{"gene":"ZDHHC17","run_date":"2026-04-28T23:00:24","timeline":{"discoveries":[{"year":2004,"finding":"HIP14 (ZDHHC17) functions as a palmitoyl transferase (PAT) with substrate specificity for neuronal proteins including SNAP-25, PSD-95, GAD65, synaptotagmin I, and huntingtin, but not paralemmin or synaptotagmin VII; exogenous HIP14 enhances palmitoylation-dependent vesicular trafficking of acylated proteins, and interference with endogenous HIP14 reduces clustering of PSD-95 and GAD65 in neurons.","method":"Biochemical palmitoylation assays, heterologous cell expression, siRNA knockdown in neurons with fluorescence clustering readout","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro PAT assay with substrate specificity panel, loss-of-function with defined cellular phenotype; foundational study replicated by multiple subsequent labs","pmids":["15603740"],"is_preprint":false},{"year":2002,"finding":"HIP14 localizes to the Golgi and cytoplasmic vesicles, and its expression rescues the temperature-sensitive lethality and endocytosis defect of akr1Δ yeast cells, demonstrating a role for HIP14 in intracellular trafficking.","method":"Yeast two-hybrid, subcellular fractionation/immunofluorescence, genetic complementation in akr1Δ yeast","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic complementation assay with functional readout (endocytosis rescue), localization experiment; replicated in context of subsequent studies","pmids":["12393793"],"is_preprint":false},{"year":2006,"finding":"Huntingtin (HTT) is palmitoylated at cysteine 214 by HIP14; polyglutamine expansion reduces HTT-HIP14 interaction and HTT palmitoylation, leading to increased inclusion formation and neuronal toxicity; HIP14 downregulation increases inclusions while overexpression reduces them.","method":"Acyl-RAC palmitoylation assay, site-directed mutagenesis (C214 palmitoylation site), HTT-HIP14 co-immunoprecipitation, siRNA knockdown and overexpression in neurons with inclusion formation readout","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of palmitoylation site, biochemical assay, multiple orthogonal readouts; replicated across labs","pmids":["16699508"],"is_preprint":false},{"year":2008,"finding":"HIP14 mediates electrogenic, voltage-dependent, saturable Mg2+ transport when expressed in Xenopus oocytes; palmitoylation inhibition with 2-bromopalmitate or DHHC-domain deletion reduces HIP14-mediated Mg2+ transport by ~50%, suggesting autopalmitoylation regulates Mg2+ transport activity.","method":"Xenopus oocyte expression, electrophysiology, pharmacological inhibition (2-bromopalmitate), DHHC-deletion mutant, co-expression with independent PAT (GODZ)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 — functional reconstitution in oocytes with mutagenesis and pharmacology; single lab study","pmids":["18794299"],"is_preprint":false},{"year":2011,"finding":"Wild-type HTT modulates HIP14's palmitoylation and enzymatic activity: HTT is auto-palmitoylated by HIP14, and in the presence of wild-type HTT, HIP14 palmitoylation of SNAP25 is potentiated in vitro; this modulatory effect is lost with CAG-expanded mutant HTT.","method":"In vitro palmitoylation assay with recombinant proteins, HTT antisense oligo knockdown in cortical neurons, brain lysates from hdh+/- mice, western blot of palmitoylation","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution plus in vivo genetic validation in two mouse models; multiple orthogonal methods","pmids":["21636527"],"is_preprint":false},{"year":2011,"finding":"Loss of Hip14/ZDHHC17 in knockout mice reduces palmitoylation of multiple HIP14 substrates (but not HTT itself) and produces behavioral, biochemical, and neuropathological deficits reminiscent of Huntington disease.","method":"Hip14 knockout mouse generation, palmitoylation assays on brain tissue, behavioral testing, neuropathological analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined biochemical (reduced palmitoylation) and phenotypic readouts; replicated by multiple subsequent studies","pmids":["21775500"],"is_preprint":false},{"year":2013,"finding":"Constitutive loss of Hip14/ZDHHC17 produces marked alterations in synaptic function across brain regions and significantly impairs hippocampal memory and synaptic plasticity, demonstrating that a single PAT has major effects on cognition.","method":"Hip14 knockout mice, electrophysiological recordings of synaptic function, hippocampal-dependent behavioral tests (memory)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — clean KO with both electrophysiological and behavioral phenotypic readouts","pmids":["24277827"],"is_preprint":false},{"year":2015,"finding":"The ankyrin repeat (AR) domain of zDHHC17 (and zDHHC13) recognizes a conserved [VIAP][VIT]XXQP consensus sequence motif (zDABM) in substrates including SNAP25, SNAP23, cysteine string protein, HTT, CLIP-170, and MAP6, which mediates substrate recruitment prior to S-acylation.","method":"Peptide array binding assays, co-immunoprecipitation of AR domain with substrates, mutational analysis of binding motif","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — systematic peptide array combined with IP validation and mutational analysis; identifies a novel recognition motif","pmids":["26198635"],"is_preprint":false},{"year":2014,"finding":"The ankyrin repeat domain of HIP14 mediates binding to HTT; HTT amino acids 1-548 are sufficient for full interaction, with partial interaction possible with HTT 1-427 and HTT 224-548, and deletion of residues 257-315 reduces but does not abolish binding.","method":"Co-immunoprecipitation with HTT deletion mutants expressed in HEK293 cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — co-IP mapping study with deletion series; single lab, single method","pmids":["24651384"],"is_preprint":false},{"year":2014,"finding":"HIP14 palmitoylates GPM6A, SPRED1, and SPRED3 (confirmed as novel substrates), and co-immunoprecipitates with optineurin (a vesicular cargo adapter) without palmitoylating it, suggesting a trafficking regulatory interaction.","method":"Yeast two-hybrid interactome screen, acylation assay confirmation of palmitoylation substrates, co-immunoprecipitation","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 — Y2H followed by biochemical validation of palmitoylation for three substrates; single lab","pmids":["24705354"],"is_preprint":false},{"year":2015,"finding":"ZDHHC17 promotes axon outgrowth by facilitating TrkA-tubulin complex formation and upregulating downstream ERK1/2 phosphorylation in a manner independent of its palmitoyl transferase activity.","method":"Zebrafish zdhhc17 loss-of-function (motor neuron axon outgrowth readout), siRNA knockdown in NSCs and PC12 cells, co-immunoprecipitation of TrkA-tubulin, phospho-ERK western blot, PAT-inactive mutant overexpression","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple model systems with Co-IP and PAT-inactive mutant; single lab","pmids":["26232532"],"is_preprint":false},{"year":2016,"finding":"Adult-specific deletion of Hip14/ZDHHC17 causes rapidly progressive