{"gene":"ZDHHC9","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2005,"finding":"ZDHHC9 (DHHC9) forms a protein complex with GCP16 and together they function as a human protein palmitoyltransferase with specificity for H-Ras and N-Ras, but not myristoylated Gαi1 or GAP-43. DHHC9 is an integral membrane protein with a DHHC cysteine-rich domain; GCP16 is required for DHHC9 enzymatic activity and protein stability. The complex co-distributes in the Golgi apparatus.","method":"Co-immunoprecipitation, purified DHHC9·GCP16 in vitro palmitoylation assay, subcellular fractionation/co-distribution studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro palmitoylation activity with purified complex, substrate specificity demonstrated, replicated in subsequent studies","pmids":["16000296"],"is_preprint":false},{"year":2007,"finding":"Loss-of-function mutations in ZDHHC9 (frameshift, splice-site, and missense) cause X-linked intellectual disability associated with Marfanoid habitus, establishing ZDHHC9 as the first palmitoyltransferase whose disruption causes intellectual disability. The mechanism involves altered palmitoylation of NRAS and HRAS, affecting their subcellular localization.","method":"DNA sequencing of 250 XLID families identifying four independent mutations in ZDHHC9; functional interpretation based on known palmitoyltransferase activity","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in multiple families with defined cellular mechanism inferred from known enzymatic activity; no direct cellular rescue experiment in this paper","pmids":["17436253"],"is_preprint":false},{"year":2014,"finding":"Two XLID-associated missense variants of ZDHHC9, R148W and P150S, reduce the steady-state level of the palmitoyl-ZDHHC9 intermediate, demonstrating that these mutations impair the autopalmitoylation step (step 1) of the two-step palmitoyltransferase reaction mechanism.","method":"In vitro autopalmitoylation assay with purified mutant ZDHHC9 proteins; biochemical characterization of enzyme-palmitoyl intermediate","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic assay with defined mutants establishing mechanism of catalytic step impairment, single lab but rigorous biochemistry","pmids":["24811172"],"is_preprint":false},{"year":2013,"finding":"miR-134 directly interacts with DHHC9 mRNA in somatostatin interneurons. Activity-dependent stimulation (bicuculline treatment) decreases DHHC9 expression in a miR-134-dependent manner, reducing membrane localization of H-Ras, establishing a miR-134 → DHHC9 → H-Ras membrane targeting axis.","method":"miRNA-mRNA complex trapping assay (CLASH), ratiometric miRNA sensor, DHHC9 expression measurement after bicuculline treatment, H-Ras membrane localization reporter assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct miRNA-mRNA interaction demonstrated by trapping assay, functional consequence on H-Ras localization measured, single lab","pmids":["24127608"],"is_preprint":false},{"year":2019,"finding":"Loss of Zdhhc9 in hippocampal neurons causes shorter dendritic arbors (via impaired Ras palmitoylation) and fewer inhibitory synapses (via impaired TC10 palmitoylation), altering the excitatory-to-inhibitory balance. Zdhhc9 knockout mice exhibit seizure-like activity and altered synaptic currents.","method":"Hippocampal neuron cultures from Zdhhc9 KO mice; dendritic morphology quantification; inhibitory synapse immunostaining; electrophysiology (mEPSC/mIPSC recording); palmitoylation assay for Ras and TC10 substrates","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple orthogonal phenotypic readouts, substrate-specific palmitoylation linkage demonstrated, in vivo and in vitro convergence","pmids":["31747610"],"is_preprint":false},{"year":2021,"finding":"ZDHHC9 palmitoylates GLUT1 at Cys207, and this S-palmitoylation is required to maintain GLUT1 plasma membrane localization. Knockout of ZDHHC9 or C207S mutation abrogates palmitoylation, causes GLUT1 mislocalization, impairs glycolysis, cell proliferation, and glioblastoma tumorigenesis in vivo.","method":"Acyl-biotin exchange (ABE) assay, ZDHHC9 knockout, site-directed mutagenesis (C207S), immunofluorescence for GLUT1 localization, glycolysis assay, xenograft tumor model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including mutagenesis, ABE assay, KO, localization imaging, and in vivo functional validation","pmids":["34620861"],"is_preprint":false},{"year":2023,"finding":"GCP16 stabilizes DHHC9 by preventing its aggregation through protein complex formation. Only properly folded DHHC9-GCP16 complex is enzymatically active in vitro. The C-terminal cysteine motif (CCM) conserved in the DHHC9 subfamily is required for DHHC9-GCP16 complex formation and activity. XLID mutations in ZDHHC9 reduce protein stability and complex formation with GCP16.","method":"Size-exclusion chromatography, in vitro palmitoyl acyltransferase assay, mutagenesis of CCM, co-expression stability assays","journal":"Frontiers in physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with biochemical fractionation and activity assay, mutagenesis of CCM, single lab but multiple orthogonal methods","pmids":["37035671"],"is_preprint":false},{"year":2023,"finding":"ZDHHC9 palmitoylates β-catenin, promoting its ubiquitination and degradation, thereby suppressing Wnt/β-catenin signaling. Acyl protein thioesterase 1 (APT1) depalmitoylates β-catenin and opposes this effect. DHHC9 ablation in tubular cells aggravates renal fibrosis, while DHHC9 overexpression is protective.","method":"Co-immunoprecipitation, ABE palmitoylation assay, ubiquitination assay, genetic knockout and overexpression in mouse UUO and IRI fibrosis models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, palmitoylation biochemistry, genetic KO/OE with defined phenotype, in vivo mouse models, multiple orthogonal approaches","pmids":["37865665"],"is_preprint":false},{"year":2023,"finding":"ZDHHC9 palmitoylates Rab3gap1, which causes Rab3gap1 spatial segregation from Rab3a, elevates Rab3a-GTP levels, promotes formation of Rab3a-positive peripheral vesicles, and impairs exocytosis, thereby limiting atrial natriuretic peptide (ANP) release from cardiomyocytes.","method":"Palmitoylation assay, co-immunoprecipitation, subcellular localization imaging, Rab3a-GTP pull-down, ANP secretion assay in cardiomyocytes","journal":"JACC. Basic to translational science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined substrate (Rab3gap1), mechanistic pathway to exocytosis established, single lab with multiple methods","pmids":["37325411"],"is_preprint":false},{"year":2024,"finding":"ZDHHC9 binds to and palmitoylates Bip/GRP78 at Cys420, enhancing Bip protein stability and preserving its ER localization, thereby inhibiting the unfolded protein response (UPR). SP1 transcriptionally activates ZDHHC9 expression.","method":"Co-immunoprecipitation, ABE palmitoylation assay, site-directed mutagenesis (C420), subcellular