{"gene":"ZDHHC23","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2012,"finding":"ZDHHC23 (together with zDHHC22) palmitoylates the intracellular S0-S1 loop of BK channel α-subunits, and this palmitoylation is essential for efficient cell surface expression of BK channels; depalmitoylated channels are retarded in the trans-Golgi network.","method":"Overexpression/knockdown of individual zDHHC enzymes in heterologous cells, surface biotinylation assays, palmitoylation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function with defined trafficking phenotype, replicated with multiple zDHHC members and corroborated by downstream thioesterase experiments","pmids":["22399288"],"is_preprint":false},{"year":2019,"finding":"S-acylation of the BK channel α-subunit S0-S1 loop by ZDHHC23 controls functional coupling to regulatory β1-subunits: in vascular smooth muscle cells expressing both subunits, genetic deletion of Zdhhc23 significantly reduces S-acylation and attenuates endogenous BK channel currents independently of changes in α-subunit surface expression.","method":"Genetic knockout of Zdhhc23 in mice, electrophysiology (patch clamp), acyl-RAC/surface biotinylation, HEK293 cell reconstitution with non-acylatable mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vivo knockout mouse model combined with electrophysiology and biochemical acylation assays, multiple orthogonal methods in one study","pmids":["31213527"],"is_preprint":false},{"year":2021,"finding":"ZDHHC5 and ZDHHC23 catalyze S-palmitoylation of the cytosolic thioesterase APT1; reduced ZDHHC5/ZDHHC23 levels in the brain of Cln1−/− (INCL model) mice suppress membrane-bound APT1, increasing plasma membrane-localized H-Ras and stimulating its proliferative signaling pathway in microglia.","method":"Overexpression of individual zDHHC enzymes, palmitoylation assays, Cln1−/− mouse model with western blot and membrane fractionation, inflammatory cytokine measurements","journal":"Journal of inherited metabolic disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function identification of specific zDHHCs palmitoylating APT1 combined with in vivo mouse model, single lab but two orthogonal approaches","pmids":["33739454"],"is_preprint":false},{"year":2019,"finding":"ZDHHC23 and ZDHHC18 competitively interact with the BMI1 E3 ligase RNF144A to regulate polyubiquitination and accumulation of BMI1, thereby influencing glioma stem cell plasticity.","method":"Co-immunoprecipitation, LC-MS/MS, western blot, colony formation and xenograft assays","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with MS validation, in vitro and in vivo assays, single lab","pmids":["30658672"],"is_preprint":false},{"year":2023,"finding":"ZDHHC23 mediates palmitoylation of PHF2; this palmitoylation enhances ubiquitin-dependent proteasomal degradation of PHF2, a tumor suppressor that functions as an E3 ubiquitin ligase for SREBP1c, thereby promoting SREBP1c-dependent lipogenesis in hepatocellular carcinoma cells.","method":"Acyl-biotin exchange, co-immunoprecipitation, ubiquitination assays, siRNA knockdown, HepG2/Hep3B cell models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical assays (ABE, Co-IP, ubiquitination assay) in two cell lines establishing a linear palmitoylation→ubiquitination→substrate degradation mechanism","pmids":["37828054"],"is_preprint":false},{"year":2024,"finding":"ZDHHC23 palmitoylates GFAP in spinal astrocytes; increased ZDHHC23 expression in a cancer pain model elevates GFAP palmitoylation and promotes secretion of inflammatory factors (CXCL10, IL-6, GM-CSF), which activate astrocytes via the STAT3 pathway. A competitive peptide blocking GFAP palmitoylation alleviates cancer pain and morphine tolerance in mice.","method":"Acyl-biotin exchange, ELISA, western blot, immunofluorescence, competitive palmitoylation peptide in vivo in C57BL/6 mice","journal":"Regional anesthesia and pain medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ABE palmitoylation assay plus competitive peptide rescue in a defined in vivo pain model, single lab","pmids":["38050183"],"is_preprint":false},{"year":2025,"finding":"ZDHHC23 mediates S-acylation of T-bet at a palmitoylation site; this S-acylation promotes T-bet protein degradation, thereby inhibiting Th1 cell differentiation. Methionine restriction increases T-bet palmitoylation and its degradation, reducing Th1 polarization and CD8+ T cell cytotoxicity in gastric cancer.","method":"Acyl-biotin exchange (ABE), cycloheximide chase (protein stability assay), 2-BP pharmacological inhibition, GPS-Palm computational screening for palmitoyltransferase, in vivo transplanted tumor model","journal":"Biotechnology journal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ABE and protein stability assay establish the modification