paralysis and death, striatal synaptic deficits (reduced transmitter release probability, altered postsynaptic currents), and cortical astro/microgliosis, establishing that HIP14 is essential for neuronal and glial integrity in the adult.","method":"Inducible conditional knockout mice (iHip14Δ/Δ), electrophysiology of striatal synapses, histological analysis of gliosis, behavioral testing","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 2 — clean inducible KO with electrophysiological, histological, and behavioral readouts; distinguishes adult vs. developmental roles","pmids":["27927242"],"is_preprint":false},{"year":2017,"finding":"PSSM-based screening of the zDHHC17 ankyrin repeat (AR) domain identified 95 human zDABM sequences across 90 proteins as putative zDHHC17 interactors, including all SNAP25, sprouty, cornifelin, ankyrin, and SLAIN-motif family members, revealing zDHHC17 as a broad interaction hub.","method":"Peptide array-based binding assay (400 peptides), PSSM construction, in vitro binding validation of predicted interactors","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — systematic peptide array with validated predictions; single lab","pmids":["28882895"],"is_preprint":false},{"year":2020,"finding":"ZDHHC17 interacts with MAP2K4 and p38/JNK to form a signaling module that activates JNK and p38 MAPK signaling, promoting GBM cell tumorigenicity and glioma stem cell self-renewal; genistein disrupts the ZDHHC17-MAP2K4 complex.","method":"Co-immunoprecipitation, GST pulldown, pharmacological inhibition (genistein), in vitro and in vivo GBM models, flow cytometry, Transwell migration","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal Co-IP and GST pulldown with functional pharmacological validation; single lab","pmids":["31938047"],"is_preprint":false},{"year":2020,"finding":"ZDHHC17 palmitoylates both DLK and NMNAT2 in retinal ganglion cells; ZDHHC17-dependent palmitoylation of DLK enables DLK-dependent somal degeneration after optic nerve crush, while palmitoylation of NMNAT2 ensures distal axon integrity in healthy optic nerves, coupling two previously considered parallel degeneration pathways.","method":"Optic nerve crush model, genetic loss-of-function of ZDHHC17, palmitoylation assays, identification of conserved zDABM motifs in DLK and NMNAT2, dorsal root ganglion neuron experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with defined substrates, palmitoylation assays, two neuronal cell types, motif identification; multiple orthogonal methods","pmids":["33207199"],"is_preprint":false},{"year":2021,"finding":"ZDHHC17 is required for SADS-CoV genomic RNA replication; CRISPR-KO of ZDHHC17 in HeLa cells reduces viral infection, and the DHHC (palmitoylation) domain is specifically required for this host-dependency function.","method":"Genome-wide CRISPR KO screen, truncation mutagenesis of ZDHHC17, palmitoylation inhibitor (2-bromopalmitate) treatment, viral RNA replication assay","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO screen confirmed by mutagenesis and pharmacology; single lab, mechanism not fully resolved","pmids":["34700373"],"is_preprint":false},{"year":2022,"finding":"zDHHC17 S-acylates Sprouty and SPRED proteins via both zDABM-dependent and zDABM-independent mechanisms; SPRED3 lacks a zDABM yet is efficiently S-acylated by zDHHC17 through interaction of its SPR cysteine-rich domain with a region of zDHHC17 outside the ankyrin repeat domain.","method":"Mutational analysis of substrate binding motifs, co-immunoprecipitation, S-acylation assays (resin-assisted capture), deletion constructs of zDHHC17","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro S-acylation assays with mutagenesis; single lab but multiple orthogonal approaches","pmids":["36442513"],"is_preprint":false},{"year":2023,"finding":"ZDHHC17 is the major palmitoyl acyltransferase for HSP90α in granulosa cells; ZDHHC17-mediated palmitoylation of HSP90α is required for CYP19A1-dependent conversion of androgen to estrogen, and ZDHHC17 depletion reduces this conversion.","method":"Palmitoylation assay (resin-assisted capture), siRNA knockdown of ZDHHC17, CYP19A1 activity assay, in vivo PCOS mouse model","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2-3 — palmitoylation assay combined with KD and enzymatic readout; single lab","pmids":["37769867"],"is_preprint":false},{"year":2024,"finding":"zDHHC17 palmitoylates Smad7 at cysteine residues Cys202, Cys225, Cys415, and Cys417; palmitoylation at Cys415/Cys417 promotes nuclear-to-cytoplasmic translocation of Smad7, enhances Smad7 protein stability, and enforces inhibition of TGF-β/Smad transcriptional responses.","method":"Resin-assisted capture and metabolic labeling (palmitoylation assays), site-directed mutagenesis of cysteine residues, subcellular fractionation/imaging, TGF-β/Smad reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — metabolic labeling plus mutagenesis of palmitoylation sites with multiple functional readouts (localization, stability, signaling); rigorous single study","pmids":["38876303"],"is_preprint":false},{"year":2025,"finding":"Drosophila Hip14 (ortholog of ZDHHC17) and Patsas (ortholog of ZDHHC13/HIP14L) are rate-limiting factors in lysosome formation and fusion; loss of Hip14 disrupts secretory granule-lysosome fusion, lysosomal acidification, and biosynthetic trafficking of lysosomal hydrolases; constitutively active Rab2 GTPase rescues lysosomal and neuronal defects caused by Hip14 loss.","method":"Drosophila genetic loss-of-function (larval salivary gland and adult neurons), live imaging of secretory granule maturation, lysosomal acidification assay, genetic epistasis with Rab2 constitutively active mutant","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with multiple orthogonal readouts; Drosophila ortholog; preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.02.06.636816"],"is_preprint":true}],"current_model":"ZDHHC17 (HIP14) is a Golgi-localized palmitoyl acyltransferase that uses its DHHC catalytic domain to S-acylate a broad set of neuronal substrates (including HTT, SNAP-25, PSD-95, DLK, NMNAT2, Smad7, HSP90α, and others), recruits substrates via a conserved ankyrin repeat domain that recognizes a [VIAP][VIT]XXQP linear motif (zDABM), and thereby regulates vesicular trafficking, synaptic protein clustering, axon integrity, lysosome biogenesis, and TGF-β/MAPK signaling; its activity is potentiated by wild-type HTT and is impaired by polyglutamine-expanded mutant HTT, linking defective palmitoylation to Huntington disease pathology."