Affinage

ZDHHC5

Palmitoyltransferase ZDHHC5 · UniProt Q9C0B5

Length
715 aa
Mass
77.5 kDa
Annotated
2026-06-11
47 papers in source corpus 33 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZDHHC5 is a plasma-membrane DHHC-family protein S-acyltransferase that palmitoylates a broad set of substrates to control their membrane localization, stability, and activity, thereby governing synaptic plasticity, innate immunity, metabolism, and cell adhesion (PMID:22325201, PMID:25422474, PMID:38092000). At neuronal synapses it is held at the membrane through a complex with PSD-95 and Fyn, in which Fyn-mediated tyrosine phosphorylation of the ZDHHC5 endocytic motif stabilizes it; neuronal activity disrupts this complex and drives ZDHHC5 endocytosis to dendritic shafts where it transiently palmitoylates δ-catenin to stabilize cadherin and remodel spines (PMID:24562000, PMID:26334723), and it likewise palmitoylates GRIP1b to accelerate AMPA-receptor recycling (PMID:22325201) and Cdc42-palm to support spine formation (PMID:35597282). Its enzymatic activity is required for substrate effects, demonstrated by catalytically inactive rescue failures across multiple systems (PMID:25422474, PMID:25573953). ZDHHC5 is stabilized at the plasma membrane by the accessory subunit GOLGA7, with which it forms a mutually stabilizing, catalytically active complex, and by palmitoylation of GOLGA7b that blocks its clathrin-mediated endocytosis (PMID:31631010, PMID:31402609); its own C-terminal tail is also palmitoylated in a stimulus-dependent manner to tune membrane dynamics (PMID:31547976). Through palmitoylation of NLRP3 it promotes inflammasome oligomerization, NLRP3-NEK7 interaction, and caspase-1 activation, with ABHD17A serving as the opposing depalmitoylase (PMID:38092000), and AMPK phosphorylation at Ser296/Ser380 weakens its GOLGA7B association to dampen NOD1 signaling, coupling metabolic state to innate immunity (PMID:41890956). ZDHHC5 also palmitoylates beclin 1 to assemble the ATG14L-containing PI3KC3-C1 autophagy complex (PMID:38177673), CD36 to drive fatty acid uptake (PMID:30605677), desmoglein-2 to pattern desmosomes and mediate adhesion (PMID:31402609), and signaling effectors including BRAF, FAK, STAT3, and Gp130 that link it to MAPK/ERK, STAT3, and retrograde axonal signaling and to tumor and myelination phenotypes (PMID:32958558, PMID:34724258, PMID:38233791, PMID:42134490).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2010 Medium

    Established where and with what ZDHHC5 associates in the brain, anchoring it physically to the postsynaptic density rather than treating it as a diffuse membrane enzyme.

    Evidence Reciprocal Co-IP with domain mapping, PSD fractionation, and immunohistochemistry in neurons

    PMID:20178993

    Open questions at the time
    • Did not identify catalytic substrates
    • Functional consequence of the PSD-95 interaction unresolved at this stage
  2. 2011 Medium

    Identified the first concrete substrates (flotillin-2, SSTR5) and showed ZDHHC5 protein levels are themselves controlled by ubiquitin-dependent degradation, establishing it as a regulated enzyme with defined targets.

    Evidence Metabolic palmitate labeling, overexpression rescue, Ras-recruitment interaction screen, and proteasome inhibitor treatment in neural stem cells and COS-1 cells

    PMID:21820437 PMID:22081607

    Open questions at the time
    • Palmitoylation site residues not mapped
    • Mechanism of differentiation-triggered degradation not defined
  3. 2012 High

    Connected ZDHHC5 catalysis to a defined neuronal trafficking output by showing GRIP1b palmitoylation routes endosomes to kinesin motors and accelerates AMPA-receptor recycling.

    Evidence Binding and palmitoylation assays, live imaging of dendritic endosomes, AMPA-R recycling assays

    PMID:22325201

    Open questions at the time
    • Redundancy with DHHC8 not fully separated
    • Endogenous regulation of this turnover not addressed
  4. 2014 High

    Resolved how ZDHHC5 selects substrates and linked its activity to physiology, mapping a substrate-recruitment region in the C-tail and showing site-specific PLM palmitoylation controls Na+/K+ ATPase regulation, plus activity-dependent δ-catenin palmitoylation driving synaptic plasticity.

