ZDHHC14

ZDHHC14 is a DHHC-family palmitoyl acyltransferase that modifies a diverse set of substrates to control their membrane localization, protein stability, and transcriptional activity across neuronal, immune, and cancer contexts. In hippocampal neurons, ZDHHC14 palmitoylates the scaffold protein PSD93, thereby clustering PSD93 and Kv1 potassium channels at the axon initial segment to regulate neuronal excitability (PMID:33185190). ZDHHC14 also palmitoylates the tumour suppressor P16/CDKN2A at Cys72 to shield it from ubiquitin-dependent proteasomal degradation (PMID:41522323), palmitoylates the amino acid transporter ASCT2 at Cys39/Cys48 to promote its lysosomal degradation—a process negatively regulated by JNK1-mediated phosphorylation of ZDHHC14 at Thr440 (PMID:41730846)—and palmitoylates TEAD4 to activate CCL20 transcription and Th17 cell recruitment in kidney injury (PMID:41112095). ZDHHC14 additionally exhibits tumour suppressor activity through caspase-dependent apoptosis induction and suppression of xenograft tumourigenesis (PMID:24407904).

1. 2014 Medium

   Establishing that ZDHHC14 functions as a tumour suppressor answered whether this palmitoyl acyltransferase had cell-autonomous growth-regulatory roles beyond enzymatic activity, revealing caspase-dependent pro-apoptotic function and anti-tumourigenic capacity in vivo.

   Evidence Inducible overexpression, heterozygous knockout, caspase assays, and mouse xenograft model in cancer cell lines

   PMID:24407904

   Open questions at the time

   • The palmitoylation substrate(s) mediating apoptosis were not identified
   • Whether the tumour suppressor activity requires catalytic DHHC activity was not tested
   • Single lab, not independently replicated
2. 2014 Medium

   Demonstrating that ZDHHC14 promotes gastric cancer cell invasion upstream of MMP-17 and integrin signalling revealed a context-dependent pro-invasive role that contrasted with the tumour-suppressive phenotype observed in other settings.

   Evidence siRNA knockdown and forced overexpression with Transwell invasion/migration assays and qRT-PCR in scirrhous gastric cancer cells

   PMID:24807047

   Open questions at the time

   • No direct palmitoylation substrate linking ZDHHC14 to MMP-17/integrin regulation was identified
   • Context dependence of pro-invasive vs. tumour-suppressive roles is unresolved
   • Single study, single lab
3. 2018 Low

   Showing that ZDHHC14 knockdown impairs trophoblast proliferation and invasion, with expression regulated by DNA methylation, extended the functional repertoire of ZDHHC14 to placental biology, though without a defined substrate.

   Evidence siRNA knockdown, 5-Aza-dC demethylation, proliferation/invasion assays in BeWo and JEG-3 trophoblast cells

   PMID:30527120

   Open questions at the time

   • No palmitoylation substrate was identified in trophoblast cells, limiting mechanistic interpretation
   • Correlation between DNA methylation and expression does not establish causal regulation in vivo
   • Single lab, single study
4. 2020 High

   Identifying PSD93 as a direct substrate of ZDHHC14 at the axon initial segment resolved how Kv1 channel clustering and neuronal excitability are controlled by palmitoylation, providing the first substrate-level mechanism for ZDHHC14 in neurons.

   Evidence Reciprocal co-immunoprecipitation, palmitoylation assays, shRNA knockdown with electrophysiology and AIS imaging in rat hippocampal neurons

   PMID:33185190

   Open questions at the time

   • The specific palmitoylation site(s) on PSD93 were not mapped
   • Whether ZDHHC14 palmitoylates Kv1 channels directly or acts solely through PSD93 is unknown
   • In vivo validation in ZDHHC14 knockout animals is lacking
5. 2025 Medium

   Discovery that ZDHHC14 palmitoylates TEAD4 to drive CCL20-dependent Th17 recruitment in injured tubular epithelial cells established ZDHHC14 as a regulator of transcription factor activity and adaptive immune signalling in kidney disease.

   Evidence Palmitoylation assay, siRNA knockdown of ZDHHC14, CCL20 measurement, and Th17 infiltration quantification in IgA nephropathy mouse models and patient samples

   PMID:41112095

   Open questions at the time

   • The palmitoylation site on TEAD4 was not mapped by mutagenesis
   • Whether ZDHHC14-mediated TEAD4 palmitoylation occurs in non-renal inflammatory contexts is untested
   • Single lab, single study
6. 2025 Medium

   Demonstrating that ZDHHC14 palmitoylates P16/CDKN2A at Cys72 to prevent ubiquitin-dependent proteasomal degradation provided a direct mechanistic link between palmitoylation and tumour suppressor protein stability.

   Evidence Co-immunoprecipitation, C72S mutagenesis, ubiquitination assays, palmitoylation inhibitor/agonist treatment, siRNA knockdown in prostate cancer cells

   PMID:41522323

   Open questions at the time

   • The E3 ubiquitin ligase counteracted by palmitoylation was not identified
   • In vivo relevance for prostate cancer progression was not tested
   • Single lab, single study
7. 2025 Medium

   Identification of HSV-2 glycoprotein B as a ZDHHC14 substrate (palmitoylated at Cys8) that enhances viral membrane localization and infectivity revealed a host–pathogen exploitation of ZDHHC14 enzymatic activity.

   Evidence Acyl-biotin exchange assay, co-immunoprecipitation, C8S mutagenesis, 2-bromopalmitate treatment, pseudotyped particle and live HSV-2 infection assays

   PMID:40582294

   Open questions at the time

   • Whether ZDHHC14 is required vs. redundant with other DHHCs for gB palmitoylation in vivo is unclear
   • No in vivo infection model was used
   • Single lab, single study
8. 2026 High

   Establishing that ZDHHC14 palmitoylates ASCT2 at Cys39/Cys48 to promote its lysosomal degradation, and that JNK1-mediated phosphorylation of ZDHHC14 at Thr440 triggers ZDHHC14 degradation under glutamine deprivation, revealed a nutrient-sensing feedback loop regulating amino acid transporter levels.

   Evidence Palmitoylation assay, mutagenesis of Cys39/48 and Thr440, in vitro JNK1 kinase assay, co-immunoprecipitation, lysosomal degradation assays, in vivo tumour models

   PMID:41730846

   Open questions at the time

   • The E3 ligase responsible for ZDHHC14 degradation upon phosphorylation was not identified
   • Whether other DHHCs compensate for ZDHHC14 loss in ASCT2 regulation is unknown
   • The structural basis for JNK1 recognition of Thr440 is uncharacterized

• A unifying structural and regulatory model for ZDHHC14 substrate selectivity across its diverse substrates (PSD93, ASCT2, P16, TEAD4, HSV-2 gB) is lacking, and whether catalytic activity is required for its pro-apoptotic tumour suppressor function remains untested.
• No crystal structure or cryo-EM structure of ZDHHC14 exists
• Catalytic-dead mutant (DHHC→DHHS) has not been tested in the apoptosis/tumour suppressor context
• A ZDHHC14 knockout mouse phenotype has not been reported