},"narrative":{"teleology":[{"year":2002,"claim":"Establishing that HIP14 localizes to the Golgi and cytoplasmic vesicles and functions in intracellular trafficking answered the foundational question of where and in what process this DHHC-domain protein acts.","evidence":"Subcellular fractionation/immunofluorescence in mammalian cells and genetic complementation of yeast akr1Δ endocytosis defect","pmids":["12393793"],"confidence":"High","gaps":["Enzymatic activity not yet demonstrated","Mammalian substrates unknown","Mechanism of trafficking function undefined"]},{"year":2004,"claim":"Demonstrating that HIP14 is a palmitoyl transferase with defined substrate specificity for neuronal proteins (SNAP-25, PSD-95, GAD65, synaptotagmin I, HTT) and that its depletion reduces synaptic protein clustering established ZDHHC17 as a bona fide PAT with neuronal function.","evidence":"Biochemical palmitoylation assays with substrate specificity panel and siRNA knockdown in neurons with fluorescence clustering readout","pmids":["15603740"],"confidence":"High","gaps":["Palmitoylation sites on substrates not mapped","Substrate recognition mechanism unknown","In vivo relevance not tested"]},{"year":2006,"claim":"Identifying HTT Cys214 as the HIP14-palmitoylated residue and showing that polyglutamine expansion reduces both the HIP14–HTT interaction and HTT palmitoylation, increasing inclusion formation and toxicity, directly linked defective palmitoylation to Huntington disease pathology.","evidence":"Acyl-RAC assay, Cys214 mutagenesis, co-IP of HTT–HIP14, siRNA/overexpression with inclusion formation readout in neurons","pmids":["16699508"],"confidence":"High","gaps":["Whether HIP14 dysfunction is causal in HD in vivo not yet shown","Mechanism by which polyQ expansion reduces binding unclear"]},{"year":2011,"claim":"Two complementary studies resolved the in vivo significance: wild-type HTT was shown to potentiate HIP14 enzymatic activity (lost with mutant HTT), and Hip14-knockout mice exhibited reduced substrate palmitoylation and HD-like neuropathology, establishing ZDHHC17 as essential for neuronal health and regulated by its own substrate.","evidence":"In vitro reconstitution of HTT-dependent potentiation of SNAP25 palmitoylation; Hip14 KO mouse with palmitoylation assays, behavioral testing, and neuropathology","pmids":["21636527","21775500"],"confidence":"High","gaps":["Whether HTT acts as allosteric activator or co-substrate not distinguished","Adult-specific roles not separated from developmental defects"]},{"year":2013,"claim":"Electrophysiological and behavioral analysis of Hip14-KO mice revealed marked synaptic dysfunction and impaired hippocampal memory, establishing that a single PAT has major consequences for cognition.","evidence":"Electrophysiological recordings and hippocampal-dependent behavioral tests in Hip14 KO mice","pmids":["24277827"],"confidence":"High","gaps":["Which specific substrate deficits underlie synaptic phenotypes unknown","Circuit-level mechanism not resolved"]},{"year":2015,"claim":"Discovery of the zDABM consensus motif ([VIAP][VIT]XXQP) recognized by the ankyrin repeat domain resolved how ZDHHC17 selects substrates from the proteome, revealing a modular recognition logic shared with ZDHHC13.","evidence":"Peptide array binding assays, co-IP of AR domain with substrates, mutational analysis of binding motif","pmids":["26198635"],"confidence":"High","gaps":["Structural basis of AR–zDABM recognition not solved","Whether all palmitoylation substrates require zDABM unknown"]},{"year":2015,"claim":"ZDHHC17 was found to promote axon outgrowth by facilitating TrkA–tubulin complex formation and ERK1/2 signaling independently of its PAT catalytic activity, revealing a non-enzymatic scaffolding function.","evidence":"Zebrafish zdhhc17 LOF, siRNA in NSCs/PC12 cells, co-IP of TrkA–tubulin, PAT-inactive mutant overexpression","pmids":["26232532"],"confidence":"Medium","gaps":["Non-enzymatic function not independently confirmed","Whether ankyrin repeat domain mediates this scaffolding not tested","In vivo mammalian validation lacking"]},{"year":2016,"claim":"Adult-specific conditional deletion showed that HIP14 is required for ongoing neuronal maintenance in the mature brain, causing rapid paralysis, striatal synaptic deficits, and gliosis, separating adult from developmental roles.","evidence":"Inducible conditional KO mice with electrophysiology, histology, and behavioral analysis","pmids":["27927242"],"confidence":"High","gaps":["Which substrates are most critical for adult neuronal survival not defined","Glial-autonomous vs. neuronal-autonomous effects not separated"]},{"year":2020,"claim":"ZDHHC17 was shown to palmitoylate both DLK (enabling somal degeneration) and NMNAT2 (maintaining distal axon integrity) in retinal ganglion cells, demonstrating that a single PAT coordinates two opposing arms of neuronal survival and degeneration.","evidence":"Optic nerve crush model, genetic LOF of ZDHHC17, palmitoylation assays, zDABM motif identification in DLK and NMNAT2","pmids":["33207199"],"confidence":"High","gaps":["Whether ZDHHC17 preference shifts between DLK and NMNAT2 under injury conditions unknown","Downstream acylation-site identification on DLK incomplete"]},{"year":2022,"claim":"Demonstration that SPRED3 is efficiently S-acylated by zDHHC17 through a zDABM-independent mechanism involving the SPR domain revealed a second substrate-binding surface outside the ankyrin repeat domain.","evidence":"Mutational analysis of binding motifs, co-IP, resin-assisted capture acylation assays with deletion constructs","pmids":["36442513"],"confidence":"Medium","gaps":["Identity of the alternative binding surface on ZDHHC17 not mapped","Prevalence of zDABM-independent substrates genome-wide unknown"]},{"year":2024,"claim":"Identification of Smad7 palmitoylation at four cysteines by ZDHHC17, with Cys415/417 palmitoylation driving nuclear-to-cytoplasmic translocation and stabilization, extended ZDHHC17's role into TGF-β signaling regulation.","evidence":"Resin-assisted capture, metabolic labeling, Cys mutagenesis, subcellular fractionation, TGF-β/Smad reporter assays","pmids":["38876303"],"confidence":"High","gaps":["Physiological context (tissue, cell type) for Smad7 palmitoylation in vivo not established","Whether ZDHHC17 palmitoylates other Smad family members unknown"]},{"year":null,"claim":"Key unresolved questions include the structural basis for ankyrin repeat–zDABM recognition, how ZDHHC17 activity is regulated beyond HTT interaction, the full scope of zDABM-independent substrates, and whether its non-enzymatic scaffolding functions are physiologically significant in mammals.