{"gene":"ZDHHC13","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2008,"finding":"HIP14L (ZDHHC13) localizes to the Golgi and possesses palmitoyl acyltransferase (PAT) activity through its DHHC cysteine-rich domain. When expressed in Xenopus oocytes, HIP14L mediates electrogenic, voltage-dependent, saturable Mg2+ uptake (Km ~0.74 mM). Deletion of the DHHC motif reduces Mg2+ transport by ~50%, and co-expression of an independent PAT (GODZ) with the DHHC-deleted mutant restores transport, consistent with autopalmitoylation regulating Mg2+ transport activity.","method":"Xenopus oocyte expression + electrophysiology; DHHC deletion mutagenesis; GFP-fusion live imaging in epithelial cells; microarray and RT-PCR for magnesium-regulated expression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — functional reconstitution in oocytes with mutagenesis, but autopalmitoylation of HIP14L was not directly measured; single lab study","pmids":["18794299"],"is_preprint":false},{"year":2010,"finding":"Loss-of-function of Zdhhc13 (nonsense mutation R425X causing truncated protein and markedly reduced mRNA, confirmed with a second gene-trap allele) in mice causes failure to thrive, shortened lifespan, alopecia, severe osteoporosis, and systemic amyloidosis, establishing that palmitoyl acyltransferase activity of ZDHHC13 is required for diverse physiological functions in vivo.","method":"ENU mutagenesis screen; SNP homozygosity mapping; Sanger sequencing; real-time PCR; two independent loss-of-function alleles (nonsense + gene trap)","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent loss-of-function alleles producing identical phenotypes, replicated genetic evidence","pmids":["20548961"],"is_preprint":false},{"year":2012,"finding":"HIP14L (ZDHHC13) palmitoylates SNAP25 as a novel neuronal substrate. Hip14l-deficient mice develop adult-onset neuropathology and HD-like motor deficits. HIP14L interacts less with mutant HTT than wild-type HTT, indicating that mutant HTT impairs HIP14L-dependent palmitoylation of neuronal substrates.","method":"Hip14l knockout mouse characterization; behavioral assays; identification of SNAP25 as substrate by palmitoylation assay; co-immunoprecipitation of HIP14L with wild-type vs. mutant HTT","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined phenotype plus substrate identification and Co-IP; single lab","pmids":["23077216"],"is_preprint":false},{"year":2014,"finding":"HIP14L (ZDHHC13) interacts with huntingtin (HTT) amino acids 1–548 through (at least) two partial binding sites around residues 224 and 427; deletion of residues 257–315 reduces but does not abolish interaction with HIP14L-GFP, demonstrating the ankyrin repeat domain-mediated HTT–HIP14L interaction interface.","method":"Co-immunoprecipitation of HIP14L-GFP with N- and C-terminal HTT deletion constructs expressed in cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple HTT deletion constructs tested by Co-IP, single lab, no reciprocal pulldown or structural validation","pmids":["24651384"],"is_preprint":false},{"year":2014,"finding":"ZDHHC13 directly palmitoylates MT1-MMP (identified by co-immunoprecipitation and acyl-biotin exchange assay). Reduced MT1-MMP palmitoylation in Zdhhc13-deficient mice alters its subcellular distribution and is associated with decreased VEGF expression in hypertrophic chondrocytes and decreased osteocalcin at the cartilage–bone interface, linking ZDHHC13-mediated palmitoylation to endochondral ossification and bone mass acquisition.","method":"Co-immunoprecipitation; acyl-biotin exchange (ABE) assay; microCT skeletal analysis; immunohistochemistry in Zdhhc13 mutant mouse epiphysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ABE assay plus Co-IP confirm direct substrate; in vivo phenotype in KO mouse; single lab","pmids":["24637783"],"is_preprint":false},{"year":2015,"finding":"A spontaneous nonsense mutation in Zdhhc13 (Zdhhc13luc) producing a truncated, loss-of-function protein causes epidermal hyperplasia, hyperkeratosis, constitutive NF-κB (RelA) activation, increased neutrophil recruitment, and markedly increased tumor multiplicity and malignant progression after chemical skin carcinogenesis, demonstrating that ZDHHC13 PAT activity suppresses skin carcinogenesis.","method":"Spontaneous mutant mouse characterization; sequencing; immunohistochemistry for NF-κB/RelA and neutrophil markers; DMBA/TPA chemical carcinogenesis protocol; comparison with WT littermates","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined loss-of-function allele with specific cellular and tumor phenotype readouts; single lab, no direct molecular substrate identified for skin carcinogenesis pathway","pmids":["26288350"],"is_preprint":false},{"year":2016,"finding":"ZDHHC13 is required for skin barrier integrity; its deficiency renders mice susceptible to environmental bacteria, causing persistent skin inflammation and atopic dermatitis-like disease driven by innate immunity. The phenotype is ameliorated in germ-free conditions and by antibiotics but not by Rag1 deletion, placing ZDHHC13 upstream of innate (not adaptive) immune activation, with elevated IL-33 and type 2 innate lymphoid cells.","method":"Zdhhc13-deficient mouse model; germ-free housing; antibiotic treatment; Rag1 knockout epistasis; immunohistochemistry/ELISA for IL-33 and ILC2 markers","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (Rag1 deletion) places ZDHHC13 in innate immune pathway; multiple intervention experiments; single lab","pmids":["28017833"],"is_preprint":false},{"year":2017,"finding":"ZDHHC13 palmitoylates MCAT and CTNND1 as confirmed substrates in liver (validated by site-specific quantitative S-palmitoylome using alkylating resin-assisted capture + MS). Loss of Zdhhc13 reduces S-palmitoylation of 400 sites on 254 proteins (enriched for lipid metabolism and mitochondrial proteins), impairs mitochondrial function in hepatocytes, and causes abnormal lipid metabolism and hypermetabolism.","method":"Alkylating resin-assisted capture (SRAC) + label-free MS for palmitoylome; TMT10-plex membrane proteome normalization; Zdhhc13-deficient mouse liver; Zdhhc13-knockdown Hep1-6 cells; mitochondrial function assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — quantitative