    Evidence Enzyme C-tail deletion and substrate C40A/C42A mutagenesis with Na pump assay in cardiomyocytes; palmitoylation, spine imaging, mEPSC, and in vivo fear conditioning

    PMID:24562000 PMID:25422474

    Open questions at the time
    • Structural basis of C-tail substrate recruitment unknown
    • How activity is transduced to palmitoylation not yet mechanistic
  5. 2015 High

    Defined the trafficking control logic of ZDHHC5 itself, showing a Fyn/PSD-95-phosphorylation switch governs its membrane retention versus endocytic relocation to reach substrates, and demonstrated strict dependence on catalytic activity for oncogenic phenotypes.

    Evidence Live imaging, Co-IP, Fyn pharmacological inhibition, and endocytosis assays; catalytic-mutant rescue in NSCLC cells and xenografts

    PMID:25573953 PMID:26334723

    Open questions at the time
    • Identity of the cancer-relevant substrate(s) not defined in the NSCLC study
    • Generality of the Fyn switch to non-neuronal cells unknown
  6. 2017 Medium

    Extended ZDHHC5 into GPCR signaling persistence and tumor biology, showing S1P1R palmitoylation enables Gi coupling and that mutant p53 transcriptionally upregulates ZDHHC5 to alter EZH2 in glioma stem cells.

    Evidence Palmitoylation assays with Gi signaling and internalization readouts; ChIP/reporter assays and stem-cell self-renewal assays

    PMID:28775165 PMID:29185452

    Open questions at the time
    • EZH2 palmitoylation sites not mapped
    • Direct enzyme-substrate proof for EZH2 limited to Co-IP/palmitoylation
  7. 2019 High

    Established the GOLGA7/Golga7b accessory module that stabilizes ZDHHC5 at the membrane and broadly expanded its substrate range to metabolism (CD36), adhesion (desmoglein-2), secretion (Furin/PC7), and G-protein/self-palmitoylation, including in vivo knockout phenotypes.

    Evidence CRISPR screen, Co-IP, conditional Dhhc5 KO mice with cold-exposure and fatty-acid-uptake phenotypes, in vitro palmitoylation with purified Gα components, adhesion and toxin-processing assays

    PMID:30605677 PMID:30610172 PMID:31402609 PMID:31547976 PMID:31631010

    Open questions at the time
    • Structural basis of the ZDHHC5-GOLGA7 complex not yet resolved at this stage
    • Rules governing which substrate is engaged in which compartment unclear
  8. 2021 Medium

    Demonstrated cell-type-specific dominant substrates, with STAT3 as the principal oligodendrocyte target controlling myelination through palmitoylation-dependent STAT3 activation.

    Evidence Conditional Zdhhc5 knockout, palmitoylation assay, STAT3 phosphorylation, and myelination histology

    PMID:34724258

    Open questions at the time
    • STAT3 palmitoylation site not specified
    • How palmitoylation couples to STAT3 phosphorylation mechanistically unclear
  9. 2023 High

    Positioned ZDHHC5 as a central node in inflammasome assembly and cytokinesis and as a druggable cancer target, showing LRR-domain NLRP3 palmitoylation (opposed by ABHD17A) drives caspase-1 activation, FAK and BRAF palmitoylation drive tumor signaling, and PCDH7 palmitoylation supports cleavage-furrow function.

    Evidence Palmitoylation and site-directed mutagenesis, NLRP3-NEK7 Co-IP, ASC speck and caspase-1 assays, Zdhhc5 KO mice, RhoA/phospho-myosin and xenograft assays, lomitapide inhibitor study

    PMID:36762613 PMID:36774350 PMID:38092000 PMID:38233791

    Open questions at the time
    • Lomitapide's direct mode of ZDHHC5 inhibition not characterized (Low-confidence)
    • Whether a single ZDHHC5 conformation handles such diverse substrates is unresolved
  10. 2024 High

    Linked ZDHHC5 to autophagy machinery assembly and additional metabolic/neuroinflammatory axes, showing beclin 1 palmitoylation builds the ATG14L PI3KC3-C1 complex with disease relevance in Alzheimer's models.

