{"gene":"ZDHHC2","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2008,"finding":"DHHC2 palmitoylates CKAP4/p63: identified as a major substrate using the PICA (palmitoyl-cysteine isolation capture and analysis) proteomics method in a living vertebrate system, establishing a direct PAT-substrate relationship.","method":"PICA proteomics method (palmitoyl-cysteine isolation capture and analysis) in living cells","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel proteomics method with direct substrate identification, single lab, single method","pmids":["18296695"],"is_preprint":false},{"year":2009,"finding":"DHHC2-mediated palmitoylation of CKAP4 is required for CKAP4 trafficking from the ER to the plasma membrane and for its nuclear localization; siRNA knockdown of DHHC2 suppressed CKAP4 palmitoylation and blocked APF-induced antiproliferative signaling and changes in E-cadherin, vimentin, and ZO-1 expression.","method":"siRNA knockdown, immunocytochemistry, palmitoylation assay, proliferation assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined subcellular trafficking and signaling phenotype, single lab, multiple orthogonal readouts","pmids":["19144824"],"is_preprint":false},{"year":2008,"finding":"DHHC2 directly palmitoylates tetraspanins CD9 and CD151; catalytically inactive DHHC2 (DH→AA or C→S mutations in the DHHC motif) fails to promote palmitoylation. DHHC2 physically associates with CD9 and CD151. DHHC2-dependent palmitoylation promotes CD9–CD151 associations, protects CD151 and CD9 from lysosomal degradation, and shifts cells toward increased cell–cell contacts.","method":"Radioactive palmitate labeling, site-directed mutagenesis of active site, Co-immunoprecipitation, siRNA knockdown","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — active-site mutagenesis demonstrating catalytic requirement, reciprocal Co-IP, knockdown with multiple functional readouts, single lab but multiple orthogonal methods","pmids":["18508921"],"is_preprint":false},{"year":2011,"finding":"DHHC2 localizes to the plasma membrane and Rab11-positive recycling endosomes, dynamically cycling between these compartments. Plasma membrane integration was confirmed by labeling an extrafacial HA epitope in non-permeabilized cells. FRAP analysis revealed constitutive refilling of the recycling endosome pool. The cytoplasmic C-terminus of DHHC2 regulates membrane targeting; a C-terminus deletion mutant relocates to the ER. Divergent C-terminal tail sequences distinguish DHHC2 from the closely related DHHC15 and account for their different membrane localizations.","method":"Live-cell fluorescence microscopy, FRAP, extracellular HA-epitope labeling, antibody-uptake trafficking assay, deletion/chimeric mutant analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal live-imaging methods (FRAP, surface labeling, antibody uptake), domain mutagenesis with functional localization consequence, single lab","pmids":["21471008"],"is_preprint":false},{"year":2011,"finding":"DHHC2 mediates de novo and turnover palmitoylation of R7BP (RGS7 family-binding protein) in neuronal cells. DHHC2 silencing redistributes R7BP from the plasma membrane to the nucleus. Gi/o signaling inhibits R7BP depalmitoylation, stabilizing its membrane association, whereas Gi/o inactivation promotes nuclear accumulation of R7BP.","method":"siRNA knockdown, palmitoylation turnover assay, subcellular fractionation/localization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined localization and palmitoylation phenotype, single lab, multiple methods","pmids":["21343290"],"is_preprint":false},{"year":2011,"finding":"DHHC2 is a protein S-acyltransferase for the T cell kinase Lck. Reducing DHHC2 in Jurkat T cells by siRNA decreases Lck S-acylation and causes partial dislocation from membranes; overexpression of DHHC2 increases S-acylation of LckN10-GFP. DHHC2 localizes primarily to the ER and Golgi.","method":"siRNA knockdown, overexpression, palmitoylation assay, membrane fractionation, fluorescence localization","journal":"Molecular membrane biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (KD and OE) with palmitoylation and membrane localization readouts, single lab","pmids":["22034844"],"is_preprint":false},{"year":2015,"finding":"DHHC2 (residing on recycling endosomes) interacts with and palmitoylates AKAP79/150; RNAi knockdown of DHHC2 in rat hippocampal neurons disrupts recycling endosome exocytosis, dendritic spine enlargement, AKAP recruitment to spines, and potentiation of AMPAR-mediated synaptic currents during LTP. Expression of a palmitoylation-independent lipidated AKAP mutant in DHHC2-deficient neurons largely restores plasticity, placing DHHC2 upstream of AKAP palmitoylation in LTP.","method":"RNAi knockdown, Co-immunoprecipitation, electrophysiology (LTP recording), live-cell imaging, genetic epistasis with palmitoylation-independent AKAP mutant","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis rescue experiment, reciprocal interaction, electrophysiology, multiple orthogonal methods in single study","pmids":["25589740"],"is_preprint":false},{"year":2017,"finding":"Two C-terminal sorting signals in zDHHC2 — a non-canonical dileucine motif [SxxxLL] and a downstream NP motif — regulate endocytic retrieval from the plasma membrane. Mutation of these signals enhanced plasma membrane and neurite accumulation of zDHHC2 in PC12 cells and hippocampal neurons. Phospho-mimetic mutations of adjacent serine/threonine residues suggest phosphorylation may modulate efficacy of these sorting signals.","method":"Site-directed mutagenesis, fluorescence live-cell imaging, phospho-mimetic mutant analysis in PC12 cells and primary neurons","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of trafficking motifs with defined localization consequences, single lab, two cell types","pmids":["28768144"],"is_preprint":false},{"year":2020,"finding":"ZDHHC2 is identified as a positive regulator of germinal center (GC) B cell differentiation; Zdhhc2-shRNA transduction severely compromised B1-8hi cell differentiation into GC B cells in vivo and impaired proliferation and survival of B cells stimulated by CD40L, BAFF, and IL-21 in vitro.","method":"In vivo shRNA screen, retroviral shRNA knockdown, in vitro B cell differentiation assay, flow cytometry","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular differentiation phenotype in vivo