localization imaging (ER marker), UPR reporter assays, ZDHHC9 knockdown","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, palmitoylation biochemistry with specific cysteine identified by mutagenesis, localization shown, single lab","pmids":["39002690"],"is_preprint":false},{"year":2025,"finding":"ZDHHC9 localizes to Golgi outposts in oligodendrocyte (OL) processes and is the most highly expressed PAT in myelinating OLs. Zdhhc9 KO mice display myelin morphological and structural abnormalities and impaired MBP palmitoylation. ZDHHC9 palmitoylates Myelin Basic Protein (MBP) in heterologous cells, and MBP palmitoylation is reduced in Zdhhc9 KO brain.","method":"Cell-type-specific expression analysis, live imaging/immunofluorescence for Golgi outpost localization, OL fate tracing, sparse cell labeling morphology, MBP palmitoylation assay in heterologous cells and KO brain","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct palmitoylation of MBP shown in heterologous cells and confirmed in KO brain, subcellular localization tied to function, single lab","pmids":["41031565"],"is_preprint":false},{"year":2025,"finding":"ZDHHC9 palmitoylates STRN4 (a STRIPAK complex component) at Cys701. This palmitoylation reduces YAP phosphorylation, promotes YAP nuclear translocation, and activates Hippo pathway transcriptional targets (CCN1, CCN2, ANKRD1), driving cancer cell migration.","method":"Proteomic analysis, co-immunoprecipitation, site-directed mutagenesis (C701), YAP phosphorylation and nuclear localization assays, ZDHHC9 knockdown migration assays in vitro and in vivo metastasis assay","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identified by proteomics, palmitoylation site validated by mutagenesis, downstream signaling mechanistically defined, single lab","pmids":["40903842"],"is_preprint":false},{"year":2025,"finding":"ZDHHC9 palmitoylates LAMTOR1 at Cys3/4 residues, enhancing mTORC1 recruitment to the lysosomal surface and activating mTOR signaling in renal cell carcinoma.","method":"Co-immunoprecipitation, ABE palmitoylation assay, site-directed mutagenesis (Cys3/4), mTORC1 lysosomal recruitment assay, ZDHHC9 knockdown with mTOR signaling readouts","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific cysteine sites identified by mutagenesis, palmitoylation biochemistry, mechanistic link to mTORC1 localization, single lab","pmids":["41856969"],"is_preprint":false},{"year":2025,"finding":"ZDHHC9 palmitoylates hnRNPU at Cys497 and Cys607, increasing its protein stability. This stabilization promotes SAT1 transcription, enhancing spermine catabolism, and contributes to prostate cancer proliferation.","method":"Mass spectrometry, co-immunoprecipitation, site-directed mutagenesis (Cys497/607), palmitoylation assay, RNA sequencing, xenograft model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific cysteine sites identified by mutagenesis, palmitoylation confirmed, downstream SAT1-spermine axis defined, single lab","pmids":["41419885"],"is_preprint":false},{"year":2025,"finding":"ZDHHC9 palmitoylates ACSL4 at Cys595, enhancing ACSL4 enzymatic activity, promoting lipid peroxidation, and driving ferroptosis in corpus cavernosum fibroblasts. PI3K/AKT signaling is identified as an upstream regulator of ZDHHC9 expression in this context.","method":"ABE palmitoylation assay, site-directed mutagenesis (C595), ACSL4 enzymatic activity assay, lipid peroxidation measurement, ZDHHC9 knockdown with siRNA-LNPs in vivo mouse model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific cysteine identified by mutagenesis, enzymatic activity of substrate measured, in vivo validation, single lab","pmids":["42085610"],"is_preprint":false},{"year":2026,"finding":"ZDHHC9 palmitoylates PCBP1 at Cys109, inhibiting PCBP1 ubiquitination and thereby stabilizing it. Stabilized PCBP1 promotes SLC7A11 RNA stability, suppressing ferroptosis and promoting gastric cancer liver metastasis.","method":"Co-immunoprecipitation, LC-MS, ABE palmitoylation assay, site-directed mutagenesis (C109), ubiquitination assay, RNA stability assay, in vivo metastasis model","journal":"NPJ precision oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identified by IP/MS, palmitoylation site confirmed by mutagenesis, ubiquitination mechanistic link established, single lab","pmids":["41535416"],"is_preprint":false},{"year":2026,"finding":"ZDHHC9 palmitoylates KLF5 at Cys438, enhancing ADCY4 activity and elevating intracellular cAMP levels, thereby activating the cAMP/PKA/CREB signaling pathway to promote colorectal cancer cell proliferation and migration.","method":"ABE palmitoylation assay, site-directed mutagenesis (C438), RNA sequencing, ADCY4 activity assay, cAMP measurement, ZDHHC9 knockdown in vitro and in vivo","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific palmitoylation site validated by mutagenesis, downstream cAMP signaling mechanistically linked, single lab","pmids":["41882103"],"is_preprint":false},{"year":2026,"finding":"ZDHHC9 palmitoylates STAT1 at Cys577, and this palmitoylation competes with/converts to Tyr701 phosphorylation via the JAK1-STAT1 pathway, modulating STAT1 nuclear activity and downstream gene transcription to promote gastric cancer progression.","method":"ABE palmitoylation assay, co-immunoprecipitation, site-directed mutagenesis (Cys577), immunofluorescence, confocal imaging, Western blot for JAK1-STAT1 phosphorylation, ZDHHC9 knockdown","journal":"Journal of gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific cysteine identified by mutagenesis, palmitoylation-phosphorylation interplay mechanistically defined, multiple methods, single lab","pmids":["41711908"],"is_preprint":false},{"year":2025,"finding":"ZDHHC9 interacts with KRAS by co-immunoprecipitation and promotes osteosarcoma progression by palmitoylating KRAS to activate the RAS/MAPK signaling pathway (Raf1, ERK1/2 activation).","method":"Co-immunoprecipitation, molecular docking, proteomic sequencing, Western blot for MAPK pathway, xenograft model, KRAS overexpression rescue experiment","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms interaction, proteomic and rescue experiments support KRAS-MAPK mechanism, single lab","pmids":["41087383"],"is_preprint":false},{"year":2025,"finding":"ZDHHC9 palmitoylates CD36 (binding confirmed by Co-IP), which promotes CD36 plasma membrane localization and formation of the CD36/Fyn/Lyn complex. This activates the JNK1 pathway and inhibits ERK1/2, impairing mammary epithelial cell proliferation under high-fat conditions.","method":"Co-immunoprecipitation, ABE palmitoylation assay, site-directed mutagenesis of CD36 cysteines, immunofluorescence for CD36 localization, DHHC9 knockdown, in vivo mouse HFD model","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, palmitoylation assay, mutagenesis, localization imaging, in vivo validation, single lab","pmids":["41087856"],"is_preprint":false},{"year":2023,"finding":"ZDHHC9 