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of ZDHHC17 AR domain bound to zDABM","Regulatory post-translational modifications of ZDHHC17 itself not systematically characterized","Non-enzymatic functions not validated in mammalian genetic models"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,4,14,17,18]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,10]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,5,6,11,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,13,18]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,7,17,18]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,0]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,5]}],"complexes":[],"partners":["HTT","SNAP25","DLK","NMNAT2","SMAD7","MAP2K4","SPRED3","OPTN"],"other_free_text":[]},"mechanistic_narrative":"ZDHHC17 (HIP14) is a Golgi-localized palmitoyl acyltransferase that S-acylates a broad repertoire of neuronal and signaling substrates—including SNAP-25, PSD-95, huntingtin, DLK, NMNAT2, Smad7, and HSP90α—thereby governing synaptic protein clustering, vesicular trafficking, axon integrity, TGF-β signaling, and lysosome biogenesis [PMID:15603740, PMID:33207199, PMID:38876303, PMID:12393793]. Substrate recruitment is mediated by an N-terminal ankyrin repeat domain that recognizes a [VIAP][VIT]XXQP linear motif (zDABM), though zDABM-independent acylation also occurs via distinct substrate-binding surfaces [PMID:26198635, PMID:36442513]. Wild-type huntingtin potentiates ZDHHC17 enzymatic activity, whereas polyglutamine-expanded mutant huntingtin impairs the interaction and reduces substrate palmitoylation, linking ZDHHC17 dysfunction to Huntington disease-like neuropathology in knockout mice [PMID:21636527, PMID:21775500, PMID:16699508]. Loss of ZDHHC17 in adult mice causes rapidly progressive paralysis, striatal synaptic failure, and gliosis, establishing it as essential for ongoing neuronal maintenance [PMID:27927242, PMID:24277827]."},"prefetch_data":{"uniprot":{"accession":"Q8IUH5","full_name":"Palmitoyltransferase ZDHHC17","aliases":["Acyltransferase ZDHHC17","DHHC domain-containing cysteine-rich protein 17","DHHC17","Huntingtin yeast partner H","Huntingtin-interacting protein 14","HIP-14","Huntingtin-interacting protein 3","HIP-3","Huntingtin-interacting protein H","Putative MAPK-activating protein PM11","Putative NF-kappa-B-activating protein 205","Zinc finger DHHC domain-containing protein 17"],"length_aa":632,"mass_kda":72.6,"function":"Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates and is involved in a variety of cellular processes (PubMed:15489887, PubMed:15603740, PubMed:24705354, PubMed:27911442, PubMed:28757145). Has no stringent fatty acid selectivity and in addition to palmitate can also transfer onto target proteins myristate from tetradecanoyl-CoA and stearate from octadecanoyl-CoA (By similarity). Palmitoyltransferase specific for a subset of neuronal proteins, including SNAP25, DLG4/PSD95, GAD2, SYT1 and HTT (PubMed:15489887, PubMed:15603740, PubMed:19139280, PubMed:28757145). Also palmitoylates neuronal protein GPM6A as well as SPRED1 and SPRED3 (PubMed:24705354). Could also play a role in axonogenesis through the regulation of NTRK1 and the downstream ERK1/ERK2 signaling cascade (By similarity). May be involved in the sorting or targeting of critical proteins involved in the initiating events of endocytosis at the plasma membrane (PubMed:12393793). May play a role in Mg(2+) transport (PubMed:18794299). Could also palmitoylate DNAJC5 and regulate its localization to the Golgi membrane (By similarity). Palmitoylates CASP6, thereby preventing its dimerization and subsequent activation (PubMed:27911442)","subcellular_location":"Golgi apparatus membrane; Cytoplasmic vesicle membrane; Presynaptic cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8IUH5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZDHHC17","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZDHHC17","total_profiled":1310},"omim":[{"mim_id":"616143","title":"LYSOPHOSPHOLIPASE II; LYPLA2","url":"https://www.omim.org/entry/616143"},{"mim_id":"612815","title":"ZDHHC PALMITOYLTRANSFERASE 13; ZDHHC13","url":"https://www.omim.org/entry/612815"},{"mim_id":"608701","title":"NICOTINAMIDE NUCLEOTIDE ADENYLYLTRANSFERASE 2; NMNAT2","url":"https://www.omim.org/entry/608701"},{"mim_id":"607799","title":"ZDHHC PALMITOYLTRANSFERASE 17; ZDHHC17","url":"https://www.omim.org/entry/607799"},{"mim_id":"605599","title":"LYSOPHOSPHOLIPASE I; LYPLA1","url":"https://www.omim.org/entry/605599"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Golgi apparatus","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZDHHC17"},"hgnc":{"alias_symbol":["HIP14","HYPH","KIAA0946"],"prev_symbol":[]},"alphafold":{"accession":"Q8IUH5","domains":[{"cath_id":"1.25.40.20","chopping":"57-149","consensus_level":"medium","plddt":97.4414,"start":57,"end":149},{"cath_id":"1.25.40.20","chopping":"184-288","consensus_level":"medium","plddt":92.8981,"start":184,"end":288},{"cath_id":"-","chopping":"355-413_479-632","consensus_level":"medium","plddt":90.8966,"start":355,"end":632},{"cath_id":"-","chopping":"416-473","consensus_level":"medium","plddt":92.7634,"start":416,"end":473},{"cath_id":"1.10.287","chopping":"297-353","consensus_level":"medium","plddt":90.8742,"start":297,"end":353}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IUH5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IUH5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IUH5-F1-predicted_aligned_error_v6.png","plddt_mean":87.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZDHHC17","jax_strain_url":"https://www.jax.org/strain/search?query=ZDHHC17"},"sequence":{"accession":"Q8IUH5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IUH5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IUH5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IUH5"}},"corpus_meta":[{"pmid":"15603740","id":"PMC_15603740","title":"Huntingtin-interacting protein HIP14 is a palmitoyl transferase involved in palmitoylation and trafficking of multiple neuronal proteins.","date":"2004","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/15603740","citation_count":252,"is_preprint":false},{"pmid":"16699508","id":"PMC_16699508","title":"Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function.","date":"2006","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16699508","citation_count":246,"is_preprint":false},{"pmid":"12393793","id":"PMC_12393793","title":"HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis.","date":"2002","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12393793","citation_count":175,"is_preprint":false},{"pmid":"21775500","id":"PMC_21775500","title":"Altered palmitoylation and neuropathological deficits in mice lacking HIP14.","date":"2011","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21775500","citation_count":94,"is_preprint":false},{"pmid":"26198635","id":"PMC_26198635","title":"Identification of a Novel Sequence Motif Recognized by the Ankyrin Repeat Domain of zDHHC17/13 S-Acyltransferases.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26198635","citation_count":81,"is_preprint":false},{"pmid":"21636527","id":"PMC_21636527","title":"Wild-type HTT modulates the enzymatic activity of the neuronal palmitoyl transferase HIP14.","date":"2011","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21636527","citation_count":76,"is_preprint":false},{"pmid":"18794299","id":"PMC_18794299","title":"Huntingtin-interacting proteins, HIP14 and HIP14L, mediate dual functions, palmitoyl acyltransferase and Mg2+ transport.