palmitoylome with orthogonal substrate confirmation, both in vivo KO and in vitro KD, multiple orthogonal methods","pmids":["28526873"],"is_preprint":false},{"year":2017,"finding":"ZDHHC13 directly interacts with and S-palmitoylates Drp1 in cortex and cerebellum (confirmed by in vivo and in vitro Co-IP and palmitoylation assays). Loss of Zdhhc13 reduces Drp1 S-palmitoylation, alters mitochondrial fission–fusion dynamics, increases glycolysis and glutaminolysis (lactic acidosis), causes neurotransmitter imbalances, and produces anxiety, hypoactivity, and impaired motor coordination in Zdhhc13-mutant mice.","method":"In vivo and in vitro Co-IP; palmitoylation assay; mitochondrial morphology imaging; behavioral assays; metabolic profiling (glycolysis, glutaminolysis, lactate) in Zdhhc13 mutant mouse brain","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct substrate confirmation by multiple methods (Co-IP in vivo and in vitro + palmitoylation assay), functional readouts in KO model","pmids":["29038583"],"is_preprint":false},{"year":2019,"finding":"ZDHHC13 enzymatic palmitoylation activity (not protein scaffolding) is required for skin barrier integrity, demonstrated by knock-in mice bearing a catalytically dead DQ-to-AA DHHC mutation phenocopying the knockout. ZDHHC13 palmitoylates loricrin, peptidyl arginine deiminase type III (PADi3), and transglutaminase 1 (TGM1); palmitoylation of PADi3 and TGM1 controls their in vivo protein stability.","method":"Catalytic dead knock-in mouse (DQ→AA DHHC mutation); quantitative proteomics for palmitoylome; ABE/biochemical palmitoylation assay confirming three substrates; protein stability analysis in vivo","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site mutagenesis knock-in phenocopies KO; multiple orthogonal methods (proteomics + biochemical assay) confirming substrates; protein stability mechanistically linked","pmids":["31669413"],"is_preprint":false},{"year":2023,"finding":"AMPK phosphorylates ZDHHC13 at serine 208 (S208), which strengthens the interaction between ZDHHC13 and MC1R red-hair-color (RHC) variants, leading to enhanced MC1R palmitoylation. AMPK-mediated phosphorylation of ZDHHC13 increases MC1R downstream signaling (cAMP/MITF pathway) and suppresses UVB-induced melanocyte transformation in vitro and delays melanomagenesis in vivo in MC1R-RHC mice.","method":"In vitro kinase assay (AMPK phosphorylation of ZDHHC13 at S208); Co-IP (ZDHHC13–MC1R interaction with phospho-mimetic/dead mutants); palmitoylation assay; UVB transformation assay; C57BL/6J-MC1R-RHC mouse melanomagenesis model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay identifies specific phosphosite, mutagenesis confirms functional role, in vivo mouse model validates suppression of melanomagenesis","pmids":["36701140"],"is_preprint":false},{"year":2024,"finding":"ZDHHC13 palmitoylates ULK1, enabling translocation of the ULK1-FIP200-ATG13-ATG101 complex from cytosol to autophagosome formation sites upon autophagy induction. ULK1 palmitoylation is required for autophagy initiation; palmitoylated ULK1 enhances phosphorylation of ATG14L, activating PI3-kinase and producing PI3P needed for autophagosome membrane formation.","method":"Palmitoylation assay confirming ULK1 as ZDHHC13 substrate; live-cell imaging of ULK1 translocation; genetic epistasis/hierarchical analysis; ATG14L phosphorylation assay; PI3P lipid detection","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct substrate identification, translocation assay, downstream signaling (ATG14L phosphorylation, PI3P) mechanistically linked, multiple orthogonal methods","pmids":["39169022"],"is_preprint":false},{"year":2025,"finding":"ZDHHC13 palmitoylates CTNND1 (p120-catenin), stabilizing E-cadherin at the plasma membrane to suppress epithelial-to-mesenchymal transition and metastatic dissemination of melanoma cells. Additionally, ZDHHC13 suppresses lysophosphatidylcholine (LPC) synthesis in melanoma cells, thereby inhibiting M2-like tumor-associated macrophage polarization and MMP12-dependent E-cadherin degradation, reshaping the tumor immune microenvironment.","method":"Palmitoylation assay confirming CTNND1 as ZDHHC13 substrate; E-cadherin co-immunoprecipitation/stability assay; lipidomics (LPC quantification); macrophage co-culture assays; MMP12 activity measurement; immunocompetent mouse melanoma metastasis model","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (palmitoylation assay, lipidomics, in vivo model), single lab, published 2025","pmids":["41321310"],"is_preprint":false},{"year":2025,"finding":"Patsas (Drosophila ortholog of HIP14L/ZDHHC13) and Hip14 are rate-limiting factors for lysosome formation and fusion. In larval salivary glands, loss of Patsas or Hip14 disrupts secretory granule–lysosome fusion, lysosomal acidification, and biosynthetic transport of lysosomal hydrolases. Constitutively active Rab2 GTPase overexpression rescues lysosomal dysfunction caused by Patsas or Hip14 loss, placing these PATs upstream of Rab2-mediated lysosomal biogenesis.","method":"Drosophila larval salivary gland RNAi knockdown; lysosomal acidification assay; lysosomal hydrolase trafficking; genetic epistasis with constitutively active Rab2; neuromuscular function assays in Hip14 KO adults","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (Rab2 rescue) places PATs upstream of lysosomal fusions; multiple organelle trafficking readouts; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.02.06.636816"],"is_preprint":true}],"current_model":"ZDHHC13 is a Golgi-resident palmitoyl acyltransferase (PAT) whose DHHC catalytic domain S-palmitoylates a broad array of substrates—including HTT, SNAP25, Drp1, MT1-MMP, MCAT, CTNND1, ULK1, PADi3, TGM1, loricrin, and MC1R—thereby regulating mitochondrial dynamics and bioenergetics, autophagosome formation, lysosomal biogenesis, skin barrier integrity, bone homeostasis, and melanoma suppression; its enzymatic activity is further regulated by AMPK-mediated phosphorylation at S208, which enhances its interaction with MC1R variants to boost downstream pigmentation signaling."