protein thioesterase 1 (PPT1); the dynamic palmitoylation-depalmitoylation cycle of SPRY4 modulates MAPK signaling and affects tumor cell proliferation, migration, apoptosis, and cisplatin resistance in osteosarcoma cells.\",\n      \"method\": \"In vitro and in vivo experiments, single-cell analysis, palmitoylation assays, MAPK signaling readouts, drug resistance assays\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — abstract describes mechanism but method details are limited; single lab, no mutagenesis or reconstitution explicitly described\",\n      \"pmids\": [\"40416361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZDHHC7 and ZDHHC3 (both Golgi-localized S-acyltransferases) mediate triple S-acylation of the small GTPase ARL15 at Cys17, Cys22, and Cys23; loss of S-acylation disrupts ARL15 membrane association, redistributing it from membranes to the cytosol.\",\n      \"method\": \"Acyl-PEGyl exchange gel-shift assay, siRNA knockdown, CRISPR/Cas9 gene disruption, confocal imaging, subcellular fractionation, cysteine-to-serine mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — site-specific mutagenesis, dual-enzyme CRISPR KO, acylation stoichiometry assay, and localization by fractionation and imaging; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"41999893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZDHHC7 S-palmitoylates the PRRSV nonstructural protein Nsp10 in an acyltransferase-dependent manner, weakening Nsp10 binding to viral RNA and restricting PRRSV replication; PRRSV counteracts this by having Nsp4 cleave ZDHHC7 at E226 (abolishing palmitoylation of Nsp10, STING, and MAVS), and by Nsp2/GP5 inducing APT1 (depalmitoylase) via NFATC3 to reverse Nsp10 palmitoylation.\",\n      \"method\": \"Palmitoylation assays, ZDHHC7 overexpression/mutation (E226A cleavage-resistant), viral replication assays, RNA-protein binding assays, transcription factor analysis\",\n      \"journal\": \"Research in veterinary science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — acyltransferase-dependent antiviral mechanism with cleavage-site mutagenesis and multiple viral protein interactions identified, single lab\",\n      \"pmids\": [\"41671757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZDHHC7 deficiency impairs synaptic plasticity in mice of both sexes; after acute stress, male Zdhhc7-KO mice show reduced mean fiber lengths of the medioventral hippocampus, while acute stress improves synaptic plasticity in female (but not male) mice; estrogen receptor α and β mRNA levels are reduced by acute stress in male mice regardless of genotype, consistent with ZDHHC7 modulating stress responses partly via estrogen receptor-mediated pathways.\",\n      \"method\": \"Zdhhc7 knockout mouse, electrophysiology, diffusion tensor imaging, mRNA expression analysis (qPCR), behavioral tests\",\n      \"journal\": \"Brain structure & function\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — KO mouse with electrophysiology and neuroimaging, but molecular mechanism linking ZDHHC7 to estrogen receptor pathway in stress context is inferred rather than directly demonstrated\",\n      \"pmids\": [\"33880616\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZDHHC7 is a Golgi-localized DHHC-family palmitoyl acyltransferase that catalyzes S-palmitoylation of multiple substrates—including Scribble (SCRIB), NLRP3, ATG16L1, CD36, SPRY4, ARL15, estrogen receptors, BACE1, and viral Nsp10—to regulate their membrane targeting and downstream signaling, thereby controlling epithelial cell polarity and tumor suppression, NLRP3 inflammasome activation via TGN localization, autophagosome formation, hepatic lipid metabolism, androgen receptor transcription, synaptic plasticity, and antiviral immunity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZDHHC7 is a Golgi-localized DHHC-family palmitoyl acyltransferase that S-palmitoylates a diverse set of substrate proteins to control their membrane targeting and downstream signaling across epithelial polarity, innate immunity, autophagy, and metabolism [#0, #1, #2]. Mechanistically, ZDHHC7 attaches palmitate to specific cysteines on its substrates: it palmitoylates Scribble to drive its targeting to cell-cell junctions, sustaining epithelial polarity and tumor suppression, such that its loss causes SCRIB mislocalization, YAP activation, and HRas(V12)-driven invasion [#0]; it palmitoylates NLRP3 at Cys126 to position the sensor on the trans-Golgi network and enable ASC recruitment and inflammasome activation [#1]; and it palmitoylates ATG16L1 at Cys153 to promote ATG16L1-WIPI2B and ATG16L1-RAB33B complex assembly, LC3 lipidation, and autophagosome formation [#2]. The same enzymatic logic extends to the small GTPase ARL15, which ZDHHC7 (together with ZDHHC3) triple-acylates at Cys17/Cys22/Cys23 to maintain its membrane association [#8]. Through substrate-specific palmitoylation ZDHHC7 also governs hepatic CD36 plasma-membrane delivery in NASH downstream of KLF10 [#4], antiviral restriction by palmitoylating the PRRSV protein Nsp10 to weaken its RNA binding [#9], and hippocampal synaptic plasticity and stress-related behavior [#5]. In prostate cancer cells ZDHHC7 suppresses androgen receptor transcription and tumor growth [#3], and in models of Alzheimer's disease elevated hippocampal zDHHC7 driven by a FoxO1 epigenetic mechanism palmitoylates BACE1 and contributes to cognitive deficits [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established ZDHHC7 as the major acyltransferase for Scribble, answering how a polarity scaffold is targeted to junctions and linking ZDHHC7 to tumor suppression.