and in vitro, single lab","pmids":["32587588"],"is_preprint":false},{"year":2020,"finding":"ZDHHC2, ZDHHC8, ZDHHC15, and ZDHHC20 palmitoylate Influenza A hemagglutinin (HA) and M2, with ZDHHC2 and ZDHHC8 having the strongest effect. CRISPR/Cas9 knockout of these ZDHHCs strongly reduced acylation of group 1 and group 2 HAs. These ZDHHCs co-localize with HA at membranes of the exocytic pathway. Influenza B and C virus HA are not substrates of ZDHHC2.","method":"siRNA library knockdown, Acyl-RAC assay, 3H-palmitate labeling, CRISPR/Cas9 knockout, co-localization microscopy","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — siRNA screen confirmed by CRISPR KO, orthogonal palmitoylation assays (Acyl-RAC + radiolabel), co-localization, single lab but rigorous multi-method","pmids":["31872235"],"is_preprint":false},{"year":2021,"finding":"ZDHHC2 is required in plasmacytoid dendritic cells (pDCs) for IRF7 phosphorylation and IFN-α production. Loss of ZDHHC2 in human CAL-1 pDCs dampened both IRF7 phosphorylation and IFN-α production. In vivo, CRISPR/Cas9 Zdhhc2-deficient mice showed dramatically reduced pDC accumulation and IFN-α in psoriatic skin following imiquimod treatment.","method":"CRISPR/Cas9 knockout mouse, siRNA/gene KO in human CAL-1 pDC cell line, phosphorylation assay (IRF7), cytokine ELISA, flow cytometry","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in both mouse model and human cell line with defined signaling (IRF7 phosphorylation) and cytokine readouts, single lab","pmids":["33488612"],"is_preprint":false},{"year":2023,"finding":"ZDHHC2 mediates S-palmitoylation of AGK, promoting its translocation to the plasma membrane and activation of the PI3K-AKT-mTOR signaling pathway in clear cell renal cell carcinoma, thereby reducing sunitinib sensitivity.","method":"Palmitoylation assay, subcellular fractionation/membrane translocation assay, AKT-mTOR pathway activity measurement, in vitro and in vivo tumor models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — palmitoylation assay with membrane translocation and downstream signaling readout, in vivo validation, single lab","pmids":["37078777"],"is_preprint":false},{"year":2023,"finding":"DHHC2 activity in the hippocampus is upregulated after fear conditioning; DHHC2 knockdown impairs fear memory and LTP. Fear learning selectively augments palmitoylation of AKAP150 (not PSD-95), an effect abolished by DHHC2 knockdown. DHHC2 knockdown also reduces GluA1 Ser845 phosphorylation and impairs LTP.","method":"Viral shRNA knockdown in hippocampus, fear conditioning behavior, LTP electrophysiology, palmitoylation assay, Co-immunoprecipitation","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with behavioral, electrophysiological, and biochemical readouts, single lab","pmids":["37664599"],"is_preprint":false},{"year":2024,"finding":"ZDHHC2, together with ZDHHC1, palmitoylates Gpm6a at Cys17, Cys18, and Cys246; this palmitoylation is required for Gpm6a-mediated lipid raft formation, which in turn stabilizes the Procr protein and maintains mammary stem cell activity.","method":"Knockout mouse model, palmitoylation assay with site identification by mutagenesis, lipid raft fractionation, protein stability assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with palmitoylation site mapping and defined downstream functional consequence (lipid raft formation, Procr stability), single lab","pmids":["39321020"],"is_preprint":false},{"year":2025,"finding":"ZDHHC2 mediates palmitoylation of B-RAF and C-RAF in macrophages, affecting their autophagic degradation and stabilizing their protein levels; increased B-RAF and C-RAF then activate the ERK signaling pathway, affecting intracellular survival of Mycobacterium tuberculosis.","method":"ZDHHC2 knockout/knockdown in macrophages, palmitoylation assay, autophagy assay, ERK pathway activity measurement, M. tuberculosis survival assay","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined palmitoylation substrates, autophagic degradation mechanism, and downstream ERK signaling readout, single lab","pmids":["39854453"],"is_preprint":false},{"year":2025,"finding":"ZDHHC2 promotes S-palmitoylation of the deubiquitinase USP19, which impairs USP19–ACSL4 interaction, reduces USP19-mediated ACSL4 stabilization, promotes ACSL4 ubiquitin-proteasome degradation, and consequently suppresses lipid peroxidation and ferroptosis in prostate cancer. ZDHHC2 is transcriptionally upregulated by a FOXA1/CXXC5/TET2 complex.","method":"Palmitoylation assay, Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, ZDHHC2 knockout/knockdown, patient-derived xenograft model, small-molecule inhibitor (TTZ1)","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic chain established by multiple orthogonal methods (Co-IP, ubiquitination, palmitoylation assays, PDX), single lab","pmids":["41126755"],"is_preprint":false}],"current_model":"ZDHHC2 is a DHHC-motif palmitoyl acyltransferase (PAT) that catalyzes S-palmitoylation of diverse substrates — including CKAP4, CD9, CD151, AKAP79/150, R7BP, Lck, AGK, B-RAF, C-RAF, USP19, and Gpm6a — from its dynamic residence on recycling endosomes and the plasma membrane (regulated by C-terminal dileucine and NP sorting motifs), thereby controlling substrate membrane targeting, stability, and downstream signaling in contexts ranging from synaptic plasticity (LTP via AKAP150–AMPAR axis) and immune responses (pDC IFN-α production, GC B cell differentiation, macrophage anti-mycobacterial ERK signaling) to tumor suppression and drug resistance."