    Evidence Palmitoylation assay, PI3K lipid-kinase activity assay, Zdhhc5 KO neuronal and AD mouse models; PKCδ and SMPDL3B substrate studies

    PMID:38177673 PMID:38250049 PMID:38266744

    Open questions at the time
    • SMPDL3B palmitoylation site and direct catalysis not established (Low-confidence)
    • Beclin 1 palmitoylation site within the corpus not detailed
  11. 2025 Medium

    Provided the first ZDHHC5-GOLGA7 cryo-EM structure and a metabolic regulatory loop (AMPK phosphorylation at Ser296/380 weakening GOLGA7B binding to dampen NOD1 signaling), plus new substrates spanning iron handling, lymphatic lipid uptake, NADK activation, spermatogenesis, and phagocytosis.

    Evidence Cryo-EM and mutagenesis (preprint), AMPK phosphosite mutagenesis with NOD1 signaling, conditional KO and KO mouse models, in vitro NADK kinase assay (preprint), Syk phagocytosis assay (preprint)

    PMID:39929269 PMID:40589731 PMID:41182177 PMID:41890956

    Open questions at the time
    • Key structural and NADK/Syk findings remain in preprint form
    • A unifying model for compartment- and stimulus-specific substrate selection is still absent

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how a single ZDHHC5 enzyme achieves selectivity across its very large substrate set and how its localization, GOLGA7/GOLGA7b association, phosphorylation, and self-palmitoylation are integrated to direct it to the right substrate in the right compartment.
  • No comprehensive substrate-recognition code defined
  • Limited structural insight into catalysis-substrate engagement
  • Cross-talk between the multiple regulatory inputs not reconstituted