and its functional consequence, but ZDHHC23 identification relied on computational prediction with pharmacological (not genetic) confirmation in vivo, single lab","pmids":["39989253"],"is_preprint":false},{"year":2026,"finding":"TDP43 undergoes S-acylation primarily at Cys244 catalyzed by zDHHC23; this S-acylation maintains the liquid-like properties of TDP43 condensates by reducing aberrant interaction with PARP1 and PARylated proteins, preventing pathological TDP43 condensation and neurotoxicity. TDP43 S-acylation is decreased in familial ALS-associated TDP43 mutants and in SOD1-G93A mice and C9orf72-ALS iPSC-derived neurons.","method":"Site-directed mutagenesis (Cys244), S-acylation assays, co-immunoprecipitation with PARP1, phase separation/condensate assays, ALS mouse model (SOD1-G93A), iPSC-derived neurons","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of catalytic site combined with biochemical reconstitution, protein-protein interaction assays, and multiple disease models (mouse + iPSC), single lab but highly orthogonal methods","pmids":["42127907"],"is_preprint":false},{"year":2026,"finding":"ZDHHC23-mediated palmitoylation of the nuclear protein NAT10 promotes its nuclear export and loading into hepatocyte-derived exosomes under lipotoxic/MASH conditions; exosomal NAT10 then drives fibrogenic signaling in hepatic stellate cells by stabilizing Ddr2 mRNA via ac4C RNA acetylation.","method":"Palmitoylation assays, proteomic analysis of exosomes, hepatocyte-specific Nat10 knockout, exosome transfer experiments, MASH murine models","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — palmitoylation assay combined with genetic deletion and exosome transfer functional studies, single lab but multiple orthogonal approaches","pmids":["42103688"],"is_preprint":false},{"year":2025,"finding":"Under hypoxic conditions, zDHHC23 shows dynamic interactome remodelling including attenuated association with the 26S proteasome and the TIM23 mitochondrial import complex, suggesting that zDHHC23 functions as a hypoxia-responsive regulator linked to protein degradation and mitochondrial import pathways in neuroblastoma.","method":"Quantitative proteomics/interactome profiling under varying oxygen conditions, in vivo chick embryo xenograft model","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-lab proteomic interactome screen; mechanistic follow-up not performed; preprint, no peer review","pmids":["bio_10.1101_2025.11.03.686197"],"is_preprint":true}],"current_model":"ZDHHC23 is a palmitoyl acyltransferase that S-acylates multiple substrates—including the BK channel α-subunit S0-S1 loop (controlling surface expression and β1-subunit coupling), APT1 (regulating H-Ras membrane localization), PHF2 (promoting its ubiquitin-dependent degradation to drive lipogenesis), GFAP (promoting astrocyte inflammatory signaling), T-bet (promoting its degradation to limit Th1 differentiation), TDP43 at Cys244 (maintaining its liquid-like condensate properties and preventing ALS-associated pathological aggregation), and NAT10 (driving nuclear export and exosomal secretion to promote liver fibrosis)—while also competing with ZDHHC18 for interaction with the RNF144A–BMI1 ubiquitination complex to regulate glioma stem cell plasticity."},"narrative":{"mechanistic_narrative":"ZDHHC23 is a palmitoyl acyltransferase (S-acyltransferase) that regulates the trafficking, stability, and signaling activity of diverse substrates by catalyzing their S-acylation [PMID:22399288, PMID:37828054]. At ion channels, it palmitoylates the intracellular S0-S1 loop of the BK channel α-subunit, an event required for efficient surface delivery from the trans-Golgi network [PMID:22399288] and, independently of surface expression, for functional coupling to regulatory β1-subunits in vascular smooth muscle, as shown by Zdhhc23 knockout [PMID:31213527]. A recurrent theme is that ZDHHC23-mediated acylation drives substrate turnover: palmitoylation of the tumor suppressor PHF2 enhances its ubiquitin-dependent proteasomal degradation to promote SREBP1c-dependent lipogenesis in hepatocellular carcinoma [PMID:37828054], and S-acylation of the transcription factor T-bet promotes its degradation to limit Th1 differentiation [PMID:39989253]. ZDHHC23 also acts on the RNA-binding protein TDP43 at Cys244, maintaining the liquid-like properties of TDP43 condensates by reducing aberrant interaction with PARP1 and preventing pathological aggregation, with this acylation decreased in ALS disease models [PMID:42127907]. Beyond direct acylation, it palmitoylates the thioesterase APT1 to control H-Ras membrane localization and microglial proliferative signaling [PMID:33739454], modifies GFAP to promote astrocyte inflammatory signaling in cancer pain [PMID:38050183], drives nuclear export