},"narrative":{"mechanistic_narrative":"ZDHHC2 is a DHHC-motif protein S-acyltransferase (palmitoyltransferase) that controls the membrane targeting, stability, and signaling output of a broad set of substrates by attaching palmitate to their cysteines [PMID:18508921, PMID:18296695]. Catalysis depends on an intact DHHC active site, since DH→AA or C→S mutations abolish substrate palmitoylation [PMID:18508921]. The enzyme dynamically cycles between the plasma membrane and Rab11-positive recycling endosomes, with its cytoplasmic C-terminus — including a non-canonical dileucine [SxxxLL] motif and a downstream NP motif — directing endocytic retrieval and membrane localization; deletion of the C-terminus relocates the enzyme to the ER [PMID:21471008, PMID:28768144]. Through this activity ZDHHC2 governs substrate trafficking and turnover: it palmitoylates CKAP4/p63 to drive its ER-to-plasma-membrane and nuclear localization and APF antiproliferative signaling [PMID:19144824, PMID:18296695], palmitoylates the tetraspanins CD9 and CD151 to promote their association and protect them from lysosomal degradation [PMID:18508921], and acylates R7BP and the kinase Lck to maintain their membrane association [PMID:21343290, PMID:22034844]. In neurons, ZDHHC2 resident on recycling endosomes palmitoylates AKAP79/150 to enable recycling-endosome exocytosis, dendritic spine enlargement, and AMPAR potentiation during LTP, and is upregulated by fear conditioning to selectively augment AKAP150 palmitoylation and support fear memory [PMID:25589740, PMID:37664599]. ZDHHC2 acts in immunity and infection by promoting IRF7 phosphorylation and IFN-α production in plasmacytoid dendritic cells [PMID:33488612], supporting germinal center B cell differentiation [PMID:32587588], and stabilizing B-RAF/C-RAF against autophagic degradation to drive ERK signaling that affects intracellular M. tuberculosis survival in macrophages [PMID:39854453]. In cancer it palmitoylates AGK to activate PI3K-AKT-mTOR signaling and reduce sunitinib sensitivity in renal carcinoma [PMID:37078777], and palmitoylates the deubiquitinase USP19 to destabilize ACSL4 and suppress ferroptosis in prostate cancer [PMID:41126755]. ZDHHC2 also acylates influenza A hemagglutinin and M2, and palmitoylates Gpm6a to support lipid raft formation and mammary stem cell activity [PMID:31872235, PMID:39321020].","teleology":[{"year":2008,"claim":"Establishing that ZDHHC2 is a bona fide palmitoyl acyltransferase required identifying a direct substrate; CKAP4/p63 was captured as a major substrate, defining a PAT-substrate relationship in a living vertebrate system.","evidence":"PICA palmitoyl-cysteine proteomics in living cells","pmids":["18296695"],"confidence":"Medium","gaps":["Did not establish catalytic dependence via active-site mutagenesis","Single proteomics method, single lab"]},{"year":2008,"claim":"To prove catalysis rather than mere association, active-site mutagenesis showed ZDHHC2 directly palmitoylates the tetraspanins CD9 and CD151, with DHHC-motif mutants inactive, linking acylation to substrate stability and cell-cell contact.","evidence":"Radioactive palmitate labeling, DHHC active-site mutagenesis, reciprocal Co-IP, siRNA knockdown","pmids":["18508921"],"confidence":"High","gaps":["Mechanism by which palmitoylation protects tetraspanins from lysosomal degradation not resolved","No structural basis for substrate selection"]},{"year":2009,"claim":"Loss-of-function defined the cellular consequence of CKAP4 palmitoylation: it controls ER-to-plasma-membrane and nuclear trafficking and is required for APF antiproliferative signaling.","evidence":"siRNA knockdown, immunocytochemistry, palmitoylation and proliferation assays","pmids":["19144824"],"confidence":"Medium","gaps":["Mechanism coupling palmitoylation to nuclear import unclear","Single cell-context for the signaling phenotype"]},{"year":2011,"claim":"Where ZDHHC2 acts was answered by live imaging showing dynamic cycling between plasma membrane and Rab11 recycling endosomes, with the C-terminus dictating localization distinct from the paralog DHHC15.","evidence":"Live-cell microscopy, FRAP, surface HA labeling, antibody-uptake, deletion/chimeric mutants","pmids":["21471008"],"confidence":"High","gaps":["Trafficking machinery recognizing the C-terminus not identified at this stage","Note: one study reports primarily ER/Golgi localization (#5), indicating context dependence"]},{"year":2011,"claim":"Two additional neuronal substrates extended the substrate range: ZDHHC2 mediates de novo and turnover palmitoylation of R7BP controlling its membrane-versus-nuclear distribution, and S-acylates Lck to maintain T cell kinase membrane association.","evidence":"siRNA knockdown/overexpression, palmitoylation turnover assays, subcellular fractionation","pmids":["21343290","22034844"],"confidence":"Medium","gaps":["Discrepant localization (ER/Golgi vs recycling endosome) across studies unresolved","No direct demonstration of catalytic dependence for Lck"]},{"year":2017,"claim":"The trafficking determinants were refined to a non-canonical dileucine [SxxxLL] motif and a downstream NP motif that drive endocytic retrieval, with phosphorylation potentially tuning their efficacy.","evidence":"Site-directed and phospho-mimetic mutagenesis, live-cell imaging in PC12 cells and neurons","pmids":["28768144"],"confidence":"Medium","gaps":["Endogenous kinase regulating the sorting signals not identified","Adaptor recognizing the motifs not defined"]},{"year":2015,"claim":"A causal role in synaptic plasticity was established by genetic epistasis: recycling-endosome-resident ZDHHC2 palmitoylates AKAP79/150 to enable spine enlargement and AMPAR potentiation during LTP, and a lipidation-independent AKAP mutant rescues the knockdown.","evidence":"RNAi, Co-IP, LTP electrophysiology, live imaging, epistatic rescue in hippocampal neurons","pmids":["25589740"],"confidence":"High","gaps":["How activity regulates ZDHHC2-AKAP engagement during LTP unclear","Other neuronal substrates contributing to plasticity not excluded"]},{"year":2020,"claim":"Substrate scope and physiological roles broadened to immunity and viral infection: ZDHHC2 supports germinal center B cell differentiation and is among the strongest acyltransferases for influenza A HA and M2.","evidence":"In vivo shRNA screen and B cell assays; siRNA library, Acyl-RAC, 3H-palmitate, CRISPR KO, co-localization for influenza substrates","pmids":["32587588","31872235"],"confidence":"High","gaps":["Substrate(s) mediating the B cell differentiation phenotype not identified","Specificity for influenza A versus B/C HA mechanistically unexplained"]},{"year":2021,"claim":"A signaling-level role in innate immunity was defined: ZDHHC2 is required for IRF7 phosphorylation and IFN-α production in plasmacytoid dendritic cells, with knockout mice showing reduced pDC accumulation and IFN-α in psoriatic skin.","evidence":"CRISPR/Cas9 KO mouse and human CAL-1 pDC KO, IRF7 phosphorylation assay, cytokine ELISA, flow cytometry","pmids":["33488612"],"confidence":"Medium","gaps":["Direct palmitoylation substrate linking ZDHHC2 to IRF7 phosphorylation not identified","Whether the effect requires catalytic activity not tested"]},{"year":2023,"claim":"ZDHHC2 