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016740 transferase activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005768 endosome 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 1
Partners
BECN1CD36FYNGOLGA7GOLGA7BNEK7NLRP3PSD-95
Complex memberships
DHHC5/PSD-95/Fyn synaptic complexZDHHC5-GOLGA7 S-acyltransferase complex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 DHHC5 co-immunoprecipitates with PSD-95 in neurons; this interaction is mediated through binding of the C-terminus of DHHC5 to the PDZ3 domain of PSD-95. DHHC5 is highly enriched in post-synaptic density preparations and localizes to CA3 and dentate gyrus of the hippocampus. Co-immunoprecipitation, subcellular fractionation (PSD preparation), immunohistochemistry The Journal of biological chemistry Medium 20178993
2011 DHHC5 palmitoylates flotillin-2; palmitoylation and oligomerization of flotillin-2 are abolished in DHHC5-deficient neuronal stem cells, and overexpression of DHHC5 in COS-1 cells markedly stimulates flotillin-2 palmitoylation, establishing a direct enzyme-substrate relationship. Bioorthogonal palmitate analog (17-octadecynoic acid) metabolic labeling, quantitative proteomics, overexpression in COS-1 cells The Journal of biological chemistry Medium 22081607
2011 DHHC5 down-regulation is triggered within minutes of growth factor withdrawal from neural stem cells (a signal for neuronal differentiation), and this degradation is partially prevented by inhibitors of ubiquitin-mediated proteolysis, indicating DHHC5 protein levels are regulated by ubiquitin-dependent degradation in response to differentiation signals. Growth factor withdrawal experiments, proteasome inhibitor treatment, time-course protein level analysis The Journal of biological chemistry Medium 22081607
2011 ZDHHC5 palmitoylates somatostatin receptor 5 (SSTR5); ZDHHC5 interacts with the membrane-proximal helix 8 of SSTR5 and co-localizes with it at the plasma membrane. Overexpression of ZDHHC5 increases SSTR5 palmitoylation and knockdown decreases it, identifying ZDHHC5 as the first palmitoyltransferase for a GPCR. Ras recruitment interaction screen, co-immunoprecipitation, siRNA knockdown, palmitoylation assay FEBS letters Medium 21820437
2012 DHHC5 (together with DHHC8) palmitoylates GRIP1b via a PDZ ligand unique to DHHC5/8. Palmitoylated GRIP1b is targeted to trafficking endosomes, where it links endosomes to kinesin motors and accelerates AMPA receptor recycling. GRIP1b palmitoylation turnover rate is among the highest reported. Binding assays, palmitoylation assays, live imaging of dendritic endosomes, AMPA-R recycling assays Neuron High 22325201
2014 DHHC5 palmitoylates phospholemman (PLM) at cysteines C40 and C42 (C40 being the principal site) in cardiac ventricular myocytes. DHHC5 localizes to caveolin-enriched cell surface microdomains and co-immunoprecipitates with PLM. Substrate recruitment requires a ~120 amino acid region of the DHHC5 C-tail immediately after the fourth transmembrane domain, not its PDZ-binding motif. PLM palmitoylation at C40, but not C42, is required for PLM-mediated inhibition of the Na+/K+ ATPase. Co-immunoprecipitation, overexpression and siRNA silencing, site-directed mutagenesis (C40A, C42A), Na pump activity assay, subcellular fractionation Proceedings of the National Academy of Sciences of the United States of America High 25422474
2014 DHHC5 transiently palmitoylates δ-catenin after enhanced synaptic activity, promoting δ-catenin-cadherin interactions at synapses. This palmitoylation is required for activity-induced stabilization of N-cadherin at synapses, enlargement of postsynaptic spines, insertion of GluA1/GluA2 into the synaptic membrane, and increased mEPSC amplitude. Context-dependent fear conditioning in mice increased δ-catenin palmitoylation and δ-catenin-cadherin associations at hippocampal synapses. Palmitoylation assay, co-immunoprecipitation, spine morphology imaging, electrophysiology (mEPSC), in vivo fear conditioning Nature neuroscience High 24562000
2015 Under basal conditions, DHHC5 is bound to PSD-95 and Fyn kinase at the synaptic membrane; Fyn-mediated phosphorylation of a tyrosine residue within the endocytic motif of DHHC5 stabilizes it at the membrane. Neuronal activity disrupts the DHHC5/PSD-95/Fyn complex, causing DHHC5 endocytosis and translocation to dendritic shafts where it encounters and palmitoylates its substrate δ-catenin, after which both return to spines. Live-cell imaging, co-immunoprecipitation, pharmacological inhibition of Fyn, endocytosis assays, palmitoylation assays Nature communications High 26334723