},"narrative":{"mechanistic_narrative":"ZDHHC13 (HIP14L) is a Golgi-resident DHHC-family palmitoyl acyltransferase that S-palmitoylates a broad substrate repertoire to control mitochondrial dynamics, autophagy, epithelial integrity, and tumor suppression [PMID:18794299, PMID:28526873]. Its cysteine-rich DHHC catalytic domain confers enzymatic activity, and active-site (DQ→AA) knock-in mice phenocopy the null, establishing that it is the palmitoyltransferase activity—not protein scaffolding—that underlies its physiological roles [PMID:31669413]. In the nervous system it palmitoylates SNAP25 and Drp1, and loss of activity perturbs mitochondrial fission–fusion balance, shifts metabolism toward glycolysis and glutaminolysis, and produces HD-like motor and behavioral deficits; its interaction with huntingtin is mediated through an ankyrin-repeat interface and is weakened by mutant HTT [PMID:23077216, PMID:24651384, PMID:29038583]. In liver, quantitative palmitoylome profiling shows ZDHHC13 governs hundreds of palmitoylation sites enriched for lipid-metabolic and mitochondrial proteins, including MCAT and CTNND1 [PMID:28526873]. It initiates autophagy by palmitoylating ULK1, driving translocation of the ULK1–FIP200–ATG13–ATG101 complex to autophagosome formation sites and downstream ATG14L phosphorylation and PI3P generation [PMID:39169022]. In skin, ZDHHC13 palmitoylates loricrin, PADi3, and TGM1—controlling the stability of PADi3 and TGM1—to maintain barrier integrity, and its loss causes hyperkeratosis, constitutive NF-κB activation, innate-immune–driven atopic dermatitis, and enhanced chemical skin carcinogenesis [PMID:26288350, PMID:28017833, PMID:31669413]. It also acts as a melanoma suppressor: AMPK phosphorylation at S208 strengthens binding to MC1R red-hair-color variants to boost MC1R palmitoylation and cAMP/MITF signaling, while CTNND1 palmitoylation stabilizes E-cadherin to restrain EMT and metastasis [PMID:36701140, PMID:41321310]. In vivo, loss-of-function mutations cause failure to thrive, alopecia, severe osteoporosis, and systemic amyloidosis, with skeletal defects linked to reduced palmitoylation of MT1-MMP [PMID:20548961, PMID:24637783].","teleology":[{"year":2008,"claim":"Established that ZDHHC13/HIP14L is a Golgi-localized DHHC palmitoyl acyltransferase, defining its core enzymatic identity and subcellular niche.","evidence":"Xenopus oocyte expression with electrophysiology, DHHC-deletion mutagenesis, and GFP-fusion live imaging in epithelial cells","pmids":["18794299"],"confidence":"Medium","gaps":["Autopalmitoylation of HIP14L was inferred but not directly measured","Physiological substrates not identified at this stage","Mg2+ transport role rests on heterologous oocyte reconstitution"]},{"year":2010,"claim":"Demonstrated that ZDHHC13 is required for diverse physiological functions in vivo, moving it from a biochemical activity to an organism-level determinant of growth, skin, bone, and protein homeostasis.","evidence":"ENU mutagenesis nonsense allele plus independent gene-trap allele in mice with homozygosity mapping","pmids":["20548961"],"confidence":"High","gaps":["Molecular substrates underlying each phenotype not yet defined","Does not distinguish enzymatic from scaffolding contributions"]},{"year":2012,"claim":"Identified SNAP25 as a neuronal substrate and linked ZDHHC13 to huntingtin biology, framing it as a palmitoyltransferase whose dysfunction contributes to HD-like neuropathology.","evidence":"Hip14l knockout mouse behavioral characterization, palmitoylation assay, and Co-IP of HIP14L with WT vs mutant HTT","pmids":["23077216"],"confidence":"Medium","gaps":["Direct demonstration that SNAP25 hypopalmitoylation causes the motor phenotype not established","Single lab"]},{"year":2014,"claim":"Mapped the HTT–HIP14L interaction interface and identified MT1-MMP as a direct substrate, connecting ZDHHC13 palmitoylation to skeletal development.","evidence":"Co-IP with HTT deletion constructs; ABE assay and Co-IP for MT1-MMP; microCT and IHC in Zdhhc13 mutant epiphysis","pmids":["24651384","24637783"],"confidence":"Medium","gaps":["HTT interaction lacks reciprocal pulldown or structural validation","Link between MT1-MMP palmitoylation and ossification is correlative in vivo"]},{"year":2015,"claim":"Showed ZDHHC13 PAT activity suppresses skin carcinogenesis, establishing a tumor-suppressive role tied to epidermal homeostasis and NF-κB control.","evidence":"Spontaneous loss-of-function mutant mouse with DMBA/TPA carcinogenesis, IHC for NF-κB/RelA and neutrophils","pmids":["26288350"],"confidence":"Medium","gaps":["No molecular substrate identified for the skin carcinogenesis pathway","Mechanism linking palmitoylation to NF-κB activation unresolved"]},{"year":2016,"claim":"Placed ZDHHC13 upstream of innate (not adaptive) immune activation in skin barrier maintenance, explaining its dermatitis phenotype as microbiota-driven.","evidence":"Germ-free housing, antibiotics, and Rag1 knockout epistasis in Zdhhc13-deficient mice with IL-33/ILC2 readouts","pmids":["28017833"],"confidence":"Medium","gaps":["Specific palmitoylated barrier substrate not yet identified here","Mechanism connecting barrier defect to IL-33 induction unclear"]},{"year":2017,"claim":"Defined the global hepatic palmitoylome of ZDHHC13 and confirmed Drp1, MCAT, and CTNND1 substrates, establishing its central role in mitochondrial dynamics and lipid/energy metabolism.","evidence":"Resin-assisted capture + MS palmitoylome, in vivo and in vitro Co-IP and palmitoylation assays, mitochondrial and metabolic profiling in KO/KD models","pmids":["28526873","29038583"],"confidence":"High","gaps":["Which of the 400 sites are direct versus indirect not all resolved","Causal hierarchy among metabolic phenotypes not fully dissected"]},{"year":2019,"claim":"Proved that catalytic palmitoyltransferase activity—not scaffolding—drives skin barrier function and identified loricrin, PADi3, and TGM1 as substrates whose stability ZDHHC13 controls.","evidence":"Catalytic-dead DQ→AA DHHC knock-in mouse phenocopying KO, quantitative palmitoylome, biochemical substrate confirmation, in vivo protein stability analysis","pmids":["31669413"],"confidence":"High","gaps":["How palmitoylation stabilizes PADi3/TGM1 mechanistically not detailed","Single lab"]},{"year":2023,"claim":"Revealed regulatory