was implicated in cancer signaling and drug resistance by palmitoylating AGK to promote its plasma-membrane translocation and PI3K-AKT-mTOR activation, lowering sunitinib sensitivity, and by augmenting AKAP150 palmitoylation upon fear learning to support memory and LTP.","evidence":"Palmitoylation and membrane translocation assays, pathway activity, tumor models; viral shRNA, fear conditioning, LTP, palmitoylation assays","pmids":["37078777","37664599"],"confidence":"Medium","gaps":["AGK palmitoylation site(s) not mapped","Whether ZDHHC2 catalytic activity is required for memory phenotype not isolated"]},{"year":2024,"claim":"Site-resolved mechanism was extended to development: ZDHHC2 (with ZDHHC1) palmitoylates Gpm6a at Cys17/18/246 to drive lipid raft formation that stabilizes Procr and sustains mammary stem cells.","evidence":"Knockout mouse, palmitoylation site mapping by mutagenesis, lipid raft fractionation, protein stability assay","pmids":["39321020"],"confidence":"Medium","gaps":["Relative contribution of ZDHHC1 versus ZDHHC2 not dissected","How raft formation stabilizes Procr mechanistically unclear"]},{"year":2025,"claim":"ZDHHC2 was placed within proteostasis-coupled signaling cascades: it palmitoylates B-RAF/C-RAF to block their autophagic degradation and sustain ERK signaling controlling M. tuberculosis survival, and palmitoylates USP19 to destabilize ACSL4 and suppress ferroptosis in prostate cancer, where ZDHHC2 is transcriptionally driven by a FOXA1/CXXC5/TET2 complex.","evidence":"ZDHHC2 KO/KD in macrophages with autophagy and ERK assays; palmitoylation, Co-IP, ubiquitination assays, PDX, small-molecule inhibitor TTZ1","pmids":["39854453","41126755"],"confidence":"Medium","gaps":["Palmitoylation sites on B-RAF/C-RAF and USP19 not fully mapped","How palmitoylation of USP19 alters its substrate engagement mechanistically incomplete"]},{"year":null,"claim":"A unifying structural and regulatory model is still missing: how ZDHHC2 selects its diverse substrates, how its localization (recycling-endosome versus ER/Golgi reports differ) dictates substrate access, and how upstream signals tune its activity across tissues remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate recognition","Localization discrepancies across studies unreconciled","Catalytic-dependence not tested for several physiological phenotypes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,9,13]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,11,14,15]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,5]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3,6]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,5]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,1,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,14,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,10,14]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[6,12]}],"complexes":[],"partners":["CKAP4","CD9","CD151","AKAP79/150","R7BP","LCK","AGK","USP19"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UIJ5","full_name":"Palmitoyltransferase ZDHHC2","aliases":["Acyltransferase ZDHHC2","Reduced expression associated with metastasis protein","Ream","Reduced expression in cancer protein","Rec","Zinc finger DHHC domain-containing protein 2","DHHC-2","Zinc finger protein 372"],"length_aa":367,"mass_kda":42.0,"function":"Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates and is involved in a variety of cellular processes (PubMed:18296695, PubMed:18508921, PubMed:19144824, PubMed:21343290, PubMed:22034844, PubMed:23793055). 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). In the nervous system, plays a role in long term synaptic potentiation by palmitoylating AKAP5 through which it regulates protein trafficking from the dendritic recycling endosomes to the plasma membrane and controls both structural and functional plasticity at excitatory synapses (By similarity). In dendrites, mediates the palmitoylation of DLG4 when synaptic activity decreases and induces synaptic clustering of DLG4 and associated AMPA-type glutamate receptors (By similarity). Also mediates the de novo and turnover palmitoylation of RGS7BP, a shuttle for Gi/o-specific GTPase-activating proteins/GAPs, promoting its localization to the plasma membrane in response to the activation of G protein-coupled receptors. Through the localization of these GTPase-activating proteins/GAPs, it also probably plays a role in G protein-coupled receptors signaling in neurons (By similarity). Also probably plays a role in cell adhesion by palmitoylating CD9 and CD151 to regulate their expression and function (PubMed:18508921). Palmitoylates the endoplasmic reticulum protein CKAP4 and regulates its localization to the plasma membrane (PubMed:18296695, PubMed:19144824). Could also palmitoylate LCK and regulate its localization to the plasma membrane (PubMed:22034844) (Microbial infection) Promotes Chikungunya virus (CHIKV) replication by mediating viral nsp1 palmitoylation","subcellular_location":"Postsynaptic density; Postsynaptic recycling endosome membrane; Cell membrane; Endoplasmic reticulum membrane; Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q9UIJ5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZDHHC2","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/ZDHHC2","total_profiled":1310},"omim":[{"mim_id":"619414","title":"MITOCHONDRIAL FISSION REGULATOR 1; MTFR1","url":"https://www.omim.org/entry/619414"},{"mim_id":"618621","title":"ZDHHC PALMITOYLTRANSFERASE 2; ZDHHC2","url":"https://www.omim.org/entry/618621"},{"mim_id":"618595","title":"CYTOSKELETON-ASSOCIATED PROTEIN 4; CKAP4","url":"https://www.omim.org/entry/618595"},{"mim_id":"602243","title":"CD151 ANTIGEN; CD151","url":"https://www.omim.org/entry/602243"},{"mim_id":"153390","title":"LCK PROTOONCOGENE, SRC FAMILY TYROSINE KINASE; LCK","url":"https://www.omim.org/entry/153390"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"retina","ntpm":72.0}],"url":"https://www.proteinatlas.org/search/ZDHHC2"},"hgnc":{"alias_symbol":["ZNF372","DHHC2"],"prev_symbol":[]},"alphafold":{"accession":"Q9UIJ5","domains":[{"cath_id":"-","chopping":"12-78_160-277","consensus_level":"high","plddt":95.0919,"start":12,"end":277},{"cath_id":"-","chopping":"82-136","consensus_level":"high","plddt":93.7249,"start":82,"end":136}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIJ5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIJ5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIJ5-F1-predicted_aligned_error_v6.png","plddt_mean":81.