2015 Catalytic activity of DHHC5 is required for NSCLC cell proliferation, colony formation, invasion, and tumor xenograft growth; rescue with wild-type but not catalytically inactive DHHC5 confirms the dependence on enzymatic activity. siRNA/shRNA knockdown, lentiviral re-expression of WT vs. catalytic mutant DHHC5, in vitro proliferation/invasion assays, xenograft mouse models Molecular cancer research : MCR Medium 25573953
2017 ZDHHC5 palmitoylates EZH2 in glioma cells; mutant p53 transcriptionally upregulates ZDHHC5 (together with NF-Y), which alters EZH2 palmitoylation and phosphorylation status, promoting glioma stem-like cell self-renewal and tumorigenicity. Co-immunoprecipitation, palmitoylation assay, ChIP/reporter assay for transcriptional regulation, glioma stem cell self-renewal assays Cancer research Medium 28775165
2017 DHHC5 palmitoylates the S1P receptor subtype 1 (S1P1R) at the plasma membrane, which is prerequisite for Gi protein coupling. Upon receptor stimulation and internalization, S1P1R is depalmitoylated. FTY720-P-induced endocytosed S1P1R vesicles subsequently associate with DHHC5, enabling persistent intracellular Gi signaling. Palmitoylation assay, co-immunoprecipitation, subcellular localization imaging, cAMP/Gi signaling assays, receptor internalization assays Scientific reports Medium 29185452
2019 DHHC4 and DHHC5 palmitoylate CD36 at different subcellular localizations to control its plasma membrane localization and fatty acid uptake activity. Depletion of DHHC5 disrupts CD36-dependent fatty acid uptake in cells, and adipose-specific Dhhc5 knockout mice show decreased fatty acid uptake in adipose tissue and develop hypothermia upon cold exposure. Palmitoylation assay, siRNA/shRNA knockdown, fatty acid uptake assay, conditional knockout mouse model, cold exposure phenotype Cell reports High 30605677
2019 ZDHHC5 forms a catalytically active protein S-acyltransferase complex with the accessory subunit GOLGA7. The ZDHHC5-GOLGA7 complex is mutually stabilizing and localizes to the plasma membrane. This complex is required for CIL56-induced nonapoptotic cell death and is involved in retrograde protein trafficking from the plasma membrane. CRISPR genetic screen, co-immunoprecipitation, subcellular localization imaging, cell death assays with catalytic mutants Cell chemical biology Medium 31631010
2019 DHHC5 palmitoylates the proprotein convertases Furin and PC7. ZDHHC5-mediated palmitoylation promotes Furin/PC7 association with plasma membrane microdomains, which is required for cleavage of anthrax toxin protective antigen (but does not inhibit protease activity per se). ZDHHC5 also affects homeostasis and trafficking of Furin/PC7 through the endocytic/recycling pathway. Palmitoylation assay, subcellular fractionation (lipid raft), siRNA knockdown, anthrax toxin processing assay Proceedings of the National Academy of Sciences of the United States of America Medium 30610172
2019 DHHC5 binds to and palmitoylates Golga7b. Palmitoylation of Golga7b prevents clathrin-mediated endocytosis of DHHC5 and stabilizes it at the plasma membrane. Desmoglein-2 and plakophilin-3 are substrates of DHHC5, and DHHC5/Golga7b are required for desmoglein-2 plasma membrane localization, desmosomal patterning, and cell adhesion. Co-immunoprecipitation, palmitoylation assay, siRNA knockdown, fluorescence imaging, proteomic analysis of complexes, cell adhesion assays EMBO reports High 31402609
2019 DHHC5 mediates β-adrenergic stimulation-dependent palmitoylation of Gαs and Gαi in cardiomyocytes. An in vitro palmitoylation assay with purified components established Gαs and Gαi as direct DHHC5 substrates. The C-terminal tail of DHHC5 itself is palmitoylated in response to stimulation, which is important for DHHC5 dynamic localization and function at the plasma membrane. In vitro palmitoylation assay with purified components, siRNA knockdown, cAMP measurement, contractility assay, subcellular localization imaging Biophysical journal High 31547976
2020 Among all mammalian PATs, only ZDHHC5 and ZDHHC8 are enriched in DRG axons. Both are required for Gp130/JAK/STAT3 (but not DLK/JNK) axon-to-soma retrograde signaling after injury. ZDHHC5 and ZDHHC8 palmitoylate Gp130 in co-transfected cells; shRNA knockdown reduces Gp130 palmitoylation and surface expression in DRG neurons. Immunofluorescence localization screen of all PATs in DRG neurons, shRNA knockdown, palmitoylation assay, STAT3/JNK signaling assays, co-transfection palmitoylation assay The Journal of biological chemistry Medium 32958558
2021 DHHC5 palmitoylates STAT3 in oligodendrocytes; STAT3 is the primary DHHC5 substrate in these cells. DHHC5 ablation reduces STAT3 palmitoylation and suppresses STAT3 phosphorylation/activation, inhibiting transcription of myelin-related and anti-apoptosis genes and suppressing myelination and remyelination. Conditional Zdhhc5 knockout, palmitoylation assay, STAT3 phosphorylation western blot, myelination histology, gene expression analysis Glia Medium 34724258