control of ZDHHC13 by AMPK phosphorylation at S208, linking metabolic signaling to MC1R palmitoylation and melanoma suppression.","evidence":"In vitro AMPK kinase assay, phospho-mutant Co-IP, palmitoylation and UVB transformation assays, MC1R-RHC mouse melanomagenesis model","pmids":["36701140"],"confidence":"High","gaps":["Upstream signals activating AMPK toward ZDHHC13 in melanocytes not defined","Structural basis of S208-dependent MC1R binding unknown"]},{"year":2024,"claim":"Established ZDHHC13 as an initiator of autophagy via ULK1 palmitoylation, providing a molecular trigger for autophagosome nucleation.","evidence":"Palmitoylation assay, live-cell ULK1 translocation imaging, genetic hierarchy analysis, ATG14L phosphorylation and PI3P detection","pmids":["39169022"],"confidence":"High","gaps":["Whether autophagy defects contribute to the in vivo ZDHHC13 phenotypes not tested","Site of ULK1 palmitoylation relative to its activation not fully mapped"]},{"year":2025,"claim":"Extended ZDHHC13 melanoma suppression to a dual mechanism—CTNND1 palmitoylation stabilizing E-cadherin and LPC suppression reshaping the tumor immune microenvironment—to restrain EMT and metastasis.","evidence":"Palmitoylation and E-cadherin stability assays, lipidomics, macrophage co-culture, MMP12 activity, immunocompetent melanoma metastasis model","pmids":["41321310"],"confidence":"Medium","gaps":["How ZDHHC13 controls LPC synthesis mechanistically not defined","Single lab, recent publication"]},{"year":2025,"claim":"Implicated ZDHHC13 orthologs in lysosomal biogenesis, placing these PATs upstream of Rab2-mediated lysosome formation and fusion.","evidence":"Drosophila salivary gland RNAi, lysosomal acidification and hydrolase trafficking assays, constitutively active Rab2 rescue (preprint)","pmids":["bio_10.1101_2025.02.06.636816"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Direct palmitoylated substrate in the Rab2 lysosomal pathway not identified","Conservation of this role in mammalian ZDHHC13 not tested"]},{"year":null,"claim":"How a single Golgi palmitoyltransferase coordinates such divergent substrate sets and tissue programs—and what determines substrate selectivity and spatial targeting—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ZDHHC13 substrate recognition","Rules governing tissue-specific substrate choice unknown","Relative contribution of each substrate to the systemic in vivo phenotypes not dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,4,7,8,9,11,12]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,7,9]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,10,12]}],"complexes":[],"partners":["HTT","SNAP25","DNM1L","MMP14","CTNND1","ULK1","MC1R","TGM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IUH4","full_name":"Palmitoyltransferase ZDHHC13","aliases":["Huntingtin-interacting protein 14-related protein","HIP14-related protein","Huntingtin-interacting protein HIP3RP","Putative MAPK-activating protein PM03","Putative NF-kappa-B-activating protein 209","Zinc finger DHHC domain-containing protein 13","DHHC-13"],"length_aa":622,"mass_kda":70.9,"function":"Palmitoyltransferase that could catalyze the addition of palmitate onto various protein substrates (By similarity). Palmitoyltransferase for HTT and GAD2. May play a role in Mg(2+) transport","subcellular_location":"Golgi apparatus membrane; Cytoplasmic vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q8IUH4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZDHHC13","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/ZDHHC13","total_profiled":1310},"omim":[{"mim_id":"612815","title":"ZDHHC PALMITOYLTRANSFERASE 13; ZDHHC13","url":"https://www.omim.org/entry/612815"},{"mim_id":"607799","title":"ZDHHC PALMITOYLTRANSFERASE 17; ZDHHC17","url":"https://www.omim.org/entry/607799"},{"mim_id":"155555","title":"MELANOCORTIN 1 RECEPTOR; MC1R","url":"https://www.omim.org/entry/155555"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZDHHC13"},"hgnc":{"alias_symbol":["FLJ10852","FLJ10941","HIP14L"],"prev_symbol":[]},"alphafold":{"accession":"Q8IUH4","domains":[{"cath_id":"1.25.40.20","chopping":"47-174","consensus_level":"medium","plddt":96.4328,"start":47,"end":174},{"cath_id":"-","chopping":"341-394_440-575","consensus_level":"medium","plddt":90.5034,"start":341,"end":575}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IUH4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IUH4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IUH4-F1-predicted_aligned_error_v6.png","plddt_mean":87.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZDHHC13","jax_strain_url":"https://www.jax.org/strain/search?query=ZDHHC13"},"sequence":{"accession":"Q8IUH4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IUH4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IUH4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IUH4"}},"corpus_meta":[{"pmid":"28526873","id":"PMC_28526873","title":"Role of S-Palmitoylation by ZDHHC13 in Mitochondrial function and Metabolism in Liver.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28526873","citation_count":71,"is_preprint":false},{"pmid":"20548961","id":"PMC_20548961","title":"Mice with alopecia, osteoporosis, and systemic amyloidosis due to mutation in Zdhhc13, a gene coding for palmitoyl acyltransferase.","date":"2010","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20548961","citation_count":69,"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":"23077216","id":"PMC_23077216","title":"Hip14l-deficient mice develop neuropathological and behavioural features of Huntington disease.","date":"2012","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23077216","citation_count":62,"is_preprint":false},{"pmid":"29038583","id":"PMC_29038583","title":"Zdhhc13-dependent Drp1 S-palmitoylation impacts brain bioenergetics, anxiety, coordination and motor skills.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29038583","citation_count":47,"is_preprint":false},{"pmid":"39169022","id":"PMC_39169022","title":"Palmitoylation of ULK1 by ZDHHC13 plays a crucial role in autophagy.