| 2002 |
GODZ (ZDHHC3) is a Golgi apparatus-specific protein with a DHHC zinc finger domain and four putative transmembrane regions; overexpression in COS7 cells suppressed sorting of the glutamate receptor GluRα1 from the Golgi apparatus, implicating ZDHHC3 in membrane protein trafficking. |
Overexpression in COS7 cells, subcellular localization by immunofluorescence |
Biochemical and biophysical research communications |
Medium |
12163046
|
| 2004 |
ZDHHC3 (GODZ) palmitoylates the γ2 subunit of GABA(A) receptors via a cytoplasmic loop cysteine-rich 14-amino acid domain conserved in γ1-3 subunits; ZDHHC3 is localized asymmetrically in the neuronal Golgi complex and interacts with γ2 through the SOS-recruitment (yeast two-hybrid) system. |
SOS-recruitment yeast two-hybrid, coexpression in heterologous cells with palmitoylation assay, subcellular localization by immunofluorescence |
The Journal of neuroscience |
High |
15229235
|
| 2006 |
ZDHHC3 and its paralog SERZ-β (DHHC7) form homomultimers and heteromultimers; ZDHHC3 is the primary enzyme palmitoylating the GABA(A) receptor γ2 subunit, and dominant-negative ZDHHC3 (C157S) or ZDHHC3 RNAi reduces GABA(A) receptor accumulation at inhibitory synapses and impairs GABAergic synaptic function without affecting AMPA receptor-mediated transmission. |
Co-immunoprecipitation, in vivo cross-linking, RNAi knockdown in neurons, dominant-negative overexpression, whole-cell and synaptic electrophysiology |
The Journal of neuroscience |
High |
17151279
|
| 2009 |
ZDHHC3 mediates Ca²⁺ transport when expressed in Xenopus oocytes; this transport is dependent on palmitoylation activity (abolished by 2-bromopalmitate or DHHC→DHHS active-site mutation by ~80%), but a separate V61R mutation abolishes Ca²⁺ transport without affecting palmitoyl acyltransferase activity, indicating the two functions are separable. |
Two-electrode voltage clamp, fluorescence Ca²⁺ imaging, ⁴⁵Ca²⁺ isotopic uptake in Xenopus oocytes, site-directed mutagenesis |
The Journal of biological chemistry |
Medium |
19955568
|
| 2012 |
ZDHHC3 is the palmitoyltransferase responsible for palmitoylation of integrin β4 and α6 subunits; DHHC3 ablation accelerates lysosomal degradation of α6β4 via increased cathepsin D exposure, impairs integrin signaling through Src, reduces β4 phosphorylation at S1356 and S1424, and blocks integrin-dependent cable formation on Matrigel, while ~10 other cell-surface proteins including α3β1 are unaffected. |
RNAi knockdown, overexpression in multiple cell lines, palmitoylation assay, Src signaling/phosphorylation assays, cathepsin D inhibitor rescue (Pepstatin A), cell-surface biotinylation |
Cellular and molecular life sciences |
High |
22314500
|
| 2012 |
ZDHHC3 interacts with the death domain of TRAIL receptor DR4 (but not DR5) through its DHHC and C-terminal transmembrane domains, and promotes localization of DR4 to the plasma membrane via the DHHC motif, thereby sensitizing tumor cells to TRAIL-induced apoptosis. |
SOS protein-recruitment yeast two-hybrid, co-immunoprecipitation, subcellular localization assay, apoptosis assays, cysteine mutagenesis of DR4 |
Cell death and differentiation |
Medium |
22240897
|
| 2015 |
ZDHHC3 undergoes autoacylation (palmitoylation) at the cysteine within the DHHC motif; conserved cysteines outside the DHHC motif coordinate two zinc ions per ZDHHC3 molecule, and mutation of these cysteines or chelation of zinc by EDTA causes structural perturbation and loss of palmitoyl acyltransferase activity. |
Mass spectrometry identification of palmitoylation site, site-directed mutagenesis of conserved CRD cysteines, limited proteolysis, metal chelation with EDTA, zinc quantification using fluorescent indicator mag-fura-2 |
The Journal of biological chemistry |
High |
26487721
|
| 2016 |
In GODZ (ZDHHC3) knockout mice, palmitoylation of γ2 subunit of GABA(A) receptors and GAP-43 is significantly reduced; GABA(A) receptor synaptic accumulation and GABAergic innervation are decreased in GODZ KO neurons competing with wild-type neurons; total cell-surface GABA(A) receptor expression and whole-cell GABAergic currents are unaltered in isolated DKO neurons, indicating GODZ-mediated palmitoylation selectively controls the synaptic pool of receptors. SERZ-β (DHHC7) KO alone does not affect γ2 palmitoylation. |