\",\n      \"evidence\": \"Chemical reporter palmitoylation assay, ZDHHC7 knockout, palmitoylation-deficient SCRIB mutants, and cell polarity/invasion assays\",\n      \"pmids\": [\"27380321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the structural basis of substrate selection\", \"Other ZDHHC7 substrates not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed ZDHHC7 is required for hippocampal excitatory transmission and synaptic plasticity in vivo, with sex-specific behavioral effects, placing palmitoylation in neuronal circuit function.\",\n      \"evidence\": \"Constitutive Zdhhc7 knockout mouse with electrophysiology, behavior, and fiber tractography\",\n      \"pmids\": [\"31183559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct neuronal substrate not identified\", \"Link to sex steroid receptors inferred, not demonstrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the neuronal role by linking ZDHHC7 to stress-dependent plasticity and estrogen receptor expression, but the molecular connection remained inferential.\",\n      \"evidence\": \"Zdhhc7-KO mouse with electrophysiology, diffusion tensor imaging, and ER mRNA quantification under acute stress\",\n      \"pmids\": [\"33880616\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Estrogen receptor pathway link inferred rather than shown by palmitoylation assay\", \"No identified palmitoylated substrate\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a KLF10\\u2192ZDHHC7\\u2192CD36 axis explaining how ZDHHC7 promotes hepatic lipid uptake, connecting the enzyme to NASH pathogenesis.\",\n      \"evidence\": \"Hepatocyte-specific gain/loss-of-function mouse models, CD36 palmitoylation assay, membrane fractionation, diet-induced NASH\",\n      \"pmids\": [\"35492028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CD36 palmitoylation site not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed an unexpected non-canonical role for ZDHHC7 in suppressing androgen receptor transcription and prostate tumor growth.\",\n      \"evidence\": \"RNA-seq, knockdown/overexpression, AR transcription/protein assays, xenograft model\",\n      \"pmids\": [\"37198397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of AR transcriptional repression unresolved\", \"Unclear whether this depends on acyltransferase activity\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped substrate-specific palmitoylation events placing ZDHHC7 in inflammasome activation (NLRP3 Cys126/TGN), autophagosome formation (ATG16L1 Cys153), and AD-associated BACE1 modification.\",\n      \"evidence\": \"Site-directed mutagenesis, KO/rescue, acyl-biotin exchange, localization imaging, in vivo inflammasome and cognitive readouts\",\n      \"pmids\": [\"38583156\", \"39087410\", \"39589870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ZDHHC7 selects between these substrates is unknown\", \"BACE1 study links palmitoylation to A\\u03b2 association but not causation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a dynamic SPRY4 palmitoylation-depalmitoylation cycle (ZDHHC7/PPT1) modulating MAPK signaling and chemoresistance in osteosarcoma.\",\n      \"evidence\": \"Palmitoylation assays, MAPK readouts, drug resistance assays, single-cell analysis\",\n      \"pmids\": [\"40416361\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mutagenesis or reconstitution explicitly described\", \"Palmitoylation site on SPRY4 not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated ZDHHC7 (with ZDHHC3) triple-acylates ARL15 to maintain membrane association, and that ZDHHC7 restricts PRRSV by palmitoylating Nsp10 to weaken RNA binding, with the virus encoding countermeasures.\",\n      \"evidence\": \"Acyl-PEGyl exchange, dual-enzyme CRISPR KO, cysteine-to-serine mutagenesis, fractionation, and antiviral replication/RNA-binding assays with cleavage-resistant mutants\",\n      \"pmids\": [\"41999893\", \"41671757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of ARL15 acylation downstream of membrane targeting not defined\", \"PRRSV mechanism in non-veterinary contexts untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"What determines ZDHHC7 substrate specificity across this broad and functionally divergent substrate set, and how its activity is regulated in different tissues, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate recognition in the corpus\", \"Regulation of ZDHHC7 expression/activity across tissues incompletely defined\", \"Acyltransferase-dependence of some phenotypes (e.g., AR suppression) unestablished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 8]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SCRIB\", \"NLRP3\", \"ATG16L1\", \"CD36\", \"ARL15\", \"SPRY4\", \"BACE1\", \"ZDHHC3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}