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39169022","citation_count":32,"is_preprint":false},{"pmid":"24637783","id":"PMC_24637783","title":"Palmitoyl acyltransferase, Zdhhc13, facilitates bone mass acquisition by regulating postnatal epiphyseal development and endochondral ossification: a mouse model.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24637783","citation_count":31,"is_preprint":false},{"pmid":"26288350","id":"PMC_26288350","title":"Increased Susceptibility to Skin Carcinogenesis Associated with a Spontaneous Mouse Mutation in the Palmitoyl Transferase Zdhhc13 Gene.","date":"2015","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/26288350","citation_count":28,"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":"36701140","id":"PMC_36701140","title":"AMPK Phosphorylates ZDHHC13 to Increase MC1R Activity and Suppress Melanomagenesis.","date":"2023","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/36701140","citation_count":23,"is_preprint":false},{"pmid":"31669413","id":"PMC_31669413","title":"Palmitoyl Acyltransferase Activity of ZDHHC13 Regulates Skin Barrier Development Partly by Controlling PADi3 and TGM1 Protein Stability.","date":"2019","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/31669413","citation_count":21,"is_preprint":false},{"pmid":"28017833","id":"PMC_28017833","title":"Protein Palmitoylation by ZDHHC13 Protects Skin against Microbial-Driven Dermatitis.","date":"2016","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/28017833","citation_count":17,"is_preprint":false},{"pmid":"40088380","id":"PMC_40088380","title":"DNA Methylation-Regulated ZDHHC13 Promotes the Progression of Parkinson's Disease.","date":"2025","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/40088380","citation_count":2,"is_preprint":false},{"pmid":"40711616","id":"PMC_40711616","title":"ZDHHC13 Reduces the Risk of Ischemic Stroke by Regulating Metabolites.","date":"2025","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/40711616","citation_count":2,"is_preprint":false},{"pmid":"41321310","id":"PMC_41321310","title":"S-acyl transferase ZDHHC13 modulates tumor microenvironment interactions to suppress metastasis in melanoma models.","date":"2025","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/41321310","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":11178,"output_tokens":4362,"usd":0.049482,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12368,"output_tokens":4426,"usd":0.086245,"stage2_stop_reason":"end_turn"},"total_usd":0.135727,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"HIP14L (ZDHHC13) localizes to the Golgi and possesses palmitoyl acyltransferase (PAT) activity through its DHHC cysteine-rich domain. When expressed in Xenopus oocytes, HIP14L mediates electrogenic, voltage-dependent, saturable Mg2+ uptake (Km ~0.74 mM). Deletion of the DHHC motif reduces Mg2+ transport by ~50%, and co-expression of an independent PAT (GODZ) with the DHHC-deleted mutant restores transport, consistent with autopalmitoylation regulating Mg2+ transport activity.\",\n      \"method\": \"Xenopus oocyte expression + electrophysiology; DHHC deletion mutagenesis; GFP-fusion live imaging in epithelial cells; microarray and RT-PCR for magnesium-regulated expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — functional reconstitution in oocytes with mutagenesis, but autopalmitoylation of HIP14L was not directly measured; single lab study\",\n      \"pmids\": [\"18794299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss-of-function of Zdhhc13 (nonsense mutation R425X causing truncated protein and markedly reduced mRNA, confirmed with a second gene-trap allele) in mice causes failure to thrive, shortened lifespan, alopecia, severe osteoporosis, and systemic amyloidosis, establishing that palmitoyl acyltransferase activity of ZDHHC13 is required for diverse physiological functions in vivo.\",\n      \"method\": \"ENU mutagenesis screen; SNP homozygosity mapping; Sanger sequencing; real-time PCR; two independent loss-of-function alleles (nonsense + gene trap)\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent loss-of-function alleles producing identical phenotypes, replicated genetic evidence\",\n      \"pmids\": [\"20548961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HIP14L (ZDHHC13) palmitoylates SNAP25 as a novel neuronal substrate. Hip14l-deficient mice develop adult-onset neuropathology and HD-like motor deficits. HIP14L interacts less with mutant HTT than wild-type HTT, indicating that mutant HTT impairs HIP14L-dependent palmitoylation of neuronal substrates.\",\n      \"method\": \"Hip14l knockout mouse characterization; behavioral assays; identification of SNAP25 as substrate by palmitoylation assay; co-immunoprecipitation of HIP14L with wild-type vs. mutant HTT\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined phenotype plus substrate identification and Co-IP; single lab\",\n      \"pmids\": [\"23077216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HIP14L (ZDHHC13) interacts with huntingtin (HTT) amino acids 1–548 through (at least) two partial binding sites around residues 224 and 427; deletion of residues 257–315 reduces but does not abolish interaction with HIP14L-GFP, demonstrating the ankyrin repeat domain-mediated HTT–HIP14L interaction interface.\",\n      \"method\": \"Co-immunoprecipitation of HIP14L-GFP with N- and C-terminal HTT deletion constructs expressed in cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple HTT deletion constructs tested by Co-IP, single lab, no reciprocal pulldown or structural validation\",\n      \"pmids\": [\"24651384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ZDHHC13 directly palmitoylates MT1-MMP (identified by co-immunoprecipitation and acyl-biotin exchange assay). Reduced MT1-MMP palmitoylation in Zdhhc13-deficient mice alters its subcellular distribution and is associated with decreased VEGF expression in hypertrophic chondrocytes and decreased osteocalcin at the cartilage–bone interface, linking ZDHHC13-mediated palmitoylation to endochondral ossification and bone mass acquisition.