2021 ZDHHC5 and GOLGA7 interact with the SARS-CoV-2 spike protein and are required for efficient SARS-CoV-2 pseudovirus entry into A549 and HeLa cells. ZDHHC5/GOLGA7 knockout had no significant effect on S protein subcellular localization or palmitoylation, but significantly decreased pseudovirus entry. CRISPR-Cas9 knockout, co-immunoprecipitation, ABE palmitoylation assay, pseudovirus entry luciferase assay, fluorescence microscopy Virology journal Medium 34961524
2022 DHHC5 palmitoylates the brain-specific isoform Cdc42-palm; DHHC5 physically interacts with Cdc42-palm. A dominant-negative DHHC5 mutant or DHHC5 knockdown decreases Cdc42-palm palmitoylation and plasma membrane localization, leading to reduced Cdc42-mediated gene transcription and spine formation in hippocampal neurons. Co-immunoprecipitation, palmitoylation assay, dominant-negative and shRNA approaches, fluorescence imaging, spine morphology analysis, transcription reporter assay The Journal of biological chemistry Medium 35597282
2023 ZDHHC5 palmitoylates NLRP3 at the LRR domain. This palmitoylation promotes NLRP3 oligomerization, NLRP3-NEK7 interaction, and ASC aggregate formation, leading to caspase-1 activation, IL-1β/18 release, and GSDMD cleavage. ABHD17A acts as the depalmitoylase for NLRP3. Zdhhc5-/- mice show defective NLRP3 inflammasome activation in vivo. Palmitoylation assay, siRNA/KO, co-immunoprecipitation (NLRP3-NEK7), ASC speck imaging, caspase-1 activation assay, IL-1β/18 ELISA, GSDMD cleavage, Zdhhc5 KO mouse model Molecular cell High 38092000
2023 ZDHHC5 palmitoylates FAK at C456, promoting FAK membrane localization and phosphorylation (activation). ZDHHC5 knockdown abolishes FAK palmitoylation and membrane distribution, reducing cell proliferation, invasion, and EMT in glioblastoma cells and tumor growth in intracranial xenografts. Acyl-PEG exchange assay, metabolic incorporation assay, subcellular fractionation/imaging, siRNA knockdown, 2-BP inhibition, CCK8/invasion/colony assays, intracranial xenograft Cell communication and signaling : CCS Medium 38233791
2023 ZDHHC5 palmitoylates protocadherin 7 (PCDH7) in a cell cycle-dependent manner. PCDH7 and ZDHHC5 colocalize at the mitotic cell surface and translocate together to the cleavage furrow. PCDH7 localization at the cell surface depends on ZDHHC5 palmitoylation activity. Loss of PCDH7 increases multinucleated cells, prolongs mitosis, and reduces active RhoA and phospho-myosin at the cleavage furrow. Co-immunoprecipitation, palmitoylation assay, live-cell imaging, siRNA knockdown, RhoA activity assay, phospho-myosin immunofluorescence Journal of cell science Medium 36762613
2023 ZDHHC5 palmitoylates SSTR5 and lomitapide, an FDA-approved drug, acts as an inhibitor of ZDHHC5, blocking palmitoylation of SSTR5 and reducing pancreatic cancer cell growth in vitro and in vivo. Palmitoylation assay, drug treatment (lomitapide), cell proliferation assays, in vivo xenograft Cell death discovery Low 36774350
2023 Frizzled-5 (Fz5) is S-acylated on three C-terminal cysteines by zDHHC5. S-acylation is essential for Fz5 localization to the cell surface, axons, and presynaptic sites; S-acylation-deficient Fz5 is internalized faster and fails to activate canonical and divergent canonical Wnt pathways. S-acylation levels of Fz5 are regulated by neuronal activity, and S-acylation-deficient Fz5 fails to induce presynaptic assembly in vivo. Palmitoylation assay, mutagenesis of acylation sites, live imaging, internalization assay, Wnt pathway reporter assay, in vivo presynaptic assembly assay Developmental cell High 37557176
2024 DHHC5 mediates palmitoylation of beclin 1, which promotes formation of the ATG14L-containing class III PI3K complex I (PI3KC3-C1) and its lipid kinase activity, by enhancing hydrophobic interactions between beclin 1 and adapter proteins ATG14L and VPS15. DHHC5 deficiency in neurons exaggerates neurodegeneration in Alzheimer's disease mouse models in an autophagy-dependent manner. Palmitoylation assay, co-immunoprecipitation, PI3K lipid kinase activity assay, Zdhhc5 KO neuronal models, autophagy flux analysis, AD mouse models Nature structural & molecular biology High 38177673
2024 ZDHHC5 palmitoylates PKCδ in hypothalamic microglia; an antimalarial drug (artemether) blocks ZDHHC5-PKCδ binding to inhibit PKCδ palmitoylation, suppressing downstream neuroinflammation signaling and improving hepatic lipid metabolism via TRH/thyroid hormone neuroendocrine axis. Biotin-labeled chemical probe pulldown, co-immunoprecipitation, palmitoylation assay, siRNA knockdown, neuroendocrine assays, high-fat diet mouse model Theranostics Medium 38250049