knockdown reduces PD-L1 palmitoylation and promotes PD-L1 protein degradation in lung adenocarcinoma cells, establishing ZDHHC9 as the palmitoyl transferase that stabilizes PD-L1 through palmitoylation.","method":"ZDHHC9 knockdown/overexpression, palmitoylation assay, PD-L1 protein stability measurement, proliferation and migration assays","journal":"In vitro cellular & developmental biology. Animal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, palmitoylation assay without specific cysteine identification or reconstitution, limited mechanistic follow-up","pmids":["37002491"],"is_preprint":false},{"year":2025,"finding":"ZDHHC9 palmitoylates CD38 at Cys16, which is required to maintain CD38 protein expression in tumor cells. APT1 acts as the opposing depalmitoylase. A competitive peptide blocking CD38 palmitoylation decreases CD38 expression and suppresses tumor progression in vivo.","method":"ABE palmitoylation assay, site-directed mutagenesis (Cys16), APT1 depalmitoylation assay, competitive peptide in vivo tumor model","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific cysteine validated by mutagenesis, writer (DHHC9) and eraser (APT1) both defined, in vivo validation, single lab","pmids":["40121269"],"is_preprint":false},{"year":2025,"finding":"ZDHHC9 palmitoylates PKG1 in osteoblasts, and this palmitoylation alters the distance between the ER and mitochondria and changes MAMs-related protein expression, contributing to osteoblast dysfunction in T2DM.","method":"Co-immunoprecipitation, fluorescence co-localization, Zdhhc9 knockdown and Prkg1 silencing in MC3T3-E1 cells and T2DM mouse model, MAMs distance measurement","journal":"Journal of dental research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP interaction confirmed, but palmitoylation site on PKG1 not directly validated by mutagenesis; single lab, limited mechanistic depth in abstract","pmids":["40102769"],"is_preprint":false}],"current_model":"ZDHHC9 is an integral membrane palmitoyltransferase that forms an obligate complex with GCP16 (which stabilizes ZDHHC9 and is required for its activity via a conserved C-terminal cysteine motif), localizes primarily to the Golgi apparatus, and catalyzes S-palmitoylation of a broad range of substrates including H-Ras, N-Ras, GLUT1, β-catenin, TC10, Rab3gap1, MBP, STRN4, LAMTOR1, ACSL4, PCBP1, KLF5, STAT1, CD38, hnRNPU, CD36, and PKG1, with palmitoylation occurring via a two-step mechanism involving an autopalmitoyl-enzyme intermediate; loss-of-function mutations impair this autopalmitoylation step and cause X-linked intellectual disability with epilepsy, at least in part through disrupted Ras and TC10 palmitoylation in neurons and impaired MBP palmitoylation/myelination in oligodendrocytes."},"narrative":{"mechanistic_narrative":"ZDHHC9 is an integral-membrane DHHC-family protein S-palmitoyltransferase that catalyzes lipid modification of substrate cysteines through a two-step mechanism requiring formation of an autopalmitoyl-enzyme intermediate, and it acts in obligate partnership with GCP16 [PMID:16000296, PMID:24811172]. GCP16 stabilizes ZDHHC9 by preventing its aggregation, and only the properly folded ZDHHC9–GCP16 complex is enzymatically active; complex formation depends on a conserved C-terminal cysteine motif, and the complex localizes to the Golgi apparatus [PMID:16000296, PMID:37035671]. The enzyme palmitoylates a broad substrate repertoire to control substrate membrane targeting, stability, or activity: it palmitoylates H-Ras and N-Ras to direct their membrane localization [PMID:16000296, PMID:24127608], GLUT1 (Cys207) to maintain its plasma-membrane localization and support glycolysis [PMID:34620861], LAMTOR1 (Cys3/4) to promote mTORC1 recruitment to the lysosome [PMID:41856969], and numerous other targets including β-catenin, STRN4, ACSL4, PCBP1, KLF5, STAT1, CD38, hnRNPU, and CD36, frequently regulating their stability or downstream signaling output across cancer and fibrosis contexts [PMID:37865665, PMID:40903842, PMID:42085610, PMID:40121269]. In the nervous system, ZDHHC9 is required for palmitoylation of Ras and TC10, shaping dendritic arborization, inhibitory synapse number, and excitatory/inhibitory balance [PMID:31747610], and it is the dominant palmitoyltransferase in myelinating oligodendrocytes where it palmitoylates Myelin Basic Protein to support normal myelin structure [PMID:41031565]. Loss-of-function mutations in ZDHHC9 impair the autopalmitoylation step and ZDHHC9–GCP16 complex formation and cause X-linked intellectual disability with Marfanoid habitus [PMID:17436253, PMID:24811172, PMID:37035671].","teleology":[{"year":2005,"claim":"Establishing that ZDHHC9 is a bona fide palmitoyltransferase answered whether it had intrinsic enzymatic activity and revealed that this activity requires a partner subunit.","evidence":"Co-IP and in vitro palmitoylation with purified DHHC9·GCP16 complex showing H-Ras/N-Ras specificity and Golgi co-distribution","pmids":["16000296"],"confidence":"High","gaps":["Substrate range beyond Ras isoforms not defined","Structural basis of GCP16 dependence not resolved","Catalytic mechanism not yet dissected"]},{"year":2007,"claim":"Identifying loss-of-function ZDHHC9 mutations in XLID families connected a palmitoyltransferase deficiency to a human neurodevelopmental disease for the first time.","evidence":"DNA sequencing of 250 XLID families identifying four independent mutations; mechanism inferred from Ras palmitoylation","pmids":["17436253"],"confidence":"Medium","gaps":["No direct cellular rescue in this study","Neuronal substrate consequences not measured directly","Marfanoid habitus mechanism unexplained"]},{"year":2013,"claim":"Demonstrating miR-134 control of DHHC9 mRNA defined how ZDHHC9 expression is dynamically tuned to neuronal activity to set H-Ras membrane targeting.","evidence":"CLASH miRNA-mRNA trapping, miRNA sensor, and H-Ras membrane localization reporter after bicuculline stimulation in somatostatin interneurons","pmids":["24127608"],"confidence":"Medium","gaps":["Single lab","In vivo relevance of the miR-134 axis not established","Effect on other substrates not tested"]},{"year":2014,"claim":"Showing that XLID variants R148W and P150S reduce the palmitoyl-enzyme intermediate located the disease defect at the autopalmitoylation step of the two-step catalytic cycle.","evidence":"In vitro autopalmitoylation assays with purified mutant ZDHHC9","pmids":["24811172"],"confidence":"High","gaps":["Does not show downstream substrate consequences in neurons","Other XLID mutations not all tested","Step-two transfer kinetics not quantified"]},{"year":2019,"claim":"Linking Zdhhc9 loss to dendritic and inhibitory-synapse phenotypes through specific substrates explained the neuronal basis of the XLID/epilepsy phenotype.","evidence":"Zdhhc9 KO mouse hippocampal neurons with morphology, electrophysiology, and Ras/TC10 palmitoylation assays","pmids":["31747610"],"confidence":"High","gaps":["Circuit-level