and exosomal secretion of NAT10 to promote liver fibrosis [PMID:42103688], and competes with ZDHHC18 for the RNF144A–BMI1 ubiquitination complex to regulate glioma stem cell plasticity [PMID:30658672].","teleology":[{"year":2012,"claim":"Established ZDHHC23 as a palmitoyl acyltransferase acting on an ion channel, defining a trafficking role: it was unknown which zDHHC enzymes control BK channel surface delivery.","evidence":"Heterologous zDHHC overexpression/knockdown with surface biotinylation and palmitoylation assays","pmids":["22399288"],"confidence":"High","gaps":["Did not resolve catalytic site or stoichiometry on the α-subunit","Physiological relevance in native tissue not addressed"]},{"year":2019,"claim":"Distinguished a function for BK α-subunit acylation beyond trafficking—regulatory subunit coupling—answering whether acylation has an electrophysiological role independent of surface expression.","evidence":"Zdhhc23 knockout mice, patch clamp electrophysiology, acyl-RAC, and non-acylatable mutant reconstitution","pmids":["31213527"],"confidence":"High","gaps":["Mechanism by which acylation enables β1 coupling not defined","Restricted to vascular smooth muscle context"]},{"year":2019,"claim":"Revealed a non-catalytic, competitive role: ZDHHC23 and ZDHHC18 compete for an E3 ligase complex, showing the enzyme can regulate ubiquitination machinery by protein interaction.","evidence":"Reciprocal Co-IP with LC-MS/MS, colony formation and xenograft assays in glioma stem cells","pmids":["30658672"],"confidence":"Medium","gaps":["Whether acyltransferase activity is required for the RNF144A interaction unknown","Single lab; binding interface not mapped"]},{"year":2021,"claim":"Identified APT1 as a ZDHHC23 (and ZDHHC5) substrate, linking the enzyme to H-Ras membrane localization and microglial signaling in a disease model.","evidence":"zDHHC overexpression palmitoylation assays plus Cln1−/− mouse fractionation and cytokine measurement","pmids":["33739454"],"confidence":"Medium","gaps":["Relative contribution of ZDHHC23 vs ZDHHC5 not separated","Single lab"]},{"year":2023,"claim":"Defined a palmitoylation→ubiquitination→degradation axis on PHF2, showing ZDHHC23 acylation can target substrates for proteasomal turnover to reprogram lipogenesis.","evidence":"Acyl-biotin exchange, Co-IP, ubiquitination assays, and siRNA in HepG2/Hep3B cells","pmids":["37828054"],"confidence":"High","gaps":["Acylation site on PHF2 not pinpointed","In vivo tumor relevance not tested in this study"]},{"year":2024,"claim":"Extended the inflammatory role by showing ZDHHC23 palmitoylates GFAP to drive astrocyte cytokine secretion, and that blocking this acylation is therapeutically tractable.","evidence":"ABE, ELISA, immunofluorescence, and competitive palmitoylation peptide rescue in a mouse cancer pain model","pmids":["38050183"],"confidence":"Medium","gaps":["GFAP acylation site and direct enzyme-substrate kinetics not defined","Single lab"]},{"year":2025,"claim":"Generalized the acylation-driven degradation theme to T-bet, connecting ZDHHC23 to Th1 differentiation control and dietary methionine sensing.","evidence":"ABE, cycloheximide chase, 2-BP inhibition, GPS-Palm prediction, and in vivo gastric cancer tumor model","pmids":["39989253"],"confidence":"Medium","gaps":["ZDHHC23 assignment rests on computational prediction with pharmacological, not genetic, confirmation","T-bet acylation site not experimentally mapped"]},{"year":2026,"claim":"Provided a mechanistic basis for ZDHHC23 in proteostasis of a phase-separating protein: Cys244 S-acylation of TDP43 preserves condensate fluidity and suppresses ALS-linked aggregation.","evidence":"Cys244 site-directed mutagenesis, S-acylation assays, PARP1 Co-IP, condensate assays, SOD1-G93A mice, and ALS iPSC neurons","pmids":["42127907"],"confidence":"High","gaps":["Whether restoring TDP43 acylation is therapeutic in vivo untested","Single lab"]},{"year":2026,"claim":"Showed ZDHHC23 controls intercellular signaling by palmitoylating NAT10 to drive its nuclear export and exosomal secretion, promoting hepatic fibrosis.","evidence":"Palmitoylation assays, exosome proteomics, hepatocyte-specific Nat10 knockout, and exosome transfer in MASH mouse models","pmids":["42103688"],"confidence":"Medium","gaps":["NAT10 acylation site not defined","Genetic ZDHHC23 loss-of-function not tested in this system"]},{"year":2025,"claim":"Profiling implicated ZDHHC23 as a hypoxia-responsive node with altered ties to the proteasome and mitochondrial import machinery in neuroblastoma.","evidence":"Quantitative interactome profiling under varied oxygen and chick embryo xenograft (preprint)","pmids":["bio_10.1101_2025.11.03.686197"],"confidence":"Low","gaps":["Single-lab proteomic screen without mechanistic follow-up","Not peer-reviewed","Functional