2024 ZDHHC5 palmitoylates SMPDL3B, and high glucose exposure increases ZDHHC5-SMPDL3B interaction. Palmitoylation by ZDHHC5 stabilizes SMPDL3B protein; inhibiting palmitoylation accelerates SMPDL3B degradation, while inhibiting depalmitoylation decreases its turnover rate in retinal endothelial cells. Co-immunoprecipitation, palmitoylation inhibitor (2-BP) and depalmitoylation inhibitor (palmostatin B) treatment, protein stability assay Cellular signalling Low 38266744
2024 ZDHHC5 palmitoylates BRAF at Cys194/195 in cholangiocarcinoma cells, promoting BRAF membrane localization and protein stabilization. This activates ERK/MAPK signaling. Knockdown of ZDHHC5 or mutation of BRAF palmitoylation sites inhibits ERK signaling and cholangiocarcinoma growth. Palmitoylation assay, site-directed mutagenesis (C194/195A), ERK western blot, siRNA knockdown, cell proliferation assay Cancer letters Medium 42134490
2025 DHHC5 palmitoylates transferrin receptor 1 (TfR1) at C98 in oligodendrocytes, which is required for regulation of TfR1 endocytosis. In neonatal sevoflurane-exposed mice, DHHC5 is specifically downregulated in oligodendrocytes, reducing TfR1 palmitoylation, enhancing TfR1 endocytosis, causing iron accumulation and ferroptosis, leading to hypomyelination. Acyl-resin assisted capture assay, co-immunoprecipitation, specific oligodendrocyte DHHC5 overexpression (Pdgfrα-CreERT), single-cell RNA sequencing, TfR1 endocytosis assay Journal of advanced research Medium 39929269
2025 ZDHHC5 mediates IFT81 palmitoylation in round spermatids; ZDHHC5 predominantly localizes to the Golgi apparatus of round spermatids (steps 2-8). Zdhhc5 KO male mice are completely infertile with defective spermatogenesis, reduced sperm motility, and sperm tail malformations linked to defective IFT81 regulation. CRISPR/Cas9 knockout, immunofluorescence localization, palmitoylation assay, sperm morphology/motility analysis, IVF, ICSI rescue Reproduction (Cambridge, England) Medium 41182177
2025 DHHC5 palmitoylates CRYBG1 (an actin-binding protein) in lymphatic endothelial cells; CRYBG1 palmitoylation is required for VEGFR2 lipid raft localization, which promotes VEGFR2 signaling and intestinal lymphatic integrity. Dhhc5 intestinal/LEC-specific knockout mice show impaired intestinal lipid absorption and resistance to diet-induced obesity. Conditional Dhhc5 knockout, palmitoylation assay, lipid raft fractionation, VEGFR2 signaling assay, lipid absorption assay Life metabolism Medium 40589731
2025 AMPK phosphorylates ZDHHC5 at Ser296 and Ser380, which weakens ZDHHC5 association with GOLGA7B and promotes ZDHHC5 displacement from the plasma membrane, thereby reducing NOD1 palmitoylation, NOD1 membrane localization, and downstream NOD1 innate immune signaling. Conversely, NOD1 agonist C12-iE-DAP suppresses AMPK activity to stabilize ZDHHC5 at the membrane. Biochemical phosphorylation assay, site-directed mutagenesis (Ser296/380), co-immunoprecipitation, palmitoylation assay, NOD1 membrane fractionation, NF-κB signaling assay iScience Medium 41890956
2025 ZDHHC5 palmitoylates NADK at Cys22, Cys23, and Cys26 within its amino-terminal domain, stimulating NADK kinase activity by relieving an autoinhibitory function of the amino terminus and promoting NADP+ synthesis. Zdhhc5-/- mice show defective NADK palmitoylation and NADP+ production. In vitro palmitoylation assay, site-directed mutagenesis, NADK kinase activity assay, Zdhhc5 KO mouse model, metabolomics (NADP+ measurement) bioRxivpreprint Medium
2025 The ZDHHC5-GOLGA7 complex structure was determined by cryo-EM. Key conserved residues in both ZDHHC5 and GOLGA7 required for complex formation were identified by mutagenesis; disruption of these residues abolished CIL56-induced nonapoptotic cell death. Cryo-EM structure determination, biochemical purification, homology modeling, mutagenesis, cell death functional assays bioRxivpreprint Medium
2025 DHHC5 palmitoylates Syk on a single cysteine residue during FcγR-mediated phagocytosis in macrophages. Syk palmitoylation is required for Syk localization to the phagocytic cup, Syk phosphorylation/activation, Cdc42 recruitment, F-actin polymerization, and phagocytosis. S-acylation assay, site-directed mutagenesis, fluorescence imaging of phagocytic cup, Syk phosphorylation western blot, phagocytosis assay bioRxivpreprint Medium
2025 ZDHHC5 palmitoylates YBX1 (via PANoptosis-related mechanism in intervertebral disc cells), and ZDHHC5-enriched extracellular vesicles modulate ZBP1 transcription through competitive inhibition of YBX1 phosphorylation via palmitoylation. Transcriptomics, scRNA-seq, co-immunoprecipitation, palmitoylation assay, extracellular vesicle delivery, transcriptional reporter assay Journal of tissue engineering Low 41179831