mechanism of seizures incomplete","Relative contribution of Ras vs TC10 not quantified","Human variant correspondence not modeled"]},{"year":2023,"claim":"Defining GCP16 as an anti-aggregation chaperone and identifying the C-terminal cysteine motif clarified why ZDHHC9 needs a partner and why XLID mutations destabilize it.","evidence":"Size-exclusion chromatography, in vitro PAT assay, and CCM mutagenesis of the reconstituted complex","pmids":["37035671"],"confidence":"High","gaps":["High-resolution structure of the complex not determined","Mechanism by which CCM mediates assembly not resolved","Single lab"]},{"year":2023,"claim":"A series of substrate-mapping studies expanded ZDHHC9 from a Ras enzyme to a broad regulator of substrate stability, localization, and signaling across diverse tissues.","evidence":"ABE/Co-IP palmitoylation assays with site mutagenesis defining β-catenin, GLUT1 (Cys207), Rab3gap1, and Bip/GRP78 (Cys420) substrates in fibrosis, glioblastoma, cardiomyocyte, and ER-stress models","pmids":["37865665","34620861","37325411","39002690"],"confidence":"High","gaps":["Substrate selectivity determinants not defined","How one enzyme accesses such varied substrates unclear","Tissue-specific cofactors not identified"]},{"year":2025,"claim":"Identifying ZDHHC9 as the dominant oligodendrocyte palmitoyltransferase that modifies MBP added a myelination arm to the XLID mechanism.","evidence":"Cell-type expression analysis, Golgi-outpost imaging, OL fate tracing, and MBP palmitoylation assays in heterologous cells and Zdhhc9 KO brain","pmids":["41031565"],"confidence":"Medium","gaps":["MBP palmitoylation site not pinpointed","Functional myelin consequence at behavioral level not connected","Single lab"]},{"year":2026,"claim":"An accumulating set of cancer studies showed ZDHHC9 palmitoylation rewires multiple signaling and metabolic pathways via stabilization or relocalization of effectors.","evidence":"ABE/Co-IP with cysteine-specific mutagenesis defining STRN4 (Cys701)–YAP, LAMTOR1–mTORC1, ACSL4 (Cys595)–ferroptosis, PCBP1 (Cys109)–SLC7A11, KLF5 (Cys438)–cAMP, STAT1 (Cys577), CD38 (Cys16), hnRNPU, CD36, and KRAS, with in vivo tumor models","pmids":["40903842","41856969","42085610","41535416","41882103","41711908","40121269","41419885","41087856","41087383"],"confidence":"Medium","gaps":["Most defined in single labs without reconstitution","Physiological vs pathological substrate prioritization unclear","Reversal by depalmitoylases mapped only for some substrates (APT1)"]},{"year":null,"claim":"How ZDHHC9 achieves such broad substrate recognition, and which substrates dominate in each physiological versus disease context, remains the central open question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of substrate-bound ZDHHC9–GCP16","No defined substrate-selectivity code","Quantitative substrate hierarchy across tissues unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,5,6,7,11,12]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,6]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,10]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,5,7,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,7,11,12,16,17,18]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[4,10]}],"complexes":["ZDHHC9-GCP16 palmitoyltransferase complex"],"partners":["GOLGA7","HRAS","NRAS","GLUT1","CTNNB1","STRN4","LAMTOR1","KRAS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y397","full_name":"Palmitoyltransferase ZDHHC9","aliases":["Zinc finger DHHC domain-containing protein 9","DHHC-9","DHHC9","Zinc finger protein 379","Zinc finger protein 380"],"length_aa":364,"mass_kda":40.9,"function":"Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates, such as ADRB2, GSDMD, HRAS, NRAS and CGAS (PubMed:16000296, PubMed:27481942, PubMed:37802025, PubMed:38530158, PubMed:38599239). The ZDHHC9-GOLGA7 complex is a palmitoyltransferase specific for HRAS and NRAS (PubMed:16000296). May have a palmitoyltransferase activity toward the beta-2 adrenergic receptor/ADRB2 and therefore regulate G protein-coupled receptor signaling (PubMed:27481942). Acts as a regulator of innate immunity by catalyzing palmitoylation of CGAS, thereby promoting CGAS homodimerization and cyclic GMP-AMP synthase activity (PubMed:37802025). Activates pyroptosis by catalyzing palmitoylation of gasdermin-D (GSDMD), thereby promoting membrane translocation and pore formation of GSDMD (PubMed:38530158, PubMed:38599239) (Microbial infection) Through a sequential action with ZDHHC20, rapidly and efficiently palmitoylates SARS coronavirus-2/SARS-CoV-2 spike protein following its synthesis in the endoplasmic reticulum (ER). In the infected cell, promotes spike biogenesis by protecting it from premature ER degradation, increases half-life and controls the lipid organization of its immediate membrane environment. Once the virus has formed, spike palmitoylation controls fusion with the target cell","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y397/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZDHHC9","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/ZDHHC9","total_profiled":1310},"omim":[{"mim_id":"617042","title":"GASDERMIN D; GSDMD","url":"https://www.omim.org/entry/617042"},{"mim_id":"609453","title":"GOLGIN A7; GOLGA7","url":"https://www.omim.org/entry/609453"},{"mim_id":"300799","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, RAYMOND TYPE; MRXSR","url":"https://www.omim.org/entry/300799"},{"mim_id":"300646","title":"ZDHHC PALMITOYLTRANSFERASE 9; ZDHHC9","url":"https://www.omim.org/entry/300646"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZDHHC9"},"hgnc":{"alias_symbol":["ZNF379","CGI-89","ZNF380","DHHC9"],"prev_symbol":["ZDHHC10","CXorf11"]},"alphafold":{"accession":"Q9Y397","domains":[{"cath_id":"-","chopping":"99-148","consensus_level":"high","plddt":85.1132,"start":99,"end":148},{"cath_id":"1.20.140","chopping":"12-94_164-287","consensus_level":"high","plddt":95.4369,"start":12,"end":287}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y397","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y397-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y397-F1-predicted_aligned_error_v6.png","plddt_mean":84.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZDHHC9","jax_strain_url":"https://www.jax.org/strain/search?query=ZDHHC9"},"sequence":{"accession":"Q9Y397","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y397.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y397/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y397"}},"corpus_meta":[{"pmid":"16000296","id":"PMC_16000296","title":"DHHC9 and GCP16 constitute a human protein fatty acyltransferase with specificity for H- and N-Ras.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16000296","citation_count":290,"is_preprint":false},{"pmid":"34620861","id":"PMC_34620861","title":"DHHC9-mediated GLUT1 S-palmitoylation promotes glioblastoma glycolysis and tumorigenesis.