\",\n      \"method\": \"Co-immunoprecipitation; acyl-biotin exchange (ABE) assay; microCT skeletal analysis; immunohistochemistry in Zdhhc13 mutant mouse epiphysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ABE assay plus Co-IP confirm direct substrate; in vivo phenotype in KO mouse; single lab\",\n      \"pmids\": [\"24637783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A spontaneous nonsense mutation in Zdhhc13 (Zdhhc13luc) producing a truncated, loss-of-function protein causes epidermal hyperplasia, hyperkeratosis, constitutive NF-κB (RelA) activation, increased neutrophil recruitment, and markedly increased tumor multiplicity and malignant progression after chemical skin carcinogenesis, demonstrating that ZDHHC13 PAT activity suppresses skin carcinogenesis.\",\n      \"method\": \"Spontaneous mutant mouse characterization; sequencing; immunohistochemistry for NF-κB/RelA and neutrophil markers; DMBA/TPA chemical carcinogenesis protocol; comparison with WT littermates\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined loss-of-function allele with specific cellular and tumor phenotype readouts; single lab, no direct molecular substrate identified for skin carcinogenesis pathway\",\n      \"pmids\": [\"26288350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ZDHHC13 is required for skin barrier integrity; its deficiency renders mice susceptible to environmental bacteria, causing persistent skin inflammation and atopic dermatitis-like disease driven by innate immunity. The phenotype is ameliorated in germ-free conditions and by antibiotics but not by Rag1 deletion, placing ZDHHC13 upstream of innate (not adaptive) immune activation, with elevated IL-33 and type 2 innate lymphoid cells.\",\n      \"method\": \"Zdhhc13-deficient mouse model; germ-free housing; antibiotic treatment; Rag1 knockout epistasis; immunohistochemistry/ELISA for IL-33 and ILC2 markers\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (Rag1 deletion) places ZDHHC13 in innate immune pathway; multiple intervention experiments; single lab\",\n      \"pmids\": [\"28017833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZDHHC13 palmitoylates MCAT and CTNND1 as confirmed substrates in liver (validated by site-specific quantitative S-palmitoylome using alkylating resin-assisted capture + MS). Loss of Zdhhc13 reduces S-palmitoylation of 400 sites on 254 proteins (enriched for lipid metabolism and mitochondrial proteins), impairs mitochondrial function in hepatocytes, and causes abnormal lipid metabolism and hypermetabolism.\",\n      \"method\": \"Alkylating resin-assisted capture (SRAC) + label-free MS for palmitoylome; TMT10-plex membrane proteome normalization; Zdhhc13-deficient mouse liver; Zdhhc13-knockdown Hep1-6 cells; mitochondrial function assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — quantitative palmitoylome with orthogonal substrate confirmation, both in vivo KO and in vitro KD, multiple orthogonal methods\",\n      \"pmids\": [\"28526873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZDHHC13 directly interacts with and S-palmitoylates Drp1 in cortex and cerebellum (confirmed by in vivo and in vitro Co-IP and palmitoylation assays). Loss of Zdhhc13 reduces Drp1 S-palmitoylation, alters mitochondrial fission–fusion dynamics, increases glycolysis and glutaminolysis (lactic acidosis), causes neurotransmitter imbalances, and produces anxiety, hypoactivity, and impaired motor coordination in Zdhhc13-mutant mice.\",\n      \"method\": \"In vivo and in vitro Co-IP; palmitoylation assay; mitochondrial morphology imaging; behavioral assays; metabolic profiling (glycolysis, glutaminolysis, lactate) in Zdhhc13 mutant mouse brain\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct substrate confirmation by multiple methods (Co-IP in vivo and in vitro + palmitoylation assay), functional readouts in KO model\",\n      \"pmids\": [\"29038583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZDHHC13 enzymatic palmitoylation activity (not protein scaffolding) is required for skin barrier integrity, demonstrated by knock-in mice bearing a catalytically dead DQ-to-AA DHHC mutation phenocopying the knockout. ZDHHC13 palmitoylates loricrin, peptidyl arginine deiminase type III (PADi3), and transglutaminase 1 (TGM1); palmitoylation of PADi3 and TGM1 controls their in vivo protein stability.\",\n      \"method\": \"Catalytic dead knock-in mouse (DQ→AA DHHC mutation); quantitative proteomics for palmitoylome; ABE/biochemical palmitoylation assay confirming three substrates; protein stability analysis in vivo\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site mutagenesis knock-in phenocopies KO; multiple orthogonal methods (proteomics + biochemical assay) confirming substrates; protein stability mechanistically linked\",\n      \"pmids\": [\"31669413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AMPK phosphorylates ZDHHC13 at serine 208 (S208), which strengthens the interaction between ZDHHC13 and MC1R red-hair-color (RHC) variants, leading to enhanced MC1R palmitoylation. AMPK-mediated phosphorylation of ZDHHC13 increases MC1R downstream signaling (cAMP/MITF pathway) and suppresses UVB-induced melanocyte transformation in vitro and delays melanomagenesis in vivo in MC1R-RHC mice.\",\n      \"method\": \"In vitro kinase assay (AMPK phosphorylation of ZDHHC13 at S208); Co-IP (ZDHHC13–MC1R interaction with phospho-mimetic/dead mutants); palmitoylation assay; UVB transformation assay; C57BL/6J-MC1R-RHC mouse melanomagenesis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay identifies specific phosphosite, mutagenesis confirms functional role, in vivo mouse model validates suppression of melanomagenesis\",\n      \"pmids\": [\"36701140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZDHHC13 palmitoylates ULK1, enabling translocation of the ULK1-FIP200-ATG13-ATG101 complex from cytosol to autophagosome formation sites upon autophagy induction. ULK1 palmitoylation is required for autophagy initiation; palmitoylated ULK1 enhances phosphorylation of ATG14L, activating PI3-kinase and producing PI3P needed for autophagosome membrane formation.