Affinage

ZDHHC14

Palmitoyltransferase ZDHHC14 · UniProt Q8IZN3

Length
488 aa
Mass
53.4 kDa
Annotated
2026-06-11
11 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZDHHC14 is a DHHC-domain palmitoyl acyltransferase that controls the membrane targeting, stability, and activity of diverse substrates through S-palmitoylation, with roles spanning neuronal excitability, cancer, and viral infection (PMID:33185190, PMID:41522323). In neurons, ZDHHC14 directly palmitoylates the scaffold PSD93 and governs PSD93 and Kv1 potassium channel clustering at the axon initial segment; its loss reduces outward Kv1 currents and increases action potential firing, establishing palmitoylation-dependent control of neuronal excitability (PMID:33185190). Beyond the nervous system, ZDHHC14 acts on a range of substrates by site-specific cysteine palmitoylation that alters their fate: it stabilizes the tumour suppressor P16/CDKN2A at Cys72 by suppressing ubiquitin-dependent degradation (PMID:41522323), palmitoylates the glutamine transporter ASCT2 at Cys39/Cys48 to promote its lysosomal degradation (PMID:41730846), modifies the transcription factors TEAD4 (driving CCL20 transcription and Th17 recruitment in IgA nephropathy) (PMID:41112095) and RUNX2 at Cys13 (activating a YAP1/GLS1 axis that inhibits ferroptosis and confers cisplatin resistance) (PMID:42149203), and palmitoylates HSV-2 glycoprotein B at Cys8 to enhance its plasma-membrane localization and viral infectivity (PMID:40582294). ZDHHC14 is itself a regulated enzyme: JNK1 phosphorylates it at Thr440 upon glutamine deprivation, triggering its degradation to stabilize ASCT2 and sustain glutamine uptake, with ABHD17B serving as the opposing depalmitoylase (PMID:41730846). Functionally, ZDHHC14 acts as a tumour suppressor in prostate and testicular cancer, inducing caspase-dependent apoptosis and inhibiting xenograft tumourigenesis (PMID:24407904).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2014 Medium

    Established that ZDHHC14 has a cell-autonomous role in tumour biology, addressing whether it functions in cancer suppression versus promotion.

    Evidence Inducible overexpression, heterozygous knockout, caspase assays, and xenografts in prostate/testicular cancer lines; separately siRNA knockdown with invasion and marker readouts in gastric cancer

    PMID:24407904 PMID:24807047

    Open questions at the time
    • No palmitoylation substrate identified to explain the apoptotic or invasion phenotypes
    • Opposing tumour-suppressor (prostate/testicular) versus pro-invasive (gastric) roles not mechanistically reconciled
    • Catalytic dependence of phenotypes not tested
  2. 2018 Low

    Showed ZDHHC14 expression supports trophoblast proliferation and invasion and is under epigenetic control, broadening its phenotypic relevance beyond cancer cell lines.

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

    PMID:30527120

    Open questions at the time
    • No direct palmitoylation substrate identified
    • Mechanism linking DNA methylation to ZDHHC14 expression not defined
    • Single cell-line system without in vivo validation
  3. 2020 High

    Provided the first direct enzyme-substrate assignment, defining ZDHHC14 as the PAT for PSD93 and linking its palmitoylation activity to ion-channel clustering and neuronal excitability.

    Evidence Reciprocal Co-IP, lentiviral shRNA knockdown, palmitoylation assays, and electrophysiology in rat hippocampal neurons

    PMID:33185190

    Open questions at the time
    • Palmitoylation site on PSD93 not mapped
    • Whether ZDHHC14 directly palmitoylates Kv1 channels versus acting through PSD93 not fully resolved
    • No structural basis for substrate selectivity
  4. 2025 Medium

    Extended ZDHHC14 substrate repertoire to transcription factors and a tumour suppressor, showing palmitoylation can either activate transcriptional output (TEAD4) or stabilize protein levels (P16).

    Evidence Knockdown and palmitoylation analysis of TEAD4 with CCL20/Th17 readouts in IgA nephropathy models; Co-IP, C72S mutagenesis, and ubiquitination assays for P16 in prostate cancer cells

    PMID:41112095 PMID:41522323

    Open questions at the time
    • TEAD4 palmitoylation site not mapped
    • How a single PAT produces divergent outcomes (transcriptional activation vs. anti-degradation) not explained
    • Single-lab studies without independent replication
  5. 2025 Medium

    Demonstrated ZDHHC14 palmitoylates a viral envelope glycoprotein, defining a host-factor role in HSV-2 membrane targeting and infectivity.