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34620861","citation_count":211,"is_preprint":false},{"pmid":"17436253","id":"PMC_17436253","title":"Mutations in ZDHHC9, which encodes a palmitoyltransferase of NRAS and HRAS, cause X-linked mental retardation associated with a Marfanoid habitus.","date":"2007","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17436253","citation_count":140,"is_preprint":false},{"pmid":"17519897","id":"PMC_17519897","title":"Differential expression of DHHC9 in microsatellite stable and instable human 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distinct mechanisms.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24811172","citation_count":47,"is_preprint":false},{"pmid":"31747610","id":"PMC_31747610","title":"The X-Linked Intellectual Disability Gene Zdhhc9 Is Essential for Dendrite Outgrowth and Inhibitory Synapse Formation.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31747610","citation_count":44,"is_preprint":false},{"pmid":"24127608","id":"PMC_24127608","title":"MicroRNA-134 activity in somatostatin interneurons regulates H-Ras localization by repressing the palmitoylation enzyme, DHHC9.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24127608","citation_count":41,"is_preprint":false},{"pmid":"39002690","id":"PMC_39002690","title":"ZDHHC9-mediated Bip/GRP78 S-palmitoylation inhibits unfolded protein response and promotes bladder cancer 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/24357419","citation_count":28,"is_preprint":false},{"pmid":"37002491","id":"PMC_37002491","title":"Involvement of ZDHHC9 in lung adenocarcinoma: regulation of PD-L1 stability via palmitoylation.","date":"2023","source":"In vitro cellular & developmental biology. Animal","url":"https://pubmed.ncbi.nlm.nih.gov/37002491","citation_count":25,"is_preprint":false},{"pmid":"37325411","id":"PMC_37325411","title":"zDHHC9 Regulates Cardiomyocyte Rab3a Activity and Atrial Natriuretic Peptide Secretion Through Palmitoylation of Rab3gap1.","date":"2023","source":"JACC. 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/29681091","citation_count":9,"is_preprint":false},{"pmid":"37875591","id":"PMC_37875591","title":"ZDHHC9: a promising therapeutic target for triple-negative breast cancer through immune modulation and immune checkpoint blockade resistance.","date":"2023","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37875591","citation_count":9,"is_preprint":false},{"pmid":"36416207","id":"PMC_36416207","title":"ZDHHC9 X-linked intellectual disability: Clinical and molecular characterization.","date":"2022","source":"American journal of medical genetics. 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DHHC9 is an integral membrane protein with a DHHC cysteine-rich domain; GCP16 is required for DHHC9 enzymatic activity and protein stability. The complex co-distributes in the Golgi apparatus.\",\n      \"method\": \"Co-immunoprecipitation, purified DHHC9·GCP16 in vitro palmitoylation assay, subcellular fractionation/co-distribution studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro palmitoylation activity with purified complex, substrate specificity demonstrated, replicated in subsequent studies\",\n      \"pmids\": [\"16000296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Loss-of-function mutations in ZDHHC9 (frameshift, splice-site, and missense) cause X-linked intellectual disability associated with Marfanoid habitus, establishing ZDHHC9 as the first palmitoyltransferase whose disruption causes intellectual disability. The mechanism involves altered palmitoylation of NRAS and HRAS, affecting their subcellular localization.\",\n      \"method\": \"DNA sequencing of 250 XLID families identifying four independent mutations in ZDHHC9; functional interpretation based on known palmitoyltransferase activity\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in multiple families with defined cellular mechanism inferred from known enzymatic activity; no direct cellular rescue experiment in this paper\",\n      \"pmids\": [\"17436253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Two XLID-associated missense variants of ZDHHC9, R148W and P150S, reduce the steady-state level of the palmitoyl-ZDHHC9 intermediate, demonstrating that these mutations impair the autopalmitoylation step (step 1) of the two-step palmitoyltransferase reaction mechanism.\",\n      \"method\": \"In vitro autopalmitoylation assay with purified mutant ZDHHC9 proteins; biochemical characterization of enzyme-palmitoyl intermediate\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic assay with defined mutants establishing mechanism of catalytic step impairment, single lab but rigorous biochemistry\",\n      \"pmids\": [\"24811172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-134 directly interacts with DHHC9 mRNA in somatostatin interneurons. Activity-dependent stimulation (bicuculline treatment) decreases DHHC9 expression in a miR-134-dependent manner, reducing membrane localization of H-Ras, establishing a miR-134 → DHHC9 → H-Ras membrane targeting axis.\",\n      \"method\": \"miRNA-mRNA complex trapping assay (CLASH), ratiometric miRNA sensor, DHHC9 expression measurement after bicuculline treatment, H-Ras membrane localization reporter assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct miRNA-mRNA interaction demonstrated by trapping assay, functional consequence on H-Ras localization measured, single lab\",\n      \"pmids\": [\"24127608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of Zdhhc9 in hippocampal neurons causes shorter dendritic arbors (via impaired Ras palmitoylation) and fewer inhibitory synapses (via impaired TC10 palmitoylation), altering the excitatory-to-inhibitory balance. Zdhhc9 knockout mice exhibit seizure-like activity and altered synaptic currents.\",\n      \"method\": \"Hippocampal neuron cultures from Zdhhc9 KO mice; dendritic morphology quantification; inhibitory synapse immunostaining; electrophysiology (mEPSC/mIPSC recording); palmitoylation assay for Ras and TC10 substrates\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple orthogonal phenotypic readouts, substrate-specific palmitoylation linkage demonstrated, in vivo and in vitro convergence\",\n      \"pmids\": [\"31747610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZDHHC9 palmitoylates GLUT1 at Cys207, and this S-palmitoylation is required to maintain GLUT1 plasma membrane localization. Knockout of ZDHHC9 or C207S mutation abrogates palmitoylation, causes GLUT1 mislocalization, impairs glycolysis, cell proliferation, and glioblastoma tumorigenesis in vivo.