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZDHHC2","jax_strain_url":"https://www.jax.org/strain/search?query=ZDHHC2"},"sequence":{"accession":"Q9UIJ5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UIJ5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UIJ5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIJ5"}},"corpus_meta":[{"pmid":"18296695","id":"PMC_18296695","title":"Identification of CKAP4/p63 as a major substrate of the palmitoyl acyltransferase DHHC2, a putative tumor suppressor, using a novel proteomics method.","date":"2008","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/18296695","citation_count":96,"is_preprint":false},{"pmid":"18508921","id":"PMC_18508921","title":"DHHC2 affects palmitoylation, stability, and functions of tetraspanins CD9 and CD151.","date":"2008","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/18508921","citation_count":79,"is_preprint":false},{"pmid":"37078777","id":"PMC_37078777","title":"ZDHHC2-Mediated AGK Palmitoylation Activates AKT-mTOR Signaling to Reduce Sunitinib Sensitivity in Renal Cell Carcinoma.","date":"2023","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/37078777","citation_count":75,"is_preprint":false},{"pmid":"21471008","id":"PMC_21471008","title":"The palmitoyl transferase DHHC2 targets a dynamic membrane cycling pathway: regulation by a C-terminal domain.","date":"2011","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/21471008","citation_count":65,"is_preprint":false},{"pmid":"25589740","id":"PMC_25589740","title":"The palmitoyl acyltransferase DHHC2 regulates recycling endosome exocytosis and synaptic potentiation through palmitoylation of AKAP79/150.","date":"2015","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25589740","citation_count":61,"is_preprint":false},{"pmid":"19144824","id":"PMC_19144824","title":"Palmitoylation of cytoskeleton associated protein 4 by DHHC2 regulates antiproliferative factor-mediated signaling.","date":"2009","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/19144824","citation_count":59,"is_preprint":false},{"pmid":"26526684","id":"PMC_26526684","title":"The Plasmodium palmitoyl-S-acyl-transferase DHHC2 is essential for ookinete morphogenesis and malaria transmission.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26526684","citation_count":38,"is_preprint":false},{"pmid":"33488612","id":"PMC_33488612","title":"Zdhhc2 Is Essential for Plasmacytoid Dendritic Cells Mediated Inflammatory Response in Psoriasis.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33488612","citation_count":31,"is_preprint":false},{"pmid":"21343290","id":"PMC_21343290","title":"Gi/o signaling and the palmitoyltransferase DHHC2 regulate palmitate cycling and shuttling of RGS7 family-binding protein.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21343290","citation_count":28,"is_preprint":false},{"pmid":"24995331","id":"PMC_24995331","title":"A critical role for ZDHHC2 in metastasis and recurrence in human hepatocellular carcinoma.","date":"2014","source":"BioMed research 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Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41126755","citation_count":6,"is_preprint":false},{"pmid":"32587588","id":"PMC_32587588","title":"In vivo Screen Identifies Zdhhc2 as a Critical Regulator of Germinal Center B Cell Differentiation.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32587588","citation_count":4,"is_preprint":false},{"pmid":"39788345","id":"PMC_39788345","title":"Unraveling the potential contribution of DHHC2 in cancer biology via untargeted metabolomics.","date":"2025","source":"Biochimica et biophysica acta. 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DHHC2 physically associates with CD9 and CD151. DHHC2-dependent palmitoylation promotes CD9–CD151 associations, protects CD151 and CD9 from lysosomal degradation, and shifts cells toward increased cell–cell contacts.\",\n      \"method\": \"Radioactive palmitate labeling, site-directed mutagenesis of active site, Co-immunoprecipitation, siRNA knockdown\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — active-site mutagenesis demonstrating catalytic requirement, reciprocal Co-IP, knockdown with multiple functional readouts, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"18508921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DHHC2 localizes to the plasma membrane and Rab11-positive recycling endosomes, dynamically cycling between these compartments. Plasma membrane integration was confirmed by labeling an extrafacial HA epitope in non-permeabilized cells. FRAP analysis revealed constitutive refilling of the recycling endosome pool. The cytoplasmic C-terminus of DHHC2 regulates membrane targeting; a C-terminus deletion mutant relocates to the ER. Divergent C-terminal tail sequences distinguish DHHC2 from the closely related DHHC15 and account for their different membrane localizations.\",\n      \"method\": \"Live-cell fluorescence microscopy, FRAP, extracellular HA-epitope labeling, antibody-uptake trafficking assay, deletion/chimeric mutant analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal live-imaging methods (FRAP, surface labeling, antibody uptake), domain mutagenesis with functional localization consequence, single lab\",\n      \"pmids\": [\"21471008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DHHC2 mediates de novo and turnover palmitoylation of R7BP (RGS7 family-binding protein) in neuronal cells. DHHC2 silencing redistributes R7BP from the plasma membrane to the nucleus. Gi/o signaling inhibits R7BP depalmitoylation, stabilizing its membrane association, whereas Gi/o inactivation promotes nuclear accumulation of R7BP.\",\n      \"method\": \"siRNA knockdown, palmitoylation turnover assay, subcellular fractionation/localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined localization and palmitoylation phenotype, single lab, multiple methods\",\n      \"pmids\": [\"21343290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DHHC2 is a protein S-acyltransferase for the T cell kinase Lck. Reducing DHHC2 in Jurkat T cells by siRNA decreases Lck S-acylation and causes partial dislocation from membranes; overexpression of DHHC2 increases S-acylation of LckN10-GFP. DHHC2 localizes primarily to the ER and Golgi.