\",\n      \"method\": \"Palmitoylation assay confirming ULK1 as ZDHHC13 substrate; live-cell imaging of ULK1 translocation; genetic epistasis/hierarchical analysis; ATG14L phosphorylation assay; PI3P lipid detection\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct substrate identification, translocation assay, downstream signaling (ATG14L phosphorylation, PI3P) mechanistically linked, multiple orthogonal methods\",\n      \"pmids\": [\"39169022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZDHHC13 palmitoylates CTNND1 (p120-catenin), stabilizing E-cadherin at the plasma membrane to suppress epithelial-to-mesenchymal transition and metastatic dissemination of melanoma cells. Additionally, ZDHHC13 suppresses lysophosphatidylcholine (LPC) synthesis in melanoma cells, thereby inhibiting M2-like tumor-associated macrophage polarization and MMP12-dependent E-cadherin degradation, reshaping the tumor immune microenvironment.\",\n      \"method\": \"Palmitoylation assay confirming CTNND1 as ZDHHC13 substrate; E-cadherin co-immunoprecipitation/stability assay; lipidomics (LPC quantification); macrophage co-culture assays; MMP12 activity measurement; immunocompetent mouse melanoma metastasis model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (palmitoylation assay, lipidomics, in vivo model), single lab, published 2025\",\n      \"pmids\": [\"41321310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Patsas (Drosophila ortholog of HIP14L/ZDHHC13) and Hip14 are rate-limiting factors for lysosome formation and fusion. In larval salivary glands, loss of Patsas or Hip14 disrupts secretory granule–lysosome fusion, lysosomal acidification, and biosynthetic transport of lysosomal hydrolases. Constitutively active Rab2 GTPase overexpression rescues lysosomal dysfunction caused by Patsas or Hip14 loss, placing these PATs upstream of Rab2-mediated lysosomal biogenesis.\",\n      \"method\": \"Drosophila larval salivary gland RNAi knockdown; lysosomal acidification assay; lysosomal hydrolase trafficking; genetic epistasis with constitutively active Rab2; neuromuscular function assays in Hip14 KO adults\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (Rab2 rescue) places PATs upstream of lysosomal fusions; multiple organelle trafficking readouts; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.02.06.636816\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ZDHHC13 is a Golgi-resident palmitoyl acyltransferase (PAT) whose DHHC catalytic domain S-palmitoylates a broad array of substrates—including HTT, SNAP25, Drp1, MT1-MMP, MCAT, CTNND1, ULK1, PADi3, TGM1, loricrin, and MC1R—thereby regulating mitochondrial dynamics and bioenergetics, autophagosome formation, lysosomal biogenesis, skin barrier integrity, bone homeostasis, and melanoma suppression; its enzymatic activity is further regulated by AMPK-mediated phosphorylation at S208, which enhances its interaction with MC1R variants to boost downstream pigmentation signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZDHHC13 (HIP14L) is a Golgi-resident DHHC-family palmitoyl acyltransferase that S-palmitoylates a broad substrate repertoire to control mitochondrial dynamics, autophagy, epithelial integrity, and tumor suppression [#0, #7]. Its cysteine-rich DHHC catalytic domain confers enzymatic activity, and active-site (DQ\\u2192AA) knock-in mice phenocopy the null, establishing that it is the palmitoyltransferase activity\\u2014not protein scaffolding\\u2014that underlies its physiological roles [#9]. In the nervous system it palmitoylates SNAP25 and Drp1, and loss of activity perturbs mitochondrial fission\\u2013fusion balance, shifts metabolism toward glycolysis and glutaminolysis, and produces HD-like motor and behavioral deficits; its interaction with huntingtin is mediated through an ankyrin-repeat interface and is weakened by mutant HTT [#2, #3, #8]. In liver, quantitative palmitoylome profiling shows ZDHHC13 governs hundreds of palmitoylation sites enriched for lipid-metabolic and mitochondrial proteins, including MCAT and CTNND1 [#7]. It initiates autophagy by palmitoylating ULK1, driving translocation of the ULK1\\u2013FIP200\\u2013ATG13\\u2013ATG101 complex to autophagosome formation sites and downstream ATG14L phosphorylation and PI3P generation [#11]. In skin, ZDHHC13 palmitoylates loricrin, PADi3, and TGM1\\u2014controlling the stability of PADi3 and TGM1\\u2014to maintain barrier integrity, and its loss causes hyperkeratosis, constitutive NF-\\u03baB activation, innate-immune\\u2013driven atopic dermatitis, and enhanced chemical skin carcinogenesis [#5, #6, #9]. It also acts as a melanoma suppressor: AMPK phosphorylation at S208 strengthens binding to MC1R red-hair-color variants to boost MC1R palmitoylation and cAMP/MITF signaling, while CTNND1 palmitoylation stabilizes E-cadherin to restrain EMT and metastasis [#10, #12]. In vivo, loss-of-function mutations cause failure to thrive, alopecia, severe osteoporosis, and systemic amyloidosis, with skeletal defects linked to reduced palmitoylation of MT1-MMP [#1, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that ZDHHC13/HIP14L is a Golgi-localized DHHC palmitoyl acyltransferase, defining its core enzymatic identity and subcellular niche.\",\n      \"evidence\": \"Xenopus oocyte expression with electrophysiology, DHHC-deletion mutagenesis, and GFP-fusion live imaging in epithelial cells\",\n      \"pmids\": [\"18794299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Autopalmitoylation of HIP14L was inferred but not directly measured\", \"Physiological substrates not identified at this stage\", \"Mg2+ transport role rests on heterologous oocyte reconstitution\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that ZDHHC13 is required for diverse physiological functions in vivo, moving it from a biochemical activity to an organism-level determinant of growth, skin, bone, and protein homeostasis.\",\n      \"evidence\": \"ENU mutagenesis nonsense allele plus independent gene-trap allele in mice with homozygosity mapping\",\n      \"pmids\": [\"20548961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular substrates underlying each phenotype not yet defined\", \"Does not distinguish enzymatic from scaffolding contributions\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified SNAP25 as a neuronal substrate and linked ZDHHC13 to huntingtin biology, framing it as a palmitoyltransferase whose dysfunction contributes to HD-like neuropathology.