consequence of interactome remodelling unestablished"]},{"year":null,"claim":"The structural determinants and substrate-selection logic that allow one acyltransferase to act on channels, condensate proteins, transcription factors, and nuclear enzymes remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure or catalytic-mechanism study in the corpus","Acylation sites unmapped for most substrates","Determinants of substrate specificity unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,4,6,7,8]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,6,7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,6]}],"complexes":[],"partners":["RNF144A","APT1","PHF2","GFAP","TDP43","NAT10","ZDHHC18"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IYP9","full_name":"Palmitoyltransferase ZDHHC23","aliases":["Zinc finger DHHC domain-containing protein 23","DHHC-23","zDHHC23"],"length_aa":409,"mass_kda":46.0,"function":"Palmitoyltransferase that could catalyze the addition of palmitate onto various protein substrates and be involved in a variety of cellular processes (Probable). Palmitoyltransferase that mediates palmitoylation of KCNMA1, regulating localization of KCNMA1 to the plasma membrane. May be involved in NOS1 regulation and targeting to the synaptic membrane","subcellular_location":"Golgi apparatus membrane; Golgi apparatus, trans-Golgi network membrane","url":"https://www.uniprot.org/uniprotkb/Q8IYP9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZDHHC23","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZDHHC23","total_profiled":1310},"omim":[{"mim_id":"617334","title":"ZDHHC PALMITOYLTRANSFERASE 23; ZDHHC23","url":"https://www.omim.org/entry/617334"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":10.2}],"url":"https://www.proteinatlas.org/search/ZDHHC23"},"hgnc":{"alias_symbol":["MGC42530"],"prev_symbol":[]},"alphafold":{"accession":"Q8IYP9","domains":[{"cath_id":"-","chopping":"28-89","consensus_level":"high","plddt":73.3087,"start":28,"end":89},{"cath_id":"-","chopping":"92-140_154-169_318-379","consensus_level":"high","plddt":92.2553,"start":92,"end":379},{"cath_id":"-","chopping":"261-297","consensus_level":"medium","plddt":93.9243,"start":261,"end":297}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYP9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYP9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYP9-F1-predicted_aligned_error_v6.png","plddt_mean":78.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZDHHC23","jax_strain_url":"https://www.jax.org/strain/search?query=ZDHHC23"},"sequence":{"accession":"Q8IYP9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IYP9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IYP9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYP9"}},"corpus_meta":[{"pmid":"22399288","id":"PMC_22399288","title":"Distinct acyl protein transferases and thioesterases control surface expression of calcium-activated potassium channels.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22399288","citation_count":113,"is_preprint":false},{"pmid":"37828054","id":"PMC_37828054","title":"Palmitoylation-driven PHF2 ubiquitination remodels lipid metabolism through the SREBP1c axis in hepatocellular carcinoma.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37828054","citation_count":67,"is_preprint":false},{"pmid":"30658672","id":"PMC_30658672","title":"DHHC protein family targets different subsets of glioma stem cells in specific niches.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/30658672","citation_count":51,"is_preprint":false},{"pmid":"37978524","id":"PMC_37978524","title":"Palmitoylation landscapes across human cancers reveal a role of palmitoylation in tumorigenesis.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37978524","citation_count":34,"is_preprint":false},{"pmid":"35664705","id":"PMC_35664705","title":"Palmitoyl transferases act as potential regulators of tumor-infiltrating immune cells and glioma progression.","date":"2022","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/35664705","citation_count":28,"is_preprint":false},{"pmid":"33739454","id":"PMC_33739454","title":"In a mouse model of INCL reduced S-palmitoylation of cytosolic thioesterase APT1 contributes to microglia proliferation and neuroinflammation.","date":"2021","source":"Journal of inherited metabolic disease","url":"https://pubmed.ncbi.nlm.nih.gov/33739454","citation_count":24,"is_preprint":false},{"pmid":"31213527","id":"PMC_31213527","title":"S-Acylation controls functional coupling of BK channel pore-forming α-subunits and β1-subunits.