Source papers

Stage 0 corpus · 47 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 DHHC4 and DHHC5 Facilitate Fatty Acid Uptake by Palmitoylating and Targeting CD36 to the Plasma Membrane. Cell reports 162 30605677
2012 Palmitoylation by DHHC5/8 targets GRIP1 to dendritic endosomes to regulate AMPA-R trafficking. Neuron 158 22325201
2023 ZDHHC5-mediated NLRP3 palmitoylation promotes NLRP3-NEK7 interaction and inflammasome activation. Molecular cell 122 38092000
2011 DHHC5 protein palmitoylates flotillin-2 and is rapidly degraded on induction of neuronal differentiation in cultured cells. The Journal of biological chemistry 122 22081607
2017 EZH2 Palmitoylation Mediated by ZDHHC5 in p53-Mutant Glioma Drives Malignant Development and Progression. Cancer research 106 28775165
2014 Substrate recognition by the cell surface palmitoyl transferase DHHC5. Proceedings of the National Academy of Sciences of the United States of America 105 25422474
2014 Palmitoylation of δ-catenin by DHHC5 mediates activity-induced synapse plasticity. Nature neuroscience 103 24562000
2015 Activity-regulated trafficking of the palmitoyl-acyl transferase DHHC5. Nature communications 97 26334723
2010 DHHC5 interacts with PDZ domain 3 of post-synaptic density-95 (PSD-95) protein and plays a role in learning and memory. The Journal of biological chemistry 73 20178993
2019 S-acylated Golga7b stabilises DHHC5 at the plasma membrane to regulate cell adhesion. EMBO reports 55 31402609
2019 A ZDHHC5-GOLGA7 Protein Acyltransferase Complex Promotes Nonapoptotic Cell Death. Cell chemical biology 55 31631010
2015 Systematic siRNA Screen Unmasks NSCLC Growth Dependence by Palmitoyltransferase DHHC5. Molecular cancer research : MCR 45 25573953
2024 Reduction of DHHC5-mediated beclin 1 S-palmitoylation underlies autophagy decline in aging. Nature structural & molecular biology 35 38177673
2019 DHHC5 Mediates β-Adrenergic Signaling in Cardiomyocytes by Targeting Gα Proteins. Biophysical journal 35 31547976
2024 Palmitoylation of PKCδ by ZDHHC5 in hypothalamic microglia presents as a therapeutic target for fatty liver disease. Theranostics 32 38250049
2020 The palmitoyl acyltransferases ZDHHC5 and ZDHHC8 are uniquely present in DRG axons and control retrograde signaling via the Gp130/JAK/STAT3 pathway. The Journal of biological chemistry 32 32958558
2024 ZDHHC5-mediated S-palmitoylation of FAK promotes its membrane localization and epithelial-mesenchymal transition in glioma. Cell communication and signaling : CCS 30 38233791
2020 Circ-ZDHHC5 Accelerates Esophageal Squamous Cell Carcinoma Progression in vitro via miR-217/ZEB1 Axis. Frontiers in cell and developmental biology 30 33392180
2023 Repositioning Lomitapide to block ZDHHC5-dependant palmitoylation on SSTR5 leads to anti-proliferation effect in preclinical pancreatic cancer models. Cell death discovery 27 36774350
2011 Somatostatin receptor 5 is palmitoylated by the interacting ZDHHC5 palmitoyltransferase. FEBS letters 27 21820437
2021 Regulation and function of the palmitoyl-acyltransferase ZDHHC5. The FEBS journal 26 33415776
2019 Anthrax toxin requires ZDHHC5-mediated palmitoylation of its surface-processing host enzymes. Proceedings of the National Academy of Sciences of the United States of America 26 30610172
2021 The interactions of ZDHHC5/GOLGA7 with SARS-CoV-2 spike (S) protein and their effects on S protein's subcellular localization, palmitoylation and pseudovirus entry. Virology journal 25 34961524
2021 DHHC5 facilitates oligodendrocyte development by palmitoylating and activating STAT3. Glia 23 34724258
2023 C-Phycocyanin Ameliorates the Senescence of Mesenchymal Stem Cells through ZDHHC5-Mediated Autophagy via PI3K/AKT/mTOR Pathway. Aging and disease 22 37163424
2022 Dynamic but discordant alterations in zDHHC5 expression and palmitoylation of its substrates in cardiac pathologies. Frontiers in physiology 21 36277202
2022 Propofol enhances stem-like properties of glioma via GABAAR-dependent Src modulation of ZDHHC5-EZH2 palmitoylation mechanism. Stