ZDHHC13

ZDHHC13 is a Golgi-resident DHHC-domain palmitoyl acyltransferase that S-palmitoylates a diverse array of substrates to regulate mitochondrial dynamics, autophagy, skin barrier formation, bone development, neuronal function, and melanoma suppression. It palmitoylates Drp1 to control mitochondrial fission-fusion balance and bioenergetics in the brain (PMID:29038583), ULK1 to enable autophagosome initiation complex translocation and PI3-kinase activation (PMID:39169022), MT1-MMP to promote endochondral ossification (PMID:24637783), and epidermal substrates loricrin, PADi3, and TGM1 whose palmitoylation-dependent stability is essential for skin barrier integrity (PMID:31669413, PMID:28017833). ZDHHC13 suppresses melanoma metastasis by palmitoylating CTNND1 to stabilize E-cadherin and by restricting lysophosphatidylcholine-driven pro-tumorigenic macrophage polarization (PMID:41321310), and its enzymatic activity toward MC1R red-hair-color variants is enhanced by AMPK-mediated phosphorylation at S208 (PMID:36701140). Loss-of-function mutations in mice cause alopecia, osteoporosis, systemic amyloidosis, neurological abnormalities, and susceptibility to skin carcinogenesis, confirming broad physiological requirements for its catalytic palmitoylation activity (PMID:20548961, PMID:26288350).

1. 2008 High

   Establishing that ZDHHC13 (HIP14L) is a Golgi-localized palmitoyl acyltransferase that additionally mediates Mg²⁺ transport partly dependent on its own DHHC-domain autopalmitoylation answered the foundational question of what enzymatic activity this protein carries and where it acts.

   Evidence Xenopus oocyte electrophysiology, GFP-fusion live imaging, and DHHC deletion mutagenesis

   PMID:18794299

   Open questions at the time

   • Mg²⁺ transport function not confirmed in mammalian cells
   • identity of endogenous substrates unknown at this stage
   • structural basis for autopalmitoylation-dependent transport not resolved
2. 2010 High

   Demonstrating that loss-of-function mutations in Zdhhc13 cause alopecia, osteoporosis, and systemic amyloidosis in two independent mouse alleles established that ZDHHC13 palmitoylation activity is essential for multiple organ systems in vivo.

   Evidence ENU mutagenesis (R425X) and independent gene-trap allele with concordant phenotypes in mice

   PMID:20548961

   Open questions at the time

   • Specific substrates responsible for each phenotype unidentified
   • human disease relevance not established
3. 2012 High

   Identification of SNAP25 as a ZDHHC13 substrate and demonstration that ZDHHC13 interacts differentially with wild-type versus mutant huntingtin linked its palmitoylation activity to synaptic vesicle machinery and Huntington disease pathogenesis.

   Evidence Hip14l knockout mice with palmitoylation assays and co-immunoprecipitation of ZDHHC13-HTT

   PMID:23077216

   Open questions at the time

   • Whether reduced SNAP25 palmitoylation is causal for neurological phenotypes not directly tested
   • HTT polyQ-dependent interaction mechanism unclear
4. 2014 High

   Discovery that ZDHHC13 palmitoylates MT1-MMP to control its subcellular distribution, with downstream effects on VEGF and osteocalcin in chondrocytes and osteoblasts, provided the first mechanistic link between ZDHHC13 and bone development.

   Evidence Co-IP, acyl-biotin exchange, microCT, and immunohistochemistry in Zdhhc13 mutant mice

   PMID:24637783

   Open questions at the time

   • Whether MT1-MMP is the sole ZDHHC13 substrate driving osteoporosis not determined
   • palmitoylation site on MT1-MMP not mapped
5. 2015 Medium

   Finding that Zdhhc13 loss causes constitutive NF-κB/RelA activation, epidermal hyperplasia, and enhanced chemical skin carcinogenesis revealed a tumor-suppressive role and connected ZDHHC13 deficiency to inflammatory signaling in skin.

   Evidence Spontaneous nonsense mutant mouse with histology, NF-κB immunostaining, and two-stage carcinogenesis assay

   PMID:26288350

   Open questions at the time

   • Direct substrate whose loss of palmitoylation activates NF-κB not identified
   • mechanism connecting palmitoylation loss to RelA activation unknown
6. 2016 High

   Genetic epistasis experiments (germ-free housing, antibiotics, Rag1 deletion) showed ZDHHC13 deficiency compromises the skin barrier, causing innate immunity-driven IL-33/ILC2-mediated dermatitis upon microbial exposure, defining the immunological pathway downstream of barrier loss.