Knockout mice (GODZ KO, SERZ-β KO, double KO), palmitoylation assay, electrophysiology, immunofluorescence, subcellular fractionation |
The Journal of biological chemistry |
High |
27875292
|
| 2016 |
ZDHHC3 is phosphorylated by FGFR1 at Tyr18 and by Src kinase at Tyr295 and Tyr297; abrogation of these tyrosine phosphorylation sites increases ZDHHC3 autopalmitoylation, enhances interaction with NCAM, upregulates NCAM palmitoylation, and promotes neurite outgrowth in hippocampal neurons. |
Pharmacological inhibition and overexpression of FGFR/Src, site-directed mutagenesis of ZDHHC3 tyrosines, cell-free and cell-based kinase assays, palmitoylation assay, co-immunoprecipitation, neurite outgrowth assay |
Molecular and cellular biology |
High |
27247265
|
| 2016 |
ZDHHC3 functions downstream of acsl1b to palmitoylate Gsα at mapped cysteine residues in Xenopus oocytes, maintaining meiotic G2/prophase I arrest; depletion of ZDHHC3 reduces palmitoylated Gsα levels and lowers the progesterone threshold for G2/M transition from 2 μM to 0.01 μM. |
RNA depletion (antisense morpholino) in Xenopus oocytes, palmitoylation assay, site-directed mutagenesis of Gsα palmitoylation sites and ZDHHC3 active site, progesterone dose-response assay |
Biology of reproduction |
Medium |
27512151
|
| 2017 |
ZDHHC3 palmitoylates ERGIC3 protein; loss of ZDHHC3-dependent palmitoylation of ERGIC3 leads to upregulation of TXNIP, increased oxidative stress, and cellular senescence in breast cancer cells; these antitumor effects are reversed by wild-type but not enzyme-active-site-deficient ZDHHC3, and are substantially negated by co-depletion of TXNIP. |
RNAi ablation, wild-type vs. catalytic mutant ZDHHC3 reconstitution, gene array, fluorescence dye oxidative stress assays, xenograft tumor model, flow cytometry for immune cell recruitment |
Cancer research |
Medium |
29055014
|
| 2017 |
ZDHHC3 binds specifically to HSV-1 UL20 (but not other HSV-1 proteins) in the Golgi apparatus via yeast two-hybrid and pulldown assays, palmitoylates UL20 (blocked by dominant-negative ZDHHC3 C157S or 2-bromopalmitate), and is required for proper localization of UL20 and glycoprotein K (gK) and for HSV-1 replication in vitro. |
Yeast two-hybrid, pulldown assay, dominant-negative ZDHHC3 overexpression, palmitoylation assay (acyl-RAC), 2-bromopalmitate inhibition, immunofluorescence localization, viral titer assay |
Journal of virology |
High |
28724772
|
| 2018 |
In ZDHHC3 (GODZ) knockout MEFs, HSV-1 replication is compromised; ZDHHC3 absence blocks UL20 palmitoylation, alters localization and expression of UL20 and gK, affects expression of gB and gC, and disrupts tegument/capsid protein localization; in vivo, GODZ KO mice show reduced corneal HSV-1 replication, lower corneal scarring, and reduced latency reactivation. |
GODZ KO mouse-derived MEFs, palmitoylation assay, electron microscopy, immunofluorescence, viral titer, in vivo ocular infection model |
Journal of virology |
High |
29187538
|
| 2020 |
Comparative mass spectrometry-based palmitoyl-proteomics of breast and prostate cancer cells ± ZDHHC3 ablation identified 22–28 antioxidant/redox-regulatory proteins as candidate ZDHHC3 substrates; ZDHHC3 ablation elevated oxidative stress, which synergized with chemotherapeutic agents to enhance anti-growth effects. |
Comparative mass spectrometry palmitoyl-proteomics, RNAi ablation, fluorescence dye oxidative stress assays, cell proliferation assays |
Cellular and molecular life sciences |
Medium |
32986127
|
| 2021 |
A high-throughput Acyl-cLIP assay was developed and validated for ZDHHC3/7/20 enzymatic activity; in vitro results from this assay correlated with cell-based palmitoylation assays, confirming ZDHHC3 catalytic activity as amenable to quantitative screening. |
Acyl-cLIP (acylation-coupled lipophilic induction of polarization) high-throughput assay, cell-based palmitoylation assay |
ACS chemical biology |
Medium |
34374518
|
| 2023 |
ZDHHC3 palmitoylates IRHOM2 at C476 within the iRhom homology domain via its DHHC (C157) catalytic domain; palmitoylation promotes IRHOM2 cytomembrane translocation and stabilization by blocking TRIM31-mediated ubiquitination and proteasomal degradation; hepatocyte-specific ZDHHC3 knockout suppresses IRHOM2 accumulation and attenuates NASH pathology in rodent and rabbit models. |