\",\n      \"method\": \"Acyl-biotin exchange (ABE) assay, ZDHHC9 knockout, site-directed mutagenesis (C207S), immunofluorescence for GLUT1 localization, glycolysis assay, xenograft tumor model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including mutagenesis, ABE assay, KO, localization imaging, and in vivo functional validation\",\n      \"pmids\": [\"34620861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GCP16 stabilizes DHHC9 by preventing its aggregation through protein complex formation. Only properly folded DHHC9-GCP16 complex is enzymatically active in vitro. The C-terminal cysteine motif (CCM) conserved in the DHHC9 subfamily is required for DHHC9-GCP16 complex formation and activity. XLID mutations in ZDHHC9 reduce protein stability and complex formation with GCP16.\",\n      \"method\": \"Size-exclusion chromatography, in vitro palmitoyl acyltransferase assay, mutagenesis of CCM, co-expression stability assays\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with biochemical fractionation and activity assay, mutagenesis of CCM, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"37035671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZDHHC9 palmitoylates β-catenin, promoting its ubiquitination and degradation, thereby suppressing Wnt/β-catenin signaling. Acyl protein thioesterase 1 (APT1) depalmitoylates β-catenin and opposes this effect. DHHC9 ablation in tubular cells aggravates renal fibrosis, while DHHC9 overexpression is protective.\",\n      \"method\": \"Co-immunoprecipitation, ABE palmitoylation assay, ubiquitination assay, genetic knockout and overexpression in mouse UUO and IRI fibrosis models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, palmitoylation biochemistry, genetic KO/OE with defined phenotype, in vivo mouse models, multiple orthogonal approaches\",\n      \"pmids\": [\"37865665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZDHHC9 palmitoylates Rab3gap1, which causes Rab3gap1 spatial segregation from Rab3a, elevates Rab3a-GTP levels, promotes formation of Rab3a-positive peripheral vesicles, and impairs exocytosis, thereby limiting atrial natriuretic peptide (ANP) release from cardiomyocytes.\",\n      \"method\": \"Palmitoylation assay, co-immunoprecipitation, subcellular localization imaging, Rab3a-GTP pull-down, ANP secretion assay in cardiomyocytes\",\n      \"journal\": \"JACC. Basic to translational science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined substrate (Rab3gap1), mechanistic pathway to exocytosis established, single lab with multiple methods\",\n      \"pmids\": [\"37325411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZDHHC9 binds to and palmitoylates Bip/GRP78 at Cys420, enhancing Bip protein stability and preserving its ER localization, thereby inhibiting the unfolded protein response (UPR). SP1 transcriptionally activates ZDHHC9 expression.\",\n      \"method\": \"Co-immunoprecipitation, ABE palmitoylation assay, site-directed mutagenesis (C420), subcellular localization imaging (ER marker), UPR reporter assays, ZDHHC9 knockdown\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, palmitoylation biochemistry with specific cysteine identified by mutagenesis, localization shown, single lab\",\n      \"pmids\": [\"39002690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZDHHC9 localizes to Golgi outposts in oligodendrocyte (OL) processes and is the most highly expressed PAT in myelinating OLs. Zdhhc9 KO mice display myelin morphological and structural abnormalities and impaired MBP palmitoylation. ZDHHC9 palmitoylates Myelin Basic Protein (MBP) in heterologous cells, and MBP palmitoylation is reduced in Zdhhc9 KO brain.\",\n      \"method\": \"Cell-type-specific expression analysis, live imaging/immunofluorescence for Golgi outpost localization, OL fate tracing, sparse cell labeling morphology, MBP palmitoylation assay in heterologous cells and KO brain\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct palmitoylation of MBP shown in heterologous cells and confirmed in KO brain, subcellular localization tied to function, single lab\",\n      \"pmids\": [\"41031565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZDHHC9 palmitoylates STRN4 (a STRIPAK complex component) at Cys701. This palmitoylation reduces YAP phosphorylation, promotes YAP nuclear translocation, and activates Hippo pathway transcriptional targets (CCN1, CCN2, ANKRD1), driving cancer cell migration.\",\n      \"method\": \"Proteomic analysis, co-immunoprecipitation, site-directed mutagenesis (C701), YAP phosphorylation and nuclear localization assays, ZDHHC9 knockdown migration assays in vitro and in vivo metastasis assay\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identified by proteomics, palmitoylation site validated by mutagenesis, downstream signaling mechanistically defined, single lab\",\n      \"pmids\": [\"40903842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZDHHC9 palmitoylates LAMTOR1 at Cys3/4 residues, enhancing mTORC1 recruitment to the lysosomal surface and activating mTOR signaling in renal cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, ABE palmitoylation assay, site-directed mutagenesis (Cys3/4), mTORC1 lysosomal recruitment assay, ZDHHC9 knockdown with mTOR signaling readouts\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific cysteine sites identified by mutagenesis, palmitoylation biochemistry, mechanistic link to mTORC1 localization, single lab\",\n      \"pmids\": [\"41856969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZDHHC9 palmitoylates hnRNPU at Cys497 and Cys607, increasing its protein stability. This stabilization promotes SAT1 transcription, enhancing spermine catabolism, and contributes to prostate cancer proliferation.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, site-directed mutagenesis (Cys497/607), palmitoylation assay, RNA sequencing, xenograft model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific cysteine sites identified by mutagenesis, palmitoylation confirmed, downstream SAT1-spermine axis defined, single lab\",\n      \"pmids\": [\"41419885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZDHHC9 palmitoylates ACSL4 at Cys595, enhancing ACSL4 enzymatic activity, promoting lipid peroxidation, and driving ferroptosis in corpus cavernosum fibroblasts. PI3K/AKT signaling is identified as an upstream regulator of ZDHHC9 expression in this context.\",\n      \"method\": \"ABE palmitoylation assay, site-directed mutagenesis (C595), ACSL4 enzymatic activity assay, lipid peroxidation measurement, ZDHHC9 knockdown with siRNA-LNPs in vivo mouse model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific cysteine identified by mutagenesis, enzymatic activity of substrate measured, in vivo validation, single lab\",\n      \"pmids\": [\"42085610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZDHHC9 palmitoylates PCBP1 at Cys109, inhibiting PCBP1 ubiquitination and thereby stabilizing it. Stabilized PCBP1 promotes SLC7A11 RNA stability, suppressing ferroptosis and promoting gastric cancer liver metastasis.\",\n      \"method\": \"Co-immunoprecipitation, LC-MS, ABE palmitoylation assay, site-directed mutagenesis (C109), ubiquitination assay, RNA stability assay, in vivo metastasis model\",\n      \"journal\": \"NPJ precision oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identified by IP/MS, palmitoylation site confirmed by mutagenesis, ubiquitination mechanistic link established, single lab\",\n      \"pmids\": [\"41535416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZDHHC9 palmitoylates KLF5 at Cys438, enhancing ADCY4 activity and elevating intracellular cAMP levels, thereby activating the cAMP/PKA/CREB signaling pathway to promote colorectal cancer cell proliferation and migration.\",\n      \"method\": \"ABE palmitoylation assay, site-directed mutagenesis (C438), RNA sequencing, ADCY4 activity assay, cAMP measurement, ZDHHC9 knockdown in vitro and in vivo\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific palmitoylation site validated by mutagenesis, downstream cAMP signaling mechanistically linked, single lab\",\n      \"pmids\": [\"41882103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZDHHC9 palmitoylates STAT1 at Cys577, and this palmitoylation competes with/converts to Tyr701 phosphorylation via the JAK1-STAT1 pathway, modulating STAT1 nuclear activity and downstream gene transcription to promote gastric cancer progression.\",\n      \"method\": \"ABE palmitoylation assay, co-immunoprecipitation, site-directed mutagenesis (Cys577), immunofluorescence, confocal imaging, Western blot for JAK1-STAT1 phosphorylation, ZDHHC9 knockdown\",\n      \"journal\": \"Journal of gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific cysteine identified by mutagenesis, palmitoylation-phosphorylation interplay mechanistically defined, multiple methods, single lab\",\n      \"pmids\": [\"41711908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZDHHC9 interacts with KRAS by co-immunoprecipitation and promotes osteosarcoma progression by palmitoylating KRAS to activate the RAS/MAPK signaling pathway (Raf1, ERK1/2 activation).\",\n      \"method\": \"Co-immunoprecipitation, molecular docking, proteomic sequencing, Western blot for MAPK pathway, xenograft model, KRAS overexpression rescue experiment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms interaction, proteomic and rescue experiments support KRAS-MAPK mechanism, single lab\",\n      \"pmids\": [\"41087383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZDHHC9 palmitoylates CD36 (binding confirmed by Co-IP), which promotes CD36 plasma membrane localization and formation of the CD36/Fyn/Lyn complex. This activates the JNK1 pathway and inhibits ERK1/2, impairing mammary epithelial cell proliferation under high-fat conditions.\",\n      \"method\": \"Co-immunoprecipitation, ABE palmitoylation assay, site-directed mutagenesis of CD36 cysteines, immunofluorescence for CD36 localization, DHHC9 knockdown, in vivo mouse HFD model\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, palmitoylation assay, mutagenesis, localization imaging, in vivo validation, single lab\",\n      \"pmids\": [\"41087856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZDHHC9 knockdown reduces PD-L1 palmitoylation and promotes PD-L1 protein degradation in lung adenocarcinoma cells, establishing ZDHHC9 as the palmitoyl transferase that stabilizes PD-L1 through palmitoylation.\",\n      \"method\": \"ZDHHC9 knockdown/overexpression, palmitoylation assay, PD-L1 protein stability measurement, proliferation and migration assays\",\n      \"journal\": \"In vitro cellular & developmental biology. Animal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, palmitoylation assay without specific cysteine identification or reconstitution, limited mechanistic follow-up\",\n      \"pmids\": [\"37002491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZDHHC9 palmitoylates CD38 at Cys16, which is required to maintain CD38 protein expression in tumor cells. APT1 acts as the opposing depalmitoylase. A competitive peptide blocking CD38 palmitoylation decreases CD38 expression and suppresses tumor progression in vivo.\",\n      \"method\": \"ABE palmitoylation assay, site-directed mutagenesis (Cys16), APT1 depalmitoylation assay, competitive peptide in vivo tumor model\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific cysteine validated by mutagenesis, writer (DHHC9) and eraser (APT1) both defined, in vivo validation, single lab\",\n      \"pmids\": [\"40121269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZDHHC9 palmitoylates PKG1 in osteoblasts, and this palmitoylation alters the distance between the ER and mitochondria and changes MAMs-related protein expression, contributing to osteoblast dysfunction in T2DM.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence co-localization, Zdhhc9 knockdown and Prkg1 silencing in MC3T3-E1 cells and T2DM mouse model, MAMs distance measurement\",\n      \"journal\": \"Journal of dental research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP interaction confirmed, but palmitoylation site on PKG1 not directly validated by mutagenesis; single lab, limited mechanistic depth in abstract\",\n      \"pmids\": [\"40102769\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZDHHC9 is an integral membrane palmitoyltransferase that forms an obligate complex with GCP16 (which stabilizes ZDHHC9 and is required for its activity via a conserved C-terminal cysteine motif), localizes primarily to the Golgi apparatus, and catalyzes S-palmitoylation of a broad range of substrates including H-Ras, N-Ras, GLUT1, β-catenin, TC10, Rab3gap1, MBP, STRN4, LAMTOR1, ACSL4, PCBP1, KLF5, STAT1, CD38, hnRNPU, CD36, and PKG1, with palmitoylation occurring via a two-step mechanism involving an autopalmitoyl-enzyme intermediate; loss-of-function mutations impair this autopalmitoylation step and cause X-linked intellectual disability with epilepsy, at least in part through disrupted Ras and TC10 palmitoylation in neurons and impaired MBP palmitoylation/myelination in oligodendrocytes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZDHHC9 is an integral-membrane DHHC-family protein S-palmitoyltransferase that catalyzes lipid modification of substrate cysteines through a two-step mechanism requiring formation of an autopalmitoyl-enzyme intermediate, and it acts in obligate partnership with GCP16 [#0, #2]. GCP16 stabilizes ZDHHC9 by preventing its aggregation, and only the properly folded ZDHHC9–GCP16 complex is enzymatically active; complex formation depends on a conserved C-terminal cysteine motif, and the complex localizes to the Golgi apparatus [#0, #6]. The enzyme palmitoylates a broad substrate repertoire to control substrate membrane targeting, stability, or activity: it palmitoylates H-Ras and N-Ras to direct their membrane localization [#0, #3], GLUT1 (Cys207) to maintain its plasma-membrane localization and support glycolysis [#5], LAMTOR1 (Cys3/4) to promote mTORC1 recruitment to the lysosome [#12], and numerous other targets including \\u03b2-catenin, STRN4, ACSL4, PCBP1, KLF5, STAT1, CD38, hnRNPU, and CD36, frequently regulating their stability or downstream signaling output across cancer and fibrosis contexts [#7, #11, #14, #21]. In the nervous system, ZDHHC9 is required for palmitoylation of Ras and TC10, shaping dendritic arborization, inhibitory synapse number, and excitatory/inhibitory balance [#4], and it is the dominant palmitoyltransferase in myelinating oligodendrocytes where it palmitoylates Myelin Basic Protein to support normal myelin structure [#10]. Loss-of-function mutations in ZDHHC9 impair the autopalmitoylation step and ZDHHC9\\u2013GCP16 complex formation and cause X-linked intellectual disability with Marfanoid habitus [#1, #2, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that ZDHHC9 is a bona fide palmitoyltransferase answered whether it had intrinsic enzymatic activity and revealed that this activity requires a partner subunit.