\",\n      \"method\": \"siRNA knockdown, overexpression, palmitoylation assay, membrane fractionation, fluorescence localization\",\n      \"journal\": \"Molecular membrane biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (KD and OE) with palmitoylation and membrane localization readouts, single lab\",\n      \"pmids\": [\"22034844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DHHC2 (residing on recycling endosomes) interacts with and palmitoylates AKAP79/150; RNAi knockdown of DHHC2 in rat hippocampal neurons disrupts recycling endosome exocytosis, dendritic spine enlargement, AKAP recruitment to spines, and potentiation of AMPAR-mediated synaptic currents during LTP. Expression of a palmitoylation-independent lipidated AKAP mutant in DHHC2-deficient neurons largely restores plasticity, placing DHHC2 upstream of AKAP palmitoylation in LTP.\",\n      \"method\": \"RNAi knockdown, Co-immunoprecipitation, electrophysiology (LTP recording), live-cell imaging, genetic epistasis with palmitoylation-independent AKAP mutant\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis rescue experiment, reciprocal interaction, electrophysiology, multiple orthogonal methods in single study\",\n      \"pmids\": [\"25589740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Two C-terminal sorting signals in zDHHC2 — a non-canonical dileucine motif [SxxxLL] and a downstream NP motif — regulate endocytic retrieval from the plasma membrane. Mutation of these signals enhanced plasma membrane and neurite accumulation of zDHHC2 in PC12 cells and hippocampal neurons. Phospho-mimetic mutations of adjacent serine/threonine residues suggest phosphorylation may modulate efficacy of these sorting signals.\",\n      \"method\": \"Site-directed mutagenesis, fluorescence live-cell imaging, phospho-mimetic mutant analysis in PC12 cells and primary neurons\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of trafficking motifs with defined localization consequences, single lab, two cell types\",\n      \"pmids\": [\"28768144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZDHHC2 is identified as a positive regulator of germinal center (GC) B cell differentiation; Zdhhc2-shRNA transduction severely compromised B1-8hi cell differentiation into GC B cells in vivo and impaired proliferation and survival of B cells stimulated by CD40L, BAFF, and IL-21 in vitro.\",\n      \"method\": \"In vivo shRNA screen, retroviral shRNA knockdown, in vitro B cell differentiation assay, flow cytometry\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular differentiation phenotype in vivo and in vitro, single lab\",\n      \"pmids\": [\"32587588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZDHHC2, ZDHHC8, ZDHHC15, and ZDHHC20 palmitoylate Influenza A hemagglutinin (HA) and M2, with ZDHHC2 and ZDHHC8 having the strongest effect. CRISPR/Cas9 knockout of these ZDHHCs strongly reduced acylation of group 1 and group 2 HAs. These ZDHHCs co-localize with HA at membranes of the exocytic pathway. Influenza B and C virus HA are not substrates of ZDHHC2.\",\n      \"method\": \"siRNA library knockdown, Acyl-RAC assay, 3H-palmitate labeling, CRISPR/Cas9 knockout, co-localization microscopy\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — siRNA screen confirmed by CRISPR KO, orthogonal palmitoylation assays (Acyl-RAC + radiolabel), co-localization, single lab but rigorous multi-method\",\n      \"pmids\": [\"31872235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZDHHC2 is required in plasmacytoid dendritic cells (pDCs) for IRF7 phosphorylation and IFN-α production. Loss of ZDHHC2 in human CAL-1 pDCs dampened both IRF7 phosphorylation and IFN-α production. In vivo, CRISPR/Cas9 Zdhhc2-deficient mice showed dramatically reduced pDC accumulation and IFN-α in psoriatic skin following imiquimod treatment.\",\n      \"method\": \"CRISPR/Cas9 knockout mouse, siRNA/gene KO in human CAL-1 pDC cell line, phosphorylation assay (IRF7), cytokine ELISA, flow cytometry\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in both mouse model and human cell line with defined signaling (IRF7 phosphorylation) and cytokine readouts, single lab\",\n      \"pmids\": [\"33488612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZDHHC2 mediates S-palmitoylation of AGK, promoting its translocation to the plasma membrane and activation of the PI3K-AKT-mTOR signaling pathway in clear cell renal cell carcinoma, thereby reducing sunitinib sensitivity.\",\n      \"method\": \"Palmitoylation assay, subcellular fractionation/membrane translocation assay, AKT-mTOR pathway activity measurement, in vitro and in vivo tumor models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — palmitoylation assay with membrane translocation and downstream signaling readout, in vivo validation, single lab\",\n      \"pmids\": [\"37078777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DHHC2 activity in the hippocampus is upregulated after fear conditioning; DHHC2 knockdown impairs fear memory and LTP. Fear learning selectively augments palmitoylation of AKAP150 (not PSD-95), an effect abolished by DHHC2 knockdown. DHHC2 knockdown also reduces GluA1 Ser845 phosphorylation and impairs LTP.\",\n      \"method\": \"Viral shRNA knockdown in hippocampus, fear conditioning behavior, LTP electrophysiology, palmitoylation assay, Co-immunoprecipitation\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with behavioral, electrophysiological, and biochemical readouts, single lab\",\n      \"pmids\": [\"37664599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZDHHC2, together with ZDHHC1, palmitoylates Gpm6a at Cys17, Cys18, and Cys246; this palmitoylation is required for Gpm6a-mediated lipid raft formation, which in turn stabilizes the Procr protein and maintains mammary stem cell activity.\",\n      \"method\": \"Knockout mouse model, palmitoylation assay with site identification by mutagenesis, lipid raft fractionation, protein stability assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with palmitoylation site mapping and defined downstream functional consequence (lipid raft formation, Procr stability), single lab\",\n      \"pmids\": [\"39321020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZDHHC2 mediates palmitoylation of B-RAF and C-RAF in macrophages, affecting their autophagic degradation and stabilizing their protein levels; increased B-RAF and C-RAF then activate the ERK signaling pathway, affecting intracellular survival of Mycobacterium tuberculosis.