   Evidence Zdhhc13 KO mice under germ-free and antibiotic conditions, Rag1 epistasis, IL-33 and ILC2 quantification

   PMID:28017833

   Open questions at the time

   • Epidermal substrates mediating barrier function not yet identified at this stage
   • human skin disease relevance not tested
7. 2017 High

   Quantitative palmitoylome profiling identified MCAT and CTNND1 as hepatic ZDHHC13 substrates and revealed broad mitochondrial and lipid metabolism protein hypo-palmitoylation upon Zdhhc13 loss, while parallel work showed ZDHHC13 palmitoylates Drp1 to regulate mitochondrial fission-fusion, bioenergetics, and neuronal function.

   Evidence Resin-assisted capture MS with TMT normalization in KO mice and hepatocytes; Co-IP and palmitoylation assays for Drp1 with behavioral and metabolic phenotyping in mutant mice

   PMID:28526873 PMID:29038583

   Open questions at the time

   • Whether Drp1 palmitoylation is the primary driver of neurological phenotypes versus other substrates not resolved
   • palmitoylation sites on Drp1 not mapped
8. 2019 High

   Catalytic-dead ZDHHC13 knock-in mice (DQ→AA) fully recapitulated knockout skin phenotypes, definitively proving enzymatic palmitoylation—not scaffolding—is required, and identified loricrin, PADi3, and TGM1 as epidermal substrates whose palmitoylation stabilizes them in vivo.

   Evidence Active-site knock-in mouse, quantitative palmitoylome, biochemical palmitoylation confirmation, protein stability assays

   PMID:31669413

   Open questions at the time

   • Whether additional epidermal substrates contribute to barrier phenotype unknown
   • how palmitoylation stabilizes PADi3/TGM1 mechanistically not resolved
9. 2023 High

   Identification of AMPK-mediated phosphorylation of ZDHHC13 at S208, which enhances its interaction with and palmitoylation of MC1R red-hair-color variants, established the first regulatory input controlling ZDHHC13 activity and linked it to melanoma chemoprevention.

   Evidence In vitro kinase assay, S208 mutagenesis, Co-IP, palmitoylation assay, UVB melanocyte transformation assay, MC1R-RHC mouse model

   PMID:36701140

   Open questions at the time

   • Whether S208 phosphorylation affects palmitoylation of other ZDHHC13 substrates unknown
   • structural basis for phosphorylation-enhanced MC1R interaction not determined
10. 2024 High

    Demonstration that ZDHHC13 palmitoylates ULK1 to promote translocation of the ULK1-FIP200-ATG13-ATG101 complex to autophagosome formation sites and activate PI3-kinase via ATG14L phosphorylation established ZDHHC13 as a critical upstream regulator of autophagy initiation.

    Evidence Palmitoylation assay, ULK1 translocation live imaging, epistasis analysis, ATG14L phosphorylation assay, ZDHHC13 knockdown/knockout

    PMID:39169022

    Open questions at the time

    • Palmitoylation site(s) on ULK1 not mapped
    • whether autophagy defects contribute to in vivo ZDHHC13-loss phenotypes (neurodegeneration, skin) not tested
11. 2025 High

    ZDHHC13 palmitoylation of CTNND1 stabilizes E-cadherin and suppresses melanoma metastasis, while also restricting LPC-driven M2 macrophage polarization, revealing a dual cell-autonomous and immune-modulatory anti-metastatic mechanism.

    Evidence ZDHHC13 loss-of-function in melanoma cells, palmitoylation and E-cadherin stability assays, LPC metabolomics, macrophage co-culture, immunocompetent mouse metastasis model

    PMID:41321310

    Open questions at the time

    • Whether ZDHHC13 loss is a common event in human melanoma progression not established
    • mechanism linking palmitoylation to LPC biosynthetic suppression not defined

• Key unresolved questions include the structural basis for ZDHHC13 substrate selectivity across its remarkably diverse substrate repertoire, whether AMPK-S208 phosphorylation globally modulates ZDHHC13 activity, and whether ZDHHC13 mutations contribute to human Mendelian skin, bone, or neurological disease.
• No crystal or cryo-EM structure of ZDHHC13
• human genetic disease association not established
• how ZDHHC13 selects among its many substrates at the Golgi is unknown