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18794299","citation_count":63,"is_preprint":false},{"pmid":"31938047","id":"PMC_31938047","title":"Activation of JNK and p38 MAPK Mediated by ZDHHC17 Drives Glioblastoma Multiforme Development and Malignant Progression.","date":"2020","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/31938047","citation_count":59,"is_preprint":false},{"pmid":"24705354","id":"PMC_24705354","title":"The palmitoyl acyltransferase HIP14 shares a high proportion of interactors with huntingtin: implications for a role in the pathogenesis of Huntington's disease.","date":"2014","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24705354","citation_count":58,"is_preprint":false},{"pmid":"24277827","id":"PMC_24277827","title":"Memory and synaptic deficits in Hip14/DHHC17 knockout mice.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24277827","citation_count":46,"is_preprint":false},{"pmid":"28882895","id":"PMC_28882895","title":"Peptide array-based screening reveals a large number of proteins interacting with the ankyrin-repeat domain of the zDHHC17 S-acyltransferase.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28882895","citation_count":31,"is_preprint":false},{"pmid":"33207199","id":"PMC_33207199","title":"Coupled Control of Distal Axon Integrity and Somal Responses to Axonal Damage by the Palmitoyl Acyltransferase ZDHHC17.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33207199","citation_count":30,"is_preprint":false},{"pmid":"24651384","id":"PMC_24651384","title":"Identification of binding sites in Huntingtin for the Huntingtin Interacting Proteins HIP14 and HIP14L.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24651384","citation_count":25,"is_preprint":false},{"pmid":"27927242","id":"PMC_27927242","title":"Sudden death due to paralysis and synaptic and behavioral deficits when Hip14/Zdhhc17 is deleted in adult mice.","date":"2016","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/27927242","citation_count":25,"is_preprint":false},{"pmid":"34700373","id":"PMC_34700373","title":"Identification of ZDHHC17 as a Potential Drug Target for Swine Acute Diarrhea Syndrome Coronavirus Infection.","date":"2021","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/34700373","citation_count":21,"is_preprint":false},{"pmid":"30269354","id":"PMC_30269354","title":"Potentially critical roles of TNPO1, RAP1B, ZDHHC17, and PPM1B in the progression of coronary atherosclerosis through microarray data analysis.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30269354","citation_count":20,"is_preprint":false},{"pmid":"26232532","id":"PMC_26232532","title":"ZDHHC17 promotes axon outgrowth by regulating TrkA-tubulin complex formation.","date":"2015","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/26232532","citation_count":15,"is_preprint":false},{"pmid":"22649491","id":"PMC_22649491","title":"Low levels of human HIP14 are sufficient to rescue neuropathological, behavioural, and enzymatic defects due to loss of murine HIP14 in Hip14-/- mice.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22649491","citation_count":12,"is_preprint":false},{"pmid":"36442513","id":"PMC_36442513","title":"S-acylation of Sprouty and SPRED proteins by the S-acyltransferase zDHHC17 involves a novel mode of enzyme-substrate interaction.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36442513","citation_count":11,"is_preprint":false},{"pmid":"24376823","id":"PMC_24376823","title":"Dysregulated striatal neuronal processing and impaired motor behavior in mice lacking huntingtin interacting protein 14 (HIP14).","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24376823","citation_count":9,"is_preprint":false},{"pmid":"38876303","id":"PMC_38876303","title":"Smad7 palmitoylation by the S-acyltransferase zDHHC17 enhances its inhibitory effect on TGF-β/Smad signaling.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38876303","citation_count":9,"is_preprint":false},{"pmid":"24961622","id":"PMC_24961622","title":"Altered Neuronal Dynamics in the Striatum on the Behavior of Huntingtin Interacting Protein 14 (HIP14) Knockout Mice.","date":"2013","source":"Brain sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24961622","citation_count":5,"is_preprint":false},{"pmid":"37769867","id":"PMC_37769867","title":"ZDHHC17 participates in the pathogenesis of polycystic ovary syndrome by affecting androgen conversion to estrogen in granulosa cells.","date":"2023","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/37769867","citation_count":2,"is_preprint":false},{"pmid":"41445853","id":"PMC_41445853","title":"DNA Methylation-Regulated ZDHHC17 Promotes the Risk of Facial Skin Aging.","date":"2025","source":"Clinical, cosmetic and investigational dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/41445853","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.06.636816","title":"Huntington’s disease-associated ankyrin repeat palmitoyl transferases are rate-limiting factors in lysosome formation and fusion","date":"2025-02-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.06.636816","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14644,"output_tokens":4920,"usd":0.058866},"stage2":{"model":"claude-opus-4-6","input_tokens":8440,"output_tokens":3045,"usd":0.177487},"total_usd":0.236353,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"HIP14 (ZDHHC17) functions as a palmitoyl transferase (PAT) with substrate specificity for neuronal proteins including SNAP-25, PSD-95, GAD65, synaptotagmin I, and huntingtin, but not paralemmin or synaptotagmin VII; exogenous HIP14 enhances palmitoylation-dependent vesicular trafficking of acylated proteins, and interference with endogenous HIP14 reduces clustering of PSD-95 and GAD65 in neurons.\",\n      \"method\": \"Biochemical palmitoylation assays, heterologous cell expression, siRNA knockdown in neurons with fluorescence clustering readout\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro PAT assay with substrate specificity panel, loss-of-function with defined cellular phenotype; foundational study replicated by multiple subsequent labs\",\n      \"pmids\": [\"15603740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"HIP14 localizes to the Golgi and cytoplasmic vesicles, and its expression rescues the temperature-sensitive lethality and endocytosis defect of akr1Δ yeast cells, demonstrating a role for HIP14 in intracellular trafficking.\",\n      \"method\": \"Yeast two-hybrid, subcellular fractionation/immunofluorescence, genetic complementation in akr1Δ yeast\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic complementation assay with functional readout (endocytosis rescue), localization experiment; replicated in context of subsequent studies\",\n      \"pmids\": [\"12393793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Huntingtin (HTT) is palmitoylated at cysteine 214 by HIP14; polyglutamine expansion reduces HTT-HIP14 interaction and HTT palmitoylation, leading to increased inclusion formation and neuronal toxicity; HIP14 downregulation increases inclusions while overexpression reduces them.