\",\n      \"method\": \"ZDHHC2 knockout/knockdown in macrophages, palmitoylation assay, autophagy assay, ERK pathway activity measurement, M. tuberculosis survival assay\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined palmitoylation substrates, autophagic degradation mechanism, and downstream ERK signaling readout, single lab\",\n      \"pmids\": [\"39854453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZDHHC2 promotes S-palmitoylation of the deubiquitinase USP19, which impairs USP19–ACSL4 interaction, reduces USP19-mediated ACSL4 stabilization, promotes ACSL4 ubiquitin-proteasome degradation, and consequently suppresses lipid peroxidation and ferroptosis in prostate cancer. ZDHHC2 is transcriptionally upregulated by a FOXA1/CXXC5/TET2 complex.\",\n      \"method\": \"Palmitoylation assay, Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, ZDHHC2 knockout/knockdown, patient-derived xenograft model, small-molecule inhibitor (TTZ1)\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic chain established by multiple orthogonal methods (Co-IP, ubiquitination, palmitoylation assays, PDX), single lab\",\n      \"pmids\": [\"41126755\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZDHHC2 is a DHHC-motif palmitoyl acyltransferase (PAT) that catalyzes S-palmitoylation of diverse substrates — including CKAP4, CD9, CD151, AKAP79/150, R7BP, Lck, AGK, B-RAF, C-RAF, USP19, and Gpm6a — from its dynamic residence on recycling endosomes and the plasma membrane (regulated by C-terminal dileucine and NP sorting motifs), thereby controlling substrate membrane targeting, stability, and downstream signaling in contexts ranging from synaptic plasticity (LTP via AKAP150–AMPAR axis) and immune responses (pDC IFN-α production, GC B cell differentiation, macrophage anti-mycobacterial ERK signaling) to tumor suppression and drug resistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZDHHC2 is a DHHC-motif protein S-acyltransferase (palmitoyltransferase) that controls the membrane targeting, stability, and signaling output of a broad set of substrates by attaching palmitate to their cysteines [#2, #0]. Catalysis depends on an intact DHHC active site, since DH→AA or C→S mutations abolish substrate palmitoylation [#2]. The enzyme dynamically cycles between the plasma membrane and Rab11-positive recycling endosomes, with its cytoplasmic C-terminus — including a non-canonical dileucine [SxxxLL] motif and a downstream NP motif — directing endocytic retrieval and membrane localization; deletion of the C-terminus relocates the enzyme to the ER [#3, #7]. Through this activity ZDHHC2 governs substrate trafficking and turnover: it palmitoylates CKAP4/p63 to drive its ER-to-plasma-membrane and nuclear localization and APF antiproliferative signaling [#1, #0], palmitoylates the tetraspanins CD9 and CD151 to promote their association and protect them from lysosomal degradation [#2], and acylates R7BP and the kinase Lck to maintain their membrane association [#4, #5]. In neurons, ZDHHC2 resident on recycling endosomes palmitoylates AKAP79/150 to enable recycling-endosome exocytosis, dendritic spine enlargement, and AMPAR potentiation during LTP, and is upregulated by fear conditioning to selectively augment AKAP150 palmitoylation and support fear memory [#6, #12]. ZDHHC2 acts in immunity and infection by promoting IRF7 phosphorylation and IFN-α production in plasmacytoid dendritic cells [#10], supporting germinal center B cell differentiation [#8], and stabilizing B-RAF/C-RAF against autophagic degradation to drive ERK signaling that affects intracellular M. tuberculosis survival in macrophages [#14]. In cancer it palmitoylates AGK to activate PI3K-AKT-mTOR signaling and reduce sunitinib sensitivity in renal carcinoma [#11], and palmitoylates the deubiquitinase USP19 to destabilize ACSL4 and suppress ferroptosis in prostate cancer [#15]. ZDHHC2 also acylates influenza A hemagglutinin and M2, and palmitoylates Gpm6a to support lipid raft formation and mammary stem cell activity [#9, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing that ZDHHC2 is a bona fide palmitoyl acyltransferase required identifying a direct substrate; CKAP4/p63 was captured as a major substrate, defining a PAT-substrate relationship in a living vertebrate system.\",\n      \"evidence\": \"PICA palmitoyl-cysteine proteomics in living cells\",\n      \"pmids\": [\"18296695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish catalytic dependence via active-site mutagenesis\", \"Single proteomics method, single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"To prove catalysis rather than mere association, active-site mutagenesis showed ZDHHC2 directly palmitoylates the tetraspanins CD9 and CD151, with DHHC-motif mutants inactive, linking acylation to substrate stability and cell-cell contact.\",\n      \"evidence\": \"Radioactive palmitate labeling, DHHC active-site mutagenesis, reciprocal Co-IP, siRNA knockdown\",\n      \"pmids\": [\"18508921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which palmitoylation protects tetraspanins from lysosomal degradation not resolved\", \"No structural basis for substrate selection\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Loss-of-function defined the cellular consequence of CKAP4 palmitoylation: it controls ER-to-plasma-membrane and nuclear trafficking and is required for APF antiproliferative signaling.\",\n      \"evidence\": \"siRNA knockdown, immunocytochemistry, palmitoylation and proliferation assays\",\n      \"pmids\": [\"19144824\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling palmitoylation to nuclear import unclear\", \"Single cell-context for the signaling phenotype\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Where ZDHHC2 acts was answered by live imaging showing dynamic cycling between plasma membrane and Rab11 recycling endosomes, with the C-terminus dictating localization distinct from the paralog DHHC15.