ZDHHC13

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).

1. 2008 Medium

   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

   PMID:18794299

   Open questions at the time

   • Autopalmitoylation of HIP14L was inferred but not directly measured
   • Physiological substrates not identified at this stage
   • Mg2+ transport role rests on heterologous oocyte reconstitution
2. 2010 High

   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

   PMID:20548961

   Open questions at the time

   • Molecular substrates underlying each phenotype not yet defined
   • Does not distinguish enzymatic from scaffolding contributions
3. 2012 Medium

   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

   PMID:23077216

   Open questions at the time

   • Direct demonstration that SNAP25 hypopalmitoylation causes the motor phenotype not established
   • Single lab
4. 2014 Medium

   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

   PMID:24637783 PMID:24651384

   Open questions at the time

   • HTT interaction lacks reciprocal pulldown or structural validation
   • Link between MT1-MMP palmitoylation and ossification is correlative in vivo
5. 2015 Medium

   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

   PMID:26288350

   Open questions at the time

   • No molecular substrate identified for the skin carcinogenesis pathway
   • Mechanism linking palmitoylation to NF-κB activation unresolved
6. 2016 Medium

   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

   PMID:28017833

   Open questions at the time

   • Specific palmitoylated barrier substrate not yet identified here
   • Mechanism connecting barrier defect to IL-33 induction unclear
7. 2017 High

   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

   PMID:28526873 PMID:29038583

   Open questions at the time

   • Which of the 400 sites are direct versus indirect not all resolved
   • Causal hierarchy among metabolic phenotypes not fully dissected
8. 2019 High

   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

   PMID:31669413

   Open questions at the time

   • How palmitoylation stabilizes PADi3/TGM1 mechanistically not detailed
   • Single lab
9. 2023 High

   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

   PMID:36701140

   Open questions at the time

   • Upstream signals activating AMPK toward ZDHHC13 in melanocytes not defined
   • Structural basis of S208-dependent MC1R binding unknown
10. 2024 High

    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

    PMID:39169022

    Open questions at the time

    • Whether autophagy defects contribute to the in vivo ZDHHC13 phenotypes not tested
    • Site of ULK1 palmitoylation relative to its activation not fully mapped
11. 2025 Medium

    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

    PMID:41321310

    Open questions at the time

    • How ZDHHC13 controls LPC synthesis mechanistically not defined
    • Single lab, recent publication
12. 2025 Medium

    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)

    PMID:bio_10.1101_2025.02.06.636816

    Open questions at the time

    • Preprint, not yet peer-reviewed
    • Direct palmitoylated substrate in the Rab2 lysosomal pathway not identified
    • Conservation of this role in mammalian ZDHHC13 not tested

• How a single Golgi palmitoyltransferase coordinates such divergent substrate sets and tissue programs—and what determines substrate selectivity and spatial targeting—remains unresolved.
• 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