\",\n      \"method\": \"Acyl-RAC palmitoylation assay, site-directed mutagenesis (C214 palmitoylation site), HTT-HIP14 co-immunoprecipitation, siRNA knockdown and overexpression in neurons with inclusion formation readout\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of palmitoylation site, biochemical assay, multiple orthogonal readouts; replicated across labs\",\n      \"pmids\": [\"16699508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HIP14 mediates electrogenic, voltage-dependent, saturable Mg2+ transport when expressed in Xenopus oocytes; palmitoylation inhibition with 2-bromopalmitate or DHHC-domain deletion reduces HIP14-mediated Mg2+ transport by ~50%, suggesting autopalmitoylation regulates Mg2+ transport activity.\",\n      \"method\": \"Xenopus oocyte expression, electrophysiology, pharmacological inhibition (2-bromopalmitate), DHHC-deletion mutant, co-expression with independent PAT (GODZ)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — functional reconstitution in oocytes with mutagenesis and pharmacology; single lab study\",\n      \"pmids\": [\"18794299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Wild-type HTT modulates HIP14's palmitoylation and enzymatic activity: HTT is auto-palmitoylated by HIP14, and in the presence of wild-type HTT, HIP14 palmitoylation of SNAP25 is potentiated in vitro; this modulatory effect is lost with CAG-expanded mutant HTT.\",\n      \"method\": \"In vitro palmitoylation assay with recombinant proteins, HTT antisense oligo knockdown in cortical neurons, brain lysates from hdh+/- mice, western blot of palmitoylation\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution plus in vivo genetic validation in two mouse models; multiple orthogonal methods\",\n      \"pmids\": [\"21636527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loss of Hip14/ZDHHC17 in knockout mice reduces palmitoylation of multiple HIP14 substrates (but not HTT itself) and produces behavioral, biochemical, and neuropathological deficits reminiscent of Huntington disease.\",\n      \"method\": \"Hip14 knockout mouse generation, palmitoylation assays on brain tissue, behavioral testing, neuropathological analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined biochemical (reduced palmitoylation) and phenotypic readouts; replicated by multiple subsequent studies\",\n      \"pmids\": [\"21775500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Constitutive loss of Hip14/ZDHHC17 produces marked alterations in synaptic function across brain regions and significantly impairs hippocampal memory and synaptic plasticity, demonstrating that a single PAT has major effects on cognition.\",\n      \"method\": \"Hip14 knockout mice, electrophysiological recordings of synaptic function, hippocampal-dependent behavioral tests (memory)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with both electrophysiological and behavioral phenotypic readouts\",\n      \"pmids\": [\"24277827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The ankyrin repeat (AR) domain of zDHHC17 (and zDHHC13) recognizes a conserved [VIAP][VIT]XXQP consensus sequence motif (zDABM) in substrates including SNAP25, SNAP23, cysteine string protein, HTT, CLIP-170, and MAP6, which mediates substrate recruitment prior to S-acylation.\",\n      \"method\": \"Peptide array binding assays, co-immunoprecipitation of AR domain with substrates, mutational analysis of binding motif\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — systematic peptide array combined with IP validation and mutational analysis; identifies a novel recognition motif\",\n      \"pmids\": [\"26198635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The ankyrin repeat domain of HIP14 mediates binding to HTT; HTT amino acids 1-548 are sufficient for full interaction, with partial interaction possible with HTT 1-427 and HTT 224-548, and deletion of residues 257-315 reduces but does not abolish binding.\",\n      \"method\": \"Co-immunoprecipitation with HTT deletion mutants expressed in HEK293 cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP mapping study with deletion series; single lab, single method\",\n      \"pmids\": [\"24651384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HIP14 palmitoylates GPM6A, SPRED1, and SPRED3 (confirmed as novel substrates), and co-immunoprecipitates with optineurin (a vesicular cargo adapter) without palmitoylating it, suggesting a trafficking regulatory interaction.\",\n      \"method\": \"Yeast two-hybrid interactome screen, acylation assay confirmation of palmitoylation substrates, co-immunoprecipitation\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Y2H followed by biochemical validation of palmitoylation for three substrates; single lab\",\n      \"pmids\": [\"24705354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ZDHHC17 promotes axon outgrowth by facilitating TrkA-tubulin complex formation and upregulating downstream ERK1/2 phosphorylation in a manner independent of its palmitoyl transferase activity.\",\n      \"method\": \"Zebrafish zdhhc17 loss-of-function (motor neuron axon outgrowth readout), siRNA knockdown in NSCs and PC12 cells, co-immunoprecipitation of TrkA-tubulin, phospho-ERK western blot, PAT-inactive mutant overexpression\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple model systems with Co-IP and PAT-inactive mutant; single lab\",\n      \"pmids\": [\"26232532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Adult-specific deletion of Hip14/ZDHHC17 causes rapidly progressive paralysis and death, striatal synaptic deficits (reduced transmitter release probability, altered postsynaptic currents), and cortical astro/microgliosis, establishing that HIP14 is essential for neuronal and glial integrity in the adult.\",\n      \"method\": \"Inducible conditional knockout mice (iHip14Δ/Δ), electrophysiology of striatal synapses, histological analysis of gliosis, behavioral testing\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean inducible KO with electrophysiological, histological, and behavioral readouts; distinguishes adult vs. developmental roles\",\n      \"pmids\": [\"27927242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PSSM-based screening of the zDHHC17 ankyrin repeat (AR) domain identified 95 human zDABM sequences across 90 proteins as putative zDHHC17 interactors, including all SNAP25, sprouty, cornifelin, ankyrin, and SLAIN-motif family members, revealing zDHHC17 as a broad interaction hub.\",\n      \"method\": \"Peptide array-based binding assay (400 peptides), PSSM construction, in vitro binding validation of predicted interactors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — systematic peptide array with validated predictions; single lab\",\n      \"pmids\": [\"28882895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZDHHC17 interacts with MAP2K4 and p38/JNK to form a signaling module that activates JNK and p38 MAPK signaling, promoting GBM cell tumorigenicity and glioma stem cell self-renewal; genistein disrupts the ZDHHC17-MAP2K4 complex.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, pharmacological inhibition (genistein), in vitro and in vivo GBM models, flow cytometry, Transwell migration\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal Co-IP and GST pulldown with functional pharmacological validation; single lab\",\n      \"pmids\": [\"31938047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZDHHC17 palmitoylates both DLK and NMNAT2 in retinal ganglion cells; ZDHHC17-dependent palmitoylation of DLK enables DLK-dependent somal degeneration after optic nerve crush, while palmitoylation of NMNAT2 ensures distal axon integrity in healthy optic nerves, coupling two previously considered parallel degeneration pathways.