    Evidence Acyl-biotin exchange, C8S mutagenesis, Co-IP, and pseudotyped particle infection assays

    PMID:40582294

    Open questions at the time
    • Whether ZDHHC14 is rate-limiting for HSV-2 in authentic infection not established
    • Subcellular site of gB palmitoylation not defined
  6. 2026 Medium

    Revealed that ZDHHC14 is itself a regulated node, with JNK1 phosphorylation controlling its turnover to tune glutamine-transporter abundance, and added a metabolic/ferroptosis dimension via ASCT2 and RUNX2 substrates.

    Evidence Palmitoylation and kinase assays, Cys/Thr mutagenesis, ABHD17B depalmitoylase identification, and xenografts for ASCT2; ABE, Click-iT, PAT assay, C13S mutagenesis, and ferroptosis readouts for RUNX2

    PMID:41730846 PMID:42149203

    Open questions at the time
    • Structural basis of Thr440 phosphorylation-triggered degradation unknown
    • How ZDHHC14 selects among membrane-degradation, transcriptional, and stabilizing substrate outcomes not unified
    • Single-lab studies pending independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unifying biochemical model of ZDHHC14 substrate recognition and the structural determinants that dictate whether palmitoylation stabilizes, degrades, relocalizes, or activates a given target remains unestablished.
  • No structure of ZDHHC14 or its DHHC domain in complex with a substrate
  • Consensus palmitoylation motif or substrate-selection rules not defined
  • Tissue-specific regulation of ZDHHC14 expression and activity incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5 GO:0140096 catalytic activity, acting on a protein 5
Localization
GO:0005886 plasma membrane 1
Pathway
R-HSA-392499 Metabolism of proteins 2
Partners
ASCT2CDKN2AJNK1PSD93RUNX2TEAD4

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 ZDHHC14 is the palmitoyl acyltransferase (PAT) that directly palmitoylates PSD93 (a PDZ domain-containing MaGUK) and controls PSD93 clustering at the axon initial segment (AIS). ZDHHC14 also controls palmitoylation and AIS clustering of Kv1 potassium channels, which bind PSD93 directly. Loss of ZDHHC14 (lentiviral shRNA in rat hippocampal neurons) decreased outward Kv1 currents and increased action potential firing, establishing a role for ZDHHC14-mediated palmitoylation in neuronal excitability. Lentiviral shRNA knockdown in rat hippocampal neurons, co-immunoprecipitation (ZDHHC14–PSD93 interaction), palmitoylation assays, electrophysiology (outward current and action potential firing measurements) eLife High 33185190
2025 ZDHHC14 mediates S-palmitoylation of the transcription factor TEAD4 in renal tubular epithelial cells. Under inflammatory conditions, ZDHHC14-driven TEAD4 palmitoylation (rather than changes in TEAD4 protein expression) activates CCL20 transcription, promoting Th17 cell recruitment in IgA nephropathy. ZDHHC14 knockdown reduced CCL20 expression and Th17 infiltration. ZDHHC14 knockdown experiments, palmitoylation analysis of TEAD4, CCL20 expression assays, IgA nephropathy patient samples and mouse models Research (Washington, D.C.) Medium 41112095
2025 ZDHHC14 palmitoylates HSV-2 glycoprotein B (gB) at cysteine residue 8 (C8), confirmed by acyl-biotin exchange assay. Palmitoylation enhances gB localization to the plasma membrane; the C8S mutation substantially impairs this localization. ZDHHC14 interacts with gB (co-immunoprecipitation) and facilitates its palmitoylation, which in turn enhances HSV-2 infectivity. Acyl-biotin exchange assay, co-immunoprecipitation (ZDHHC14–gB interaction), site-directed mutagenesis (C8S), 2-bromopalmitate treatment, HSV-2 pseudotyped particle infection assay Virology Medium 40582294
2026 ZDHHC14 is the palmitoyltransferase that palmitoylates the glutamine transporter ASCT2 at conserved Cys39 and Cys48, promoting lysosomal degradation of ASCT2. JNK1 phosphorylates ZDHHC14 at Thr440 in response to glutamine deprivation, triggering ZDHHC14 degradation and thereby stabilizing ASCT2 and sustaining glutamine uptake. ABHD17B acts as the depalmitoylase that stabilizes ASCT2. Palmitoylation assays, site-directed mutagenesis (Cys39/48 of ASCT2, Thr440 of ZDHHC14), kinase assay (JNK1 phosphorylation of ZDHHC14), in vivo xenograft tumor models, combination inhibitor studies Cell discovery Medium 41730846
2026 ZDHHC14 drives S-palmitoylation of RUNX2 at Cys13 in ovarian cancer cells. Exogenous ZDHHC14 induces RUNX2 palmitoylation; RUNX2-C13S mutation abolishes this. Palmitoylated RUNX2 transcriptionally activates YAP1 and the YAP1/GLS1 axis, inhibiting ferroptosis and increasing cisplatin resistance. Loss of this palmitoylation site (C13S) reverses chemoresistance. Acyl-biotin exchange assay, Click-iT pull-down, palmitoyl acyltransferase assay, site-directed mutagenesis (C13S), co-immunoprecipitation, xenograft models, flow cytometry (ferroptosis markers) Apoptosis : an international journal on programmed cell death Medium 42149203
2025 ZDHHC14 palmitoylates P16 (CDKN2A) at Cys72, enhancing P16 protein stability by suppressing ubiquitination-dependent proteasomal degradation. ZDHHC14 directly interacts with P16 (confirmed by co-immunoprecipitation). Knockdown of ZDHHC14 markedly reduces P16 protein levels. This palmitoylation-mediated stabilization suppresses prostate cancer cell proliferation, migration, and invasion. Co-immunoprecipitation (ZDHHC14–P16 interaction), site-directed mutagenesis (C72S), palmitoylation inhibitor (2-BP) and agonist (HAM) treatment, ubiquitination assays, siRNA knockdown, colony formation and Transwell assays Translational andrology and urology Medium 41522323
2014 Inducible overexpression of ZDHHC14 in prostate/testicular cancer cell lines reduced cell viability and increased apoptosis via the caspase-dependent apoptotic pathway. Heterozygous knockout of ZDHHC14 increased colony formation. Overexpression of ZDHHC14 inhibited tumourigenesis in a mouse xenograft model, establishing ZDHHC14 as a functional tumour suppressor. Inducible overexpression, heterozygous knockout, caspase activity assays, mouse xenograft model The Journal of pathology Medium 24407904
2014 ZDHHC14 knockdown in scirrhous-type gastric cancer cells decreased invasiveness and was accompanied by downregulation of MMP-17 mRNA and downregulation of integrins α5 and β1. Forced expression of ZDHHC14 activated gastric cancer cell migration and invasion in vitro, placing ZDHHC14 upstream of MMP-17 and integrin signaling in cancer cell invasion. siRNA knockdown, forced overexpression, Transwell invasion assay, qRT-PCR (MMP-17, integrin α5/β1 mRNA) Oncology reports Low 24807047
2018 siRNA-mediated knockdown of ZDHHC14 significantly inhibited trophoblast cell (BeWo and JEG-3) proliferation and invasion. ZDHHC14 expression in these cells is regulated by DNA methylation; hypomethylation (5-Aza-dC treatment) decreased ZDHHC14 gene expression. siRNA knockdown, 5-Aza-dC demethylation treatment, proliferation and invasion assays in trophoblast cell lines Pregnancy hypertension Low 30527120