\",\n      \"evidence\": \"Co-IP and in vitro palmitoylation with purified DHHC9\\u00b7GCP16 complex showing H-Ras/N-Ras specificity and Golgi co-distribution\",\n      \"pmids\": [\"16000296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate range beyond Ras isoforms not defined\", \"Structural basis of GCP16 dependence not resolved\", \"Catalytic mechanism not yet dissected\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying loss-of-function ZDHHC9 mutations in XLID families connected a palmitoyltransferase deficiency to a human neurodevelopmental disease for the first time.\",\n      \"evidence\": \"DNA sequencing of 250 XLID families identifying four independent mutations; mechanism inferred from Ras palmitoylation\",\n      \"pmids\": [\"17436253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct cellular rescue in this study\", \"Neuronal substrate consequences not measured directly\", \"Marfanoid habitus mechanism unexplained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating miR-134 control of DHHC9 mRNA defined how ZDHHC9 expression is dynamically tuned to neuronal activity to set H-Ras membrane targeting.\",\n      \"evidence\": \"CLASH miRNA-mRNA trapping, miRNA sensor, and H-Ras membrane localization reporter after bicuculline stimulation in somatostatin interneurons\",\n      \"pmids\": [\"24127608\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"In vivo relevance of the miR-134 axis not established\", \"Effect on other substrates not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing that XLID variants R148W and P150S reduce the palmitoyl-enzyme intermediate located the disease defect at the autopalmitoylation step of the two-step catalytic cycle.\",\n      \"evidence\": \"In vitro autopalmitoylation assays with purified mutant ZDHHC9\",\n      \"pmids\": [\"24811172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not show downstream substrate consequences in neurons\", \"Other XLID mutations not all tested\", \"Step-two transfer kinetics not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linking Zdhhc9 loss to dendritic and inhibitory-synapse phenotypes through specific substrates explained the neuronal basis of the XLID/epilepsy phenotype.\",\n      \"evidence\": \"Zdhhc9 KO mouse hippocampal neurons with morphology, electrophysiology, and Ras/TC10 palmitoylation assays\",\n      \"pmids\": [\"31747610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Circuit-level mechanism of seizures incomplete\", \"Relative contribution of Ras vs TC10 not quantified\", \"Human variant correspondence not modeled\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defining GCP16 as an anti-aggregation chaperone and identifying the C-terminal cysteine motif clarified why ZDHHC9 needs a partner and why XLID mutations destabilize it.\",\n      \"evidence\": \"Size-exclusion chromatography, in vitro PAT assay, and CCM mutagenesis of the reconstituted complex\",\n      \"pmids\": [\"37035671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the complex not determined\", \"Mechanism by which CCM mediates assembly not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A series of substrate-mapping studies expanded ZDHHC9 from a Ras enzyme to a broad regulator of substrate stability, localization, and signaling across diverse tissues.\",\n      \"evidence\": \"ABE/Co-IP palmitoylation assays with site mutagenesis defining \\u03b2-catenin, GLUT1 (Cys207), Rab3gap1, and Bip/GRP78 (Cys420) substrates in fibrosis, glioblastoma, cardiomyocyte, and ER-stress models\",\n      \"pmids\": [\"37865665\", \"34620861\", \"37325411\", \"39002690\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate selectivity determinants not defined\", \"How one enzyme accesses such varied substrates unclear\", \"Tissue-specific cofactors not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying ZDHHC9 as the dominant oligodendrocyte palmitoyltransferase that modifies MBP added a myelination arm to the XLID mechanism.\",\n      \"evidence\": \"Cell-type expression analysis, Golgi-outpost imaging, OL fate tracing, and MBP palmitoylation assays in heterologous cells and Zdhhc9 KO brain\",\n      \"pmids\": [\"41031565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MBP palmitoylation site not pinpointed\", \"Functional myelin consequence at behavioral level not connected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"An accumulating set of cancer studies showed ZDHHC9 palmitoylation rewires multiple signaling and metabolic pathways via stabilization or relocalization of effectors.\",\n      \"evidence\": \"ABE/Co-IP with cysteine-specific mutagenesis defining STRN4 (Cys701)\\u2013YAP, LAMTOR1\\u2013mTORC1, ACSL4 (Cys595)\\u2013ferroptosis, PCBP1 (Cys109)\\u2013SLC7A11, KLF5 (Cys438)\\u2013cAMP, STAT1 (Cys577), CD38 (Cys16), hnRNPU, CD36, and KRAS, with in vivo tumor models\",\n      \"pmids\": [\"40903842\", \"41856969\", \"42085610\", \"41535416\", \"41882103\", \"41711908\", \"40121269\", \"41419885\", \"41087856\", \"41087383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Most defined in single labs without reconstitution\", \"Physiological vs pathological substrate prioritization unclear\", \"Reversal by depalmitoylases mapped only for some substrates (APT1)\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ZDHHC9 achieves such broad substrate recognition, and which substrates dominate in each physiological versus disease context, remains the central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of substrate-bound ZDHHC9\\u2013GCP16\", \"No defined substrate-selectivity code\", \"Quantitative substrate hierarchy across tissues unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 5, 6, 7, 11, 12]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 5, 7, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 7, 11, 12, 16, 17, 18]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"complexes\": [\"ZDHHC9-GCP16 palmitoyltransferase complex\"],\n    \"partners\": [\"GOLGA7\", \"HRAS\", \"NRAS\", \"GLUT1\", \"CTNNB1\", \"STRN4\", \"LAMTOR1\", \"KRAS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}