\",\n      \"method\": \"Optic nerve crush model, genetic loss-of-function of ZDHHC17, palmitoylation assays, identification of conserved zDABM motifs in DLK and NMNAT2, dorsal root ganglion neuron experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined substrates, palmitoylation assays, two neuronal cell types, motif identification; multiple orthogonal methods\",\n      \"pmids\": [\"33207199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZDHHC17 is required for SADS-CoV genomic RNA replication; CRISPR-KO of ZDHHC17 in HeLa cells reduces viral infection, and the DHHC (palmitoylation) domain is specifically required for this host-dependency function.\",\n      \"method\": \"Genome-wide CRISPR KO screen, truncation mutagenesis of ZDHHC17, palmitoylation inhibitor (2-bromopalmitate) treatment, viral RNA replication assay\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO screen confirmed by mutagenesis and pharmacology; single lab, mechanism not fully resolved\",\n      \"pmids\": [\"34700373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"zDHHC17 S-acylates Sprouty and SPRED proteins via both zDABM-dependent and zDABM-independent mechanisms; SPRED3 lacks a zDABM yet is efficiently S-acylated by zDHHC17 through interaction of its SPR cysteine-rich domain with a region of zDHHC17 outside the ankyrin repeat domain.\",\n      \"method\": \"Mutational analysis of substrate binding motifs, co-immunoprecipitation, S-acylation assays (resin-assisted capture), deletion constructs of zDHHC17\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro S-acylation assays with mutagenesis; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"36442513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZDHHC17 is the major palmitoyl acyltransferase for HSP90α in granulosa cells; ZDHHC17-mediated palmitoylation of HSP90α is required for CYP19A1-dependent conversion of androgen to estrogen, and ZDHHC17 depletion reduces this conversion.\",\n      \"method\": \"Palmitoylation assay (resin-assisted capture), siRNA knockdown of ZDHHC17, CYP19A1 activity assay, in vivo PCOS mouse model\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — palmitoylation assay combined with KD and enzymatic readout; single lab\",\n      \"pmids\": [\"37769867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"zDHHC17 palmitoylates Smad7 at cysteine residues Cys202, Cys225, Cys415, and Cys417; palmitoylation at Cys415/Cys417 promotes nuclear-to-cytoplasmic translocation of Smad7, enhances Smad7 protein stability, and enforces inhibition of TGF-β/Smad transcriptional responses.\",\n      \"method\": \"Resin-assisted capture and metabolic labeling (palmitoylation assays), site-directed mutagenesis of cysteine residues, subcellular fractionation/imaging, TGF-β/Smad reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — metabolic labeling plus mutagenesis of palmitoylation sites with multiple functional readouts (localization, stability, signaling); rigorous single study\",\n      \"pmids\": [\"38876303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Drosophila Hip14 (ortholog of ZDHHC17) and Patsas (ortholog of ZDHHC13/HIP14L) are rate-limiting factors in lysosome formation and fusion; loss of Hip14 disrupts secretory granule-lysosome fusion, lysosomal acidification, and biosynthetic trafficking of lysosomal hydrolases; constitutively active Rab2 GTPase rescues lysosomal and neuronal defects caused by Hip14 loss.\",\n      \"method\": \"Drosophila genetic loss-of-function (larval salivary gland and adult neurons), live imaging of secretory granule maturation, lysosomal acidification assay, genetic epistasis with Rab2 constitutively active mutant\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple orthogonal readouts; Drosophila ortholog; preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.02.06.636816\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ZDHHC17 (HIP14) is a Golgi-localized palmitoyl acyltransferase that uses its DHHC catalytic domain to S-acylate a broad set of neuronal substrates (including HTT, SNAP-25, PSD-95, DLK, NMNAT2, Smad7, HSP90α, and others), recruits substrates via a conserved ankyrin repeat domain that recognizes a [VIAP][VIT]XXQP linear motif (zDABM), and thereby regulates vesicular trafficking, synaptic protein clustering, axon integrity, lysosome biogenesis, and TGF-β/MAPK signaling; its activity is potentiated by wild-type HTT and is impaired by polyglutamine-expanded mutant HTT, linking defective palmitoylation to Huntington disease pathology.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ZDHHC17 (HIP14) is a Golgi-localized palmitoyl acyltransferase that S-acylates a broad repertoire of neuronal and signaling substrates—including SNAP-25, PSD-95, huntingtin, DLK, NMNAT2, Smad7, and HSP90α—thereby governing synaptic protein clustering, vesicular trafficking, axon integrity, TGF-β signaling, and lysosome biogenesis [PMID:15603740, PMID:33207199, PMID:38876303, PMID:12393793]. Substrate recruitment is mediated by an N-terminal ankyrin repeat domain that recognizes a [VIAP][VIT]XXQP linear motif (zDABM), though zDABM-independent acylation also occurs via distinct substrate-binding surfaces [PMID:26198635, PMID:36442513]. Wild-type huntingtin potentiates ZDHHC17 enzymatic activity, whereas polyglutamine-expanded mutant huntingtin impairs the interaction and reduces substrate palmitoylation, linking ZDHHC17 dysfunction to Huntington disease-like neuropathology in knockout mice [PMID:21636527, PMID:21775500, PMID:16699508]. Loss of ZDHHC17 in adult mice causes rapidly progressive paralysis, striatal synaptic failure, and gliosis, establishing it as essential for ongoing neuronal maintenance [PMID:27927242, PMID:24277827].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that HIP14 localizes to the Golgi and cytoplasmic vesicles and functions in intracellular trafficking answered the foundational question of where and in what process this DHHC-domain protein acts.\",\n      \"evidence\": \"Subcellular fractionation/immunofluorescence in mammalian cells and genetic complementation of yeast akr1Δ endocytosis defect\",\n      \"pmids\": [\"12393793\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymatic activity not yet demonstrated\", \"Mammalian substrates unknown\", \"Mechanism of trafficking function undefined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that HIP14 is a palmitoyl transferase with defined substrate specificity for neuronal proteins (SNAP-25, PSD-95, GAD65, synaptotagmin I, HTT) and that its depletion reduces synaptic protein clustering established ZDHHC17 as a bona fide PAT with neuronal function.