Co-immunoprecipitation, site-directed mutagenesis (C476 of IRHOM2, C157 of ZDHHC3), acyl-RAC palmitoylation assay, ubiquitination assay, hepatocyte-specific KO mice, in vivo NASH diet models |
Advanced science |
High |
37544908
|
| 2024 |
ZDHHC3 inhibits PD-L1 lysosomal degradation by palmitoylating PD-L1; the natural compound benzosceptrin C (BC) inhibits ZDHHC3 enzymatic activity, causing PD-L1 to relocate from the membrane to the cytoplasm, preventing recycling endosome-mediated return to the membrane, and triggering lysosomal degradation of PD-L1. |
Palmitoylation assay, ZDHHC3 enzymatic inhibition assay, subcellular localization imaging, lysosomal inhibitor rescue, in vivo MC38 tumor model, T cell cytotoxicity assay |
Cell reports. Medicine |
High |
38237597
|
| 2024 |
ZDHHC3 S-acylates SCAP at C264, antagonizing HACE1-mediated ubiquitination of SCAP and preventing its proteasomal degradation; SREBP2 transcriptionally upregulates ZDHHC3, forming a positive feedback loop that sustains cholesterol biosynthesis in HCC; depalmitoylase ABHD17A reverses this modification. |
Site-directed mutagenesis (SCAP C264), palmitoylation assay, ubiquitination assay, ChIP/transcription factor binding assay, CRISPR/siRNA knockdown, in vivo DEN/CCl4 HCC mouse model, ZDHHC3 small-molecule inhibitor |
Cell reports |
High |
39522165
|
| 2024 |
ZDHHC3 palmitoylates Cadm4 at cysteine-347 (C347) to stabilize its plasma membrane localization in oligodendrocytes; genetic deletion of ZDHHC3 reduces Cadm4 palmitoylation, causes Cadm4 internalization and degradation, and leads to CNS myelination defects and impaired neuronal transmission/cognitive behavior phenocopying Cadm4-C347A knock-in mice. |
Site-directed mutagenesis (Cadm4 C347A knock-in), ZDHHC3 knockout mice, palmitoylation assay, subcellular fractionation, confocal imaging, electrophysiology, behavioral assays |
Signal transduction and targeted therapy |
High |
39327467
|
| 2024 |
ZDHHC3 catalyzes palmitoylation of the PML/RARα oncofusion protein, which is required for its oncogenic transcriptional activity; ZDHHC3 knockdown or overexpression respectively suppresses or promotes APL cell proliferation and blocks differentiation, and ZDHHC3 inhibition arrests malignant progression including in drug-resistant APL. |
RNAi knockdown, overexpression, palmitoylation assay, gene expression profiling (proliferation/differentiation markers), in vivo APL mouse model |
Acta pharmacologica Sinica |
Medium |
39227737
|
| 2025 |
ZDHHC3 palmitoylates PRRSV nucleocapsid (N) protein at cysteine 90, which prevents N protein interaction with Nsp9 and inhibits viral RNA synthesis; the depalmitoylase LYPLA1 reverses this modification, counteracting ZDHHC3 activity and thereby promoting PRRSV replication. |
Palmitoylation assay, site-directed mutagenesis (N protein C90), co-immunoprecipitation (Nsp9-N interaction), viral RNA synthesis assay, siRNA knockdown, LYPLA1 inhibitor ML348 |
Veterinary microbiology |
Medium |
39787744
|
| 2026 |
ZDHHC3 (together with ZDHHC7) mediates S-acylation of the small GTPase ARL15 at three conserved N-terminal cysteine residues (Cys17, Cys22, Cys23); loss of S-acylation disrupts ARL15 membrane association; dual siRNA knockdown and CRISPR knockout of both ZDHHC3 and ZDHHC7 markedly reduces ARL15 S-acylation and redistributes ARL15 from membranes to cytosol. |
Acyl-PEGyl exchange gel-shift assay (APEGS), site-directed mutagenesis of ARL15 cysteines, siRNA knockdown, CRISPR/Cas9 gene disruption, confocal imaging, subcellular fractionation |
The Journal of biological chemistry |
Medium |
41999893
|
| 2026 |
ZDHHC3 S-acylates CRY1 (the core circadian transcriptional repressor) at four cysteine residues; this S-acylation is required for CRY1 nuclear import and interaction with key clock components; loss of CRY1 S-acylation via cysteine mutagenesis or genetic deletion of DHHC3 impairs CRY1 repressor function and disrupts cellular circadian rhythms. |
Unbiased palmitoylation screen of clock proteins, site-directed mutagenesis of CRY1 cysteines, DHHC3 genetic deletion, nuclear import assay, co-immunoprecipitation of clock components, circadian rhythm bioluminescence reporter assay |
bioRxivpreprint |
Medium |
42239456
|