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Identification of ZDHHC14 as a novel human tumour suppressor gene. The Journal of pathology 53 24407904
2014 Overexpression of ZDHHC14 promotes migration and invasion of scirrhous type gastric cancer. Oncology reports 41 24807047
2020 The palmitoyl acyltransferase ZDHHC14 controls Kv1-family potassium channel clustering at the axon initial segment. eLife 36 33185190
2018 Reduced methylation downregulates CD39/ENTPD1 and ZDHHC14 to suppress trophoblast cell proliferation and invasion: Implications in preeclampsia. Pregnancy hypertension 12 30527120
2025 ZDHHC14 and APT2 regulate the palmitoylation of HSV-2 gB. Virology 1 40582294
2025 ZDHHC14-Mediated TEAD4 Palmitoylation Drives Th17 Cell Recruitment in Renal Immunopathology. Research (Washington, D.C.) 1 41112095
2026 ASCT2 palmitoylation regulated by JNK1-ZDHHC14 axis orchestrates glutamine metabolism and NSCLC progression. Cell discovery 0 41730846
2026 ZDHHC14 Attenuates Osteoarthritis Progression through Metabolic Pathways: Multi-omics Fusion and Functional Validation. Experimental gerontology 0 41962640
2026 ZDHHC14-driven RUNX2 S-palmitoylation attenuates ferroptosis and enhances chemoresistance in ovarian cancer via the YAP1/GLS1 axis. Apoptosis : an international journal on programmed cell death 0 42149203
2025 ZDHHC5 and ZDHHC14 promote depression via the mediation of double-negative T cells. Mammalian genome : official journal of the International Mammalian Genome Society 0 41388152
2025 ZDHHC14 enhances P16 stability via palmitoylation to inhibit prostate cancer progression. Translational andrology and urology 0 41522323

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