\",\n      \"evidence\": \"Hip14l knockout mouse behavioral characterization, palmitoylation assay, and Co-IP of HIP14L with WT vs mutant HTT\",\n      \"pmids\": [\"23077216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration that SNAP25 hypopalmitoylation causes the motor phenotype not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped the HTT\\u2013HIP14L interaction interface and identified MT1-MMP as a direct substrate, connecting ZDHHC13 palmitoylation to skeletal development.\",\n      \"evidence\": \"Co-IP with HTT deletion constructs; ABE assay and Co-IP for MT1-MMP; microCT and IHC in Zdhhc13 mutant epiphysis\",\n      \"pmids\": [\"24651384\", \"24637783\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HTT interaction lacks reciprocal pulldown or structural validation\", \"Link between MT1-MMP palmitoylation and ossification is correlative in vivo\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed ZDHHC13 PAT activity suppresses skin carcinogenesis, establishing a tumor-suppressive role tied to epidermal homeostasis and NF-\\u03baB control.\",\n      \"evidence\": \"Spontaneous loss-of-function mutant mouse with DMBA/TPA carcinogenesis, IHC for NF-\\u03baB/RelA and neutrophils\",\n      \"pmids\": [\"26288350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular substrate identified for the skin carcinogenesis pathway\", \"Mechanism linking palmitoylation to NF-\\u03baB activation unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed ZDHHC13 upstream of innate (not adaptive) immune activation in skin barrier maintenance, explaining its dermatitis phenotype as microbiota-driven.\",\n      \"evidence\": \"Germ-free housing, antibiotics, and Rag1 knockout epistasis in Zdhhc13-deficient mice with IL-33/ILC2 readouts\",\n      \"pmids\": [\"28017833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific palmitoylated barrier substrate not yet identified here\", \"Mechanism connecting barrier defect to IL-33 induction unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the global hepatic palmitoylome of ZDHHC13 and confirmed Drp1, MCAT, and CTNND1 substrates, establishing its central role in mitochondrial dynamics and lipid/energy metabolism.\",\n      \"evidence\": \"Resin-assisted capture + MS palmitoylome, in vivo and in vitro Co-IP and palmitoylation assays, mitochondrial and metabolic profiling in KO/KD models\",\n      \"pmids\": [\"28526873\", \"29038583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which of the 400 sites are direct versus indirect not all resolved\", \"Causal hierarchy among metabolic phenotypes not fully dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Proved that catalytic palmitoyltransferase activity\\u2014not scaffolding\\u2014drives skin barrier function and identified loricrin, PADi3, and TGM1 as substrates whose stability ZDHHC13 controls.\",\n      \"evidence\": \"Catalytic-dead DQ\\u2192AA DHHC knock-in mouse phenocopying KO, quantitative palmitoylome, biochemical substrate confirmation, in vivo protein stability analysis\",\n      \"pmids\": [\"31669413\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How palmitoylation stabilizes PADi3/TGM1 mechanistically not detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed regulatory control of ZDHHC13 by AMPK phosphorylation at S208, linking metabolic signaling to MC1R palmitoylation and melanoma suppression.\",\n      \"evidence\": \"In vitro AMPK kinase assay, phospho-mutant Co-IP, palmitoylation and UVB transformation assays, MC1R-RHC mouse melanomagenesis model\",\n      \"pmids\": [\"36701140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals activating AMPK toward ZDHHC13 in melanocytes not defined\", \"Structural basis of S208-dependent MC1R binding unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established ZDHHC13 as an initiator of autophagy via ULK1 palmitoylation, providing a molecular trigger for autophagosome nucleation.\",\n      \"evidence\": \"Palmitoylation assay, live-cell ULK1 translocation imaging, genetic hierarchy analysis, ATG14L phosphorylation and PI3P detection\",\n      \"pmids\": [\"39169022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether autophagy defects contribute to the in vivo ZDHHC13 phenotypes not tested\", \"Site of ULK1 palmitoylation relative to its activation not fully mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended ZDHHC13 melanoma suppression to a dual mechanism\\u2014CTNND1 palmitoylation stabilizing E-cadherin and LPC suppression reshaping the tumor immune microenvironment\\u2014to restrain EMT and metastasis.\",\n      \"evidence\": \"Palmitoylation and E-cadherin stability assays, lipidomics, macrophage co-culture, MMP12 activity, immunocompetent melanoma metastasis model\",\n      \"pmids\": [\"41321310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ZDHHC13 controls LPC synthesis mechanistically not defined\", \"Single lab, recent publication\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated ZDHHC13 orthologs in lysosomal biogenesis, placing these PATs upstream of Rab2-mediated lysosome formation and fusion.\",\n      \"evidence\": \"Drosophila salivary gland RNAi, lysosomal acidification and hydrolase trafficking assays, constitutively active Rab2 rescue (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.02.06.636816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Direct palmitoylated substrate in the Rab2 lysosomal pathway not identified\", \"Conservation of this role in mammalian ZDHHC13 not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single Golgi palmitoyltransferase coordinates such divergent substrate sets and tissue programs\\u2014and what determines substrate selectivity and spatial targeting\\u2014remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ZDHHC13 substrate recognition\", \"Rules governing tissue-specific substrate choice unknown\", \"Relative contribution of each substrate to the systemic in vivo phenotypes not dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 4, 7, 8, 9, 11, 12]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 7, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 10, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HTT\", \"SNAP25\", \"DNM1L\", \"MMP14\", \"CTNND1\", \"ULK1\", \"MC1R\", \"TGM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}