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31213527","citation_count":11,"is_preprint":false},{"pmid":"38050183","id":"PMC_38050183","title":"GFAP palmitoylcation mediated by ZDHHC23 in spinal astrocytes contributes to the development of neuropathic pain.","date":"2024","source":"Regional anesthesia and pain medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38050183","citation_count":10,"is_preprint":false},{"pmid":"36456979","id":"PMC_36456979","title":"Identification of the miRNA-mRNA regulatory network associated with radiosensitivity in esophageal cancer based on integrative analysis of the TCGA and GEO data.","date":"2022","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/36456979","citation_count":9,"is_preprint":false},{"pmid":"27536776","id":"PMC_27536776","title":"Gene Signature of High White Blood Cell Count in B-Precursor Acute Lymphoblastic Leukemia.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27536776","citation_count":7,"is_preprint":false},{"pmid":"38868779","id":"PMC_38868779","title":"The anti-inflammatory role of zDHHC23 through the promotion of macrophage M2 polarization and macrophage necroptosis in large yellow croaker (Larimichthys crocea).","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38868779","citation_count":6,"is_preprint":false},{"pmid":"23675470","id":"PMC_23675470","title":"Fine-mapping and genetic analysis of the loci affecting hepatic iron overload in mice.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23675470","citation_count":5,"is_preprint":false},{"pmid":"39989253","id":"PMC_39989253","title":"Methionine Restriction Exerts Anti-Tumor Immunity via Joint Intervention of T-Bet Palmitoylation in Gastric Cancer.","date":"2025","source":"Biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/39989253","citation_count":4,"is_preprint":false},{"pmid":"24375959","id":"PMC_24375959","title":"Microduplication 3q13.2q13.31 identified in a male with dysmorphic features and multiple congenital anomalies.","date":"2013","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/24375959","citation_count":4,"is_preprint":false},{"pmid":"41364644","id":"PMC_41364644","title":"S-palmitoylation-related genes in Crohn's disease: Bioinformatic identification and validation.","date":"2025","source":"Biomolecules & biomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/41364644","citation_count":0,"is_preprint":false},{"pmid":"42127907","id":"PMC_42127907","title":"S-acylation of TDP43 regulates its condensation in amyotrophic lateral sclerosis.","date":"2026","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/42127907","citation_count":0,"is_preprint":false},{"pmid":"42103688","id":"PMC_42103688","title":"Palmitoylation-mediated exosomal trafficking of nuclear protein NAT10 potentiates liver fibrosis in MASH.","date":"2026","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/42103688","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.03.686197","title":"Hypoxia-induced regulation of zDHHC23 opens avenues for new biomarkers for NON MYCN-amplified neuroblastoma","date":"2025-11-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.03.686197","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12146,"output_tokens":2813,"usd":0.039316,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10125,"output_tokens":3417,"usd":0.068025,"stage2_stop_reason":"end_turn"},"total_usd":0.107341,"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\": 2012,\n      \"finding\": \"ZDHHC23 (together with zDHHC22) palmitoylates the intracellular S0-S1 loop of BK channel α-subunits, and this palmitoylation is essential for efficient cell surface expression of BK channels; depalmitoylated channels are retarded in the trans-Golgi network.\",\n      \"method\": \"Overexpression/knockdown of individual zDHHC enzymes in heterologous cells, surface biotinylation assays, palmitoylation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function with defined trafficking phenotype, replicated with multiple zDHHC members and corroborated by downstream thioesterase experiments\",\n      \"pmids\": [\"22399288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"S-acylation of the BK channel α-subunit S0-S1 loop by ZDHHC23 controls functional coupling to regulatory β1-subunits: in vascular smooth muscle cells expressing both subunits, genetic deletion of Zdhhc23 significantly reduces S-acylation and attenuates endogenous BK channel currents independently of changes in α-subunit surface expression.\",\n      \"method\": \"Genetic knockout of Zdhhc23 in mice, electrophysiology (patch clamp), acyl-RAC/surface biotinylation, HEK293 cell reconstitution with non-acylatable mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vivo knockout mouse model combined with electrophysiology and biochemical acylation assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"31213527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZDHHC5 and ZDHHC23 catalyze S-palmitoylation of the cytosolic thioesterase APT1; reduced ZDHHC5/ZDHHC23 levels in the brain of Cln1−/− (INCL model) mice suppress membrane-bound APT1, increasing plasma membrane-localized H-Ras and stimulating its proliferative signaling pathway in microglia.