\",\n      \"evidence\": \"Biochemical palmitoylation assays with substrate specificity panel and siRNA knockdown in neurons with fluorescence clustering readout\",\n      \"pmids\": [\"15603740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Palmitoylation sites on substrates not mapped\", \"Substrate recognition mechanism unknown\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying HTT Cys214 as the HIP14-palmitoylated residue and showing that polyglutamine expansion reduces both the HIP14–HTT interaction and HTT palmitoylation, increasing inclusion formation and toxicity, directly linked defective palmitoylation to Huntington disease pathology.\",\n      \"evidence\": \"Acyl-RAC assay, Cys214 mutagenesis, co-IP of HTT–HIP14, siRNA/overexpression with inclusion formation readout in neurons\",\n      \"pmids\": [\"16699508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HIP14 dysfunction is causal in HD in vivo not yet shown\", \"Mechanism by which polyQ expansion reduces binding unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Two complementary studies resolved the in vivo significance: wild-type HTT was shown to potentiate HIP14 enzymatic activity (lost with mutant HTT), and Hip14-knockout mice exhibited reduced substrate palmitoylation and HD-like neuropathology, establishing ZDHHC17 as essential for neuronal health and regulated by its own substrate.\",\n      \"evidence\": \"In vitro reconstitution of HTT-dependent potentiation of SNAP25 palmitoylation; Hip14 KO mouse with palmitoylation assays, behavioral testing, and neuropathology\",\n      \"pmids\": [\"21636527\", \"21775500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HTT acts as allosteric activator or co-substrate not distinguished\", \"Adult-specific roles not separated from developmental defects\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Electrophysiological and behavioral analysis of Hip14-KO mice revealed marked synaptic dysfunction and impaired hippocampal memory, establishing that a single PAT has major consequences for cognition.\",\n      \"evidence\": \"Electrophysiological recordings and hippocampal-dependent behavioral tests in Hip14 KO mice\",\n      \"pmids\": [\"24277827\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific substrate deficits underlie synaptic phenotypes unknown\", \"Circuit-level mechanism not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery of the zDABM consensus motif ([VIAP][VIT]XXQP) recognized by the ankyrin repeat domain resolved how ZDHHC17 selects substrates from the proteome, revealing a modular recognition logic shared with ZDHHC13.\",\n      \"evidence\": \"Peptide array binding assays, co-IP of AR domain with substrates, mutational analysis of binding motif\",\n      \"pmids\": [\"26198635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of AR–zDABM recognition not solved\", \"Whether all palmitoylation substrates require zDABM unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"ZDHHC17 was found to promote axon outgrowth by facilitating TrkA–tubulin complex formation and ERK1/2 signaling independently of its PAT catalytic activity, revealing a non-enzymatic scaffolding function.\",\n      \"evidence\": \"Zebrafish zdhhc17 LOF, siRNA in NSCs/PC12 cells, co-IP of TrkA–tubulin, PAT-inactive mutant overexpression\",\n      \"pmids\": [\"26232532\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Non-enzymatic function not independently confirmed\", \"Whether ankyrin repeat domain mediates this scaffolding not tested\", \"In vivo mammalian validation lacking\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Adult-specific conditional deletion showed that HIP14 is required for ongoing neuronal maintenance in the mature brain, causing rapid paralysis, striatal synaptic deficits, and gliosis, separating adult from developmental roles.\",\n      \"evidence\": \"Inducible conditional KO mice with electrophysiology, histology, and behavioral analysis\",\n      \"pmids\": [\"27927242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which substrates are most critical for adult neuronal survival not defined\", \"Glial-autonomous vs. neuronal-autonomous effects not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"ZDHHC17 was shown to palmitoylate both DLK (enabling somal degeneration) and NMNAT2 (maintaining distal axon integrity) in retinal ganglion cells, demonstrating that a single PAT coordinates two opposing arms of neuronal survival and degeneration.\",\n      \"evidence\": \"Optic nerve crush model, genetic LOF of ZDHHC17, palmitoylation assays, zDABM motif identification in DLK and NMNAT2\",\n      \"pmids\": [\"33207199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ZDHHC17 preference shifts between DLK and NMNAT2 under injury conditions unknown\", \"Downstream acylation-site identification on DLK incomplete\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstration that SPRED3 is efficiently S-acylated by zDHHC17 through a zDABM-independent mechanism involving the SPR domain revealed a second substrate-binding surface outside the ankyrin repeat domain.\",\n      \"evidence\": \"Mutational analysis of binding motifs, co-IP, resin-assisted capture acylation assays with deletion constructs\",\n      \"pmids\": [\"36442513\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the alternative binding surface on ZDHHC17 not mapped\", \"Prevalence of zDABM-independent substrates genome-wide unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of Smad7 palmitoylation at four cysteines by ZDHHC17, with Cys415/417 palmitoylation driving nuclear-to-cytoplasmic translocation and stabilization, extended ZDHHC17's role into TGF-β signaling regulation.\",\n      \"evidence\": \"Resin-assisted capture, metabolic labeling, Cys mutagenesis, subcellular fractionation, TGF-β/Smad reporter assays\",\n      \"pmids\": [\"38876303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological context (tissue, cell type) for Smad7 palmitoylation in vivo not established\", \"Whether ZDHHC17 palmitoylates other Smad family members unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for ankyrin repeat–zDABM recognition, how ZDHHC17 activity is regulated beyond HTT interaction, the full scope of zDABM-independent substrates, and whether its non-enzymatic scaffolding functions are physiologically significant in mammals.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of ZDHHC17 AR domain bound to zDABM\", \"Regulatory post-translational modifications of ZDHHC17 itself not systematically characterized\", \"Non-enzymatic functions not validated in mammalian genetic models\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 4, 14, 17, 18]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 5, 6, 11, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 13, 18]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 7, 17, 18]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 0]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"HTT\",\n      \"SNAP25\",\n      \"DLK\",\n      \"NMNAT2\",\n      \"SMAD7\",\n      \"MAP2K4\",\n      \"SPRED3\",\n      \"OPTN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}