\",\n      \"evidence\": \"Live-cell microscopy, FRAP, surface HA labeling, antibody-uptake, deletion/chimeric mutants\",\n      \"pmids\": [\"21471008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking machinery recognizing the C-terminus not identified at this stage\", \"Note: one study reports primarily ER/Golgi localization (#5), indicating context dependence\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Two additional neuronal substrates extended the substrate range: ZDHHC2 mediates de novo and turnover palmitoylation of R7BP controlling its membrane-versus-nuclear distribution, and S-acylates Lck to maintain T cell kinase membrane association.\",\n      \"evidence\": \"siRNA knockdown/overexpression, palmitoylation turnover assays, subcellular fractionation\",\n      \"pmids\": [\"21343290\", \"22034844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Discrepant localization (ER/Golgi vs recycling endosome) across studies unresolved\", \"No direct demonstration of catalytic dependence for Lck\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The trafficking determinants were refined to a non-canonical dileucine [SxxxLL] motif and a downstream NP motif that drive endocytic retrieval, with phosphorylation potentially tuning their efficacy.\",\n      \"evidence\": \"Site-directed and phospho-mimetic mutagenesis, live-cell imaging in PC12 cells and neurons\",\n      \"pmids\": [\"28768144\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous kinase regulating the sorting signals not identified\", \"Adaptor recognizing the motifs not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A causal role in synaptic plasticity was established by genetic epistasis: recycling-endosome-resident ZDHHC2 palmitoylates AKAP79/150 to enable spine enlargement and AMPAR potentiation during LTP, and a lipidation-independent AKAP mutant rescues the knockdown.\",\n      \"evidence\": \"RNAi, Co-IP, LTP electrophysiology, live imaging, epistatic rescue in hippocampal neurons\",\n      \"pmids\": [\"25589740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How activity regulates ZDHHC2-AKAP engagement during LTP unclear\", \"Other neuronal substrates contributing to plasticity not excluded\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Substrate scope and physiological roles broadened to immunity and viral infection: ZDHHC2 supports germinal center B cell differentiation and is among the strongest acyltransferases for influenza A HA and M2.\",\n      \"evidence\": \"In vivo shRNA screen and B cell assays; siRNA library, Acyl-RAC, 3H-palmitate, CRISPR KO, co-localization for influenza substrates\",\n      \"pmids\": [\"32587588\", \"31872235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate(s) mediating the B cell differentiation phenotype not identified\", \"Specificity for influenza A versus B/C HA mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A signaling-level role in innate immunity was defined: ZDHHC2 is required for IRF7 phosphorylation and IFN-α production in plasmacytoid dendritic cells, with knockout mice showing reduced pDC accumulation and IFN-α in psoriatic skin.\",\n      \"evidence\": \"CRISPR/Cas9 KO mouse and human CAL-1 pDC KO, IRF7 phosphorylation assay, cytokine ELISA, flow cytometry\",\n      \"pmids\": [\"33488612\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct palmitoylation substrate linking ZDHHC2 to IRF7 phosphorylation not identified\", \"Whether the effect requires catalytic activity not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"ZDHHC2 was implicated in cancer signaling and drug resistance by palmitoylating AGK to promote its plasma-membrane translocation and PI3K-AKT-mTOR activation, lowering sunitinib sensitivity, and by augmenting AKAP150 palmitoylation upon fear learning to support memory and LTP.\",\n      \"evidence\": \"Palmitoylation and membrane translocation assays, pathway activity, tumor models; viral shRNA, fear conditioning, LTP, palmitoylation assays\",\n      \"pmids\": [\"37078777\", \"37664599\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AGK palmitoylation site(s) not mapped\", \"Whether ZDHHC2 catalytic activity is required for memory phenotype not isolated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Site-resolved mechanism was extended to development: ZDHHC2 (with ZDHHC1) palmitoylates Gpm6a at Cys17/18/246 to drive lipid raft formation that stabilizes Procr and sustains mammary stem cells.\",\n      \"evidence\": \"Knockout mouse, palmitoylation site mapping by mutagenesis, lipid raft fractionation, protein stability assay\",\n      \"pmids\": [\"39321020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of ZDHHC1 versus ZDHHC2 not dissected\", \"How raft formation stabilizes Procr mechanistically unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ZDHHC2 was placed within proteostasis-coupled signaling cascades: it palmitoylates B-RAF/C-RAF to block their autophagic degradation and sustain ERK signaling controlling M. tuberculosis survival, and palmitoylates USP19 to destabilize ACSL4 and suppress ferroptosis in prostate cancer, where ZDHHC2 is transcriptionally driven by a FOXA1/CXXC5/TET2 complex.\",\n      \"evidence\": \"ZDHHC2 KO/KD in macrophages with autophagy and ERK assays; palmitoylation, Co-IP, ubiquitination assays, PDX, small-molecule inhibitor TTZ1\",\n      \"pmids\": [\"39854453\", \"41126755\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Palmitoylation sites on B-RAF/C-RAF and USP19 not fully mapped\", \"How palmitoylation of USP19 alters its substrate engagement mechanistically incomplete\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying structural and regulatory model is still missing: how ZDHHC2 selects its diverse substrates, how its localization (recycling-endosome versus ER/Golgi reports differ) dictates substrate access, and how upstream signals tune its activity across tissues remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate recognition\", \"Localization discrepancies across studies unreconciled\", \"Catalytic-dependence not tested for several physiological phenotypes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 9, 13]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 11, 14, 15]},\n      {\"term_id\": \"GO:0016747\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 1, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 14, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 10, 14]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [6, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CKAP4\", \"CD9\", \"CD151\", \"AKAP79/150\", \"R7BP\", \"Lck\", \"AGK\", \"USP19\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}