\",\n      \"method\": \"Overexpression of individual zDHHC enzymes, palmitoylation assays, Cln1−/− mouse model with western blot and membrane fractionation, inflammatory cytokine measurements\",\n      \"journal\": \"Journal of inherited metabolic disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function identification of specific zDHHCs palmitoylating APT1 combined with in vivo mouse model, single lab but two orthogonal approaches\",\n      \"pmids\": [\"33739454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZDHHC23 and ZDHHC18 competitively interact with the BMI1 E3 ligase RNF144A to regulate polyubiquitination and accumulation of BMI1, thereby influencing glioma stem cell plasticity.\",\n      \"method\": \"Co-immunoprecipitation, LC-MS/MS, western blot, colony formation and xenograft assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with MS validation, in vitro and in vivo assays, single lab\",\n      \"pmids\": [\"30658672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZDHHC23 mediates palmitoylation of PHF2; this palmitoylation enhances ubiquitin-dependent proteasomal degradation of PHF2, a tumor suppressor that functions as an E3 ubiquitin ligase for SREBP1c, thereby promoting SREBP1c-dependent lipogenesis in hepatocellular carcinoma cells.\",\n      \"method\": \"Acyl-biotin exchange, co-immunoprecipitation, ubiquitination assays, siRNA knockdown, HepG2/Hep3B cell models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical assays (ABE, Co-IP, ubiquitination assay) in two cell lines establishing a linear palmitoylation→ubiquitination→substrate degradation mechanism\",\n      \"pmids\": [\"37828054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZDHHC23 palmitoylates GFAP in spinal astrocytes; increased ZDHHC23 expression in a cancer pain model elevates GFAP palmitoylation and promotes secretion of inflammatory factors (CXCL10, IL-6, GM-CSF), which activate astrocytes via the STAT3 pathway. A competitive peptide blocking GFAP palmitoylation alleviates cancer pain and morphine tolerance in mice.\",\n      \"method\": \"Acyl-biotin exchange, ELISA, western blot, immunofluorescence, competitive palmitoylation peptide in vivo in C57BL/6 mice\",\n      \"journal\": \"Regional anesthesia and pain medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ABE palmitoylation assay plus competitive peptide rescue in a defined in vivo pain model, single lab\",\n      \"pmids\": [\"38050183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZDHHC23 mediates S-acylation of T-bet at a palmitoylation site; this S-acylation promotes T-bet protein degradation, thereby inhibiting Th1 cell differentiation. Methionine restriction increases T-bet palmitoylation and its degradation, reducing Th1 polarization and CD8+ T cell cytotoxicity in gastric cancer.\",\n      \"method\": \"Acyl-biotin exchange (ABE), cycloheximide chase (protein stability assay), 2-BP pharmacological inhibition, GPS-Palm computational screening for palmitoyltransferase, in vivo transplanted tumor model\",\n      \"journal\": \"Biotechnology journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ABE and protein stability assay establish the modification and its functional consequence, but ZDHHC23 identification relied on computational prediction with pharmacological (not genetic) confirmation in vivo, single lab\",\n      \"pmids\": [\"39989253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TDP43 undergoes S-acylation primarily at Cys244 catalyzed by zDHHC23; this S-acylation maintains the liquid-like properties of TDP43 condensates by reducing aberrant interaction with PARP1 and PARylated proteins, preventing pathological TDP43 condensation and neurotoxicity. TDP43 S-acylation is decreased in familial ALS-associated TDP43 mutants and in SOD1-G93A mice and C9orf72-ALS iPSC-derived neurons.\",\n      \"method\": \"Site-directed mutagenesis (Cys244), S-acylation assays, co-immunoprecipitation with PARP1, phase separation/condensate assays, ALS mouse model (SOD1-G93A), iPSC-derived neurons\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of catalytic site combined with biochemical reconstitution, protein-protein interaction assays, and multiple disease models (mouse + iPSC), single lab but highly orthogonal methods\",\n      \"pmids\": [\"42127907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZDHHC23-mediated palmitoylation of the nuclear protein NAT10 promotes its nuclear export and loading into hepatocyte-derived exosomes under lipotoxic/MASH conditions; exosomal NAT10 then drives fibrogenic signaling in hepatic stellate cells by stabilizing Ddr2 mRNA via ac4C RNA acetylation.\",\n      \"method\": \"Palmitoylation assays, proteomic analysis of exosomes, hepatocyte-specific Nat10 knockout, exosome transfer experiments, MASH murine models\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — palmitoylation assay combined with genetic deletion and exosome transfer functional studies, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"42103688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Under hypoxic conditions, zDHHC23 shows dynamic interactome remodelling including attenuated association with the 26S proteasome and the TIM23 mitochondrial import complex, suggesting that zDHHC23 functions as a hypoxia-responsive regulator linked to protein degradation and mitochondrial import pathways in neuroblastoma.\",\n      \"method\": \"Quantitative proteomics/interactome profiling under varying oxygen conditions, in vivo chick embryo xenograft model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-lab proteomic interactome screen; mechanistic follow-up not performed; preprint, no peer review\",\n      \"pmids\": [\"bio_10.1101_2025.11.03.686197\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ZDHHC23 is a palmitoyl acyltransferase that S-acylates multiple substrates—including the BK channel α-subunit S0-S1 loop (controlling surface expression and β1-subunit coupling), APT1 (regulating H-Ras membrane localization), PHF2 (promoting its ubiquitin-dependent degradation to drive lipogenesis), GFAP (promoting astrocyte inflammatory signaling), T-bet (promoting its degradation to limit Th1 differentiation), TDP43 at Cys244 (maintaining its liquid-like condensate properties and preventing ALS-associated pathological aggregation), and NAT10 (driving nuclear export and exosomal secretion to promote liver fibrosis)—while also competing with ZDHHC18 for interaction with the RNF144A–BMI1 ubiquitination complex to regulate glioma stem cell plasticity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZDHHC23 is a palmitoyl acyltransferase (S-acyltransferase) that regulates the trafficking, stability, and signaling activity of diverse substrates by catalyzing their S-acylation [#0, #4]. At ion channels, it palmitoylates the intracellular S0-S1 loop of the BK channel \\u03b1-subunit, an event required for efficient surface delivery from the trans-Golgi network [#0] and, independently of surface expression, for functional coupling to regulatory \\u03b21-subunits in vascular smooth muscle, as shown by Zdhhc23 knockout [#1]. A recurrent theme is that ZDHHC23-mediated acylation drives substrate turnover: palmitoylation of the tumor suppressor PHF2 enhances its ubiquitin-dependent proteasomal degradation to promote SREBP1c-dependent lipogenesis in hepatocellular carcinoma [#4], and S-acylation of the transcription factor T-bet promotes its degradation to limit Th1 differentiation [#6]. ZDHHC23 also acts on the RNA-binding protein TDP43 at Cys244, maintaining the liquid-like properties of TDP43 condensates by reducing aberrant interaction with PARP1 and preventing pathological aggregation, with this acylation decreased in ALS disease models [#7]. Beyond direct acylation, it palmitoylates the thioesterase APT1 to control H-Ras membrane localization and microglial proliferative signaling [#2], modifies GFAP to promote astrocyte inflammatory signaling in cancer pain [#5], drives nuclear export and exosomal secretion of NAT10 to promote liver fibrosis [#8], and competes with ZDHHC18 for the RNF144A\\u2013BMI1 ubiquitination complex to regulate glioma stem cell plasticity [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established ZDHHC23 as a palmitoyl acyltransferase acting on an ion channel, defining a trafficking role: it was unknown which zDHHC enzymes control BK channel surface delivery.\",\n      \"evidence\": \"Heterologous zDHHC overexpression/knockdown with surface biotinylation and palmitoylation assays\",\n      \"pmids\": [\"22399288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve catalytic site or stoichiometry on the \\u03b1-subunit\", \"Physiological relevance in native tissue not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Distinguished a function for BK \\u03b1-subunit acylation beyond trafficking\\u2014regulatory subunit coupling\\u2014answering whether acylation has an electrophysiological role independent of surface expression.\",\n      \"evidence\": \"Zdhhc23 knockout mice, patch clamp electrophysiology, acyl-RAC, and non-acylatable mutant reconstitution\",\n      \"pmids\": [\"31213527\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which acylation enables \\u03b21 coupling not defined\", \"Restricted to vascular smooth muscle context\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a non-catalytic, competitive role: ZDHHC23 and ZDHHC18 compete for an E3 ligase complex, showing the enzyme can regulate ubiquitination machinery by protein interaction.\",\n      \"evidence\": \"Reciprocal Co-IP with LC-MS/MS, colony formation and xenograft assays in glioma stem cells\",\n      \"pmids\": [\"30658672\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether acyltransferase activity is required for the RNF144A interaction unknown\", \"Single lab; binding interface not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified APT1 as a ZDHHC23 (and ZDHHC5) substrate, linking the enzyme to H-Ras membrane localization and microglial signaling in a disease model.\",\n      \"evidence\": \"zDHHC overexpression palmitoylation assays plus Cln1\\u2212/\\u2212 mouse fractionation and cytokine measurement\",\n      \"pmids\": [\"33739454\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of ZDHHC23 vs ZDHHC5 not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a palmitoylation\\u2192ubiquitination\\u2192degradation axis on PHF2, showing ZDHHC23 acylation can target substrates for proteasomal turnover to reprogram lipogenesis.\",\n      \"evidence\": \"Acyl-biotin exchange, Co-IP, ubiquitination assays, and siRNA in HepG2/Hep3B cells\",\n      \"pmids\": [\"37828054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acylation site on PHF2 not pinpointed\", \"In vivo tumor relevance not tested in this study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the inflammatory role by showing ZDHHC23 palmitoylates GFAP to drive astrocyte cytokine secretion, and that blocking this acylation is therapeutically tractable.\",\n      \"evidence\": \"ABE, ELISA, immunofluorescence, and competitive palmitoylation peptide rescue in a mouse cancer pain model\",\n      \"pmids\": [\"38050183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GFAP acylation site and direct enzyme-substrate kinetics not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Generalized the acylation-driven degradation theme to T-bet, connecting ZDHHC23 to Th1 differentiation control and dietary methionine sensing.\",\n      \"evidence\": \"ABE, cycloheximide chase, 2-BP inhibition, GPS-Palm prediction, and in vivo gastric cancer tumor model\",\n      \"pmids\": [\"39989253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ZDHHC23 assignment rests on computational prediction with pharmacological, not genetic, confirmation\", \"T-bet acylation site not experimentally mapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided a mechanistic basis for ZDHHC23 in proteostasis of a phase-separating protein: Cys244 S-acylation of TDP43 preserves condensate fluidity and suppresses ALS-linked aggregation.\",\n      \"evidence\": \"Cys244 site-directed mutagenesis, S-acylation assays, PARP1 Co-IP, condensate assays, SOD1-G93A mice, and ALS iPSC neurons\",\n      \"pmids\": [\"42127907\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether restoring TDP43 acylation is therapeutic in vivo untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed ZDHHC23 controls intercellular signaling by palmitoylating NAT10 to drive its nuclear export and exosomal secretion, promoting hepatic fibrosis.\",\n      \"evidence\": \"Palmitoylation assays, exosome proteomics, hepatocyte-specific Nat10 knockout, and exosome transfer in MASH mouse models\",\n      \"pmids\": [\"42103688\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NAT10 acylation site not defined\", \"Genetic ZDHHC23 loss-of-function not tested in this system\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Profiling implicated ZDHHC23 as a hypoxia-responsive node with altered ties to the proteasome and mitochondrial import machinery in neuroblastoma.\",\n      \"evidence\": \"Quantitative interactome profiling under varied oxygen and chick embryo xenograft (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.11.03.686197\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-lab proteomic screen without mechanistic follow-up\", \"Not peer-reviewed\", \"Functional consequence of interactome remodelling unestablished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural determinants and substrate-selection logic that allow one acyltransferase to act on channels, condensate proteins, transcription factors, and nuclear enzymes remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure or catalytic-mechanism study in the corpus\", \"Acylation sites unmapped for most substrates\", \"Determinants of substrate specificity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 4, 6, 7, 8]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 6, 7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RNF144A\", \"APT1\", \"PHF2\", \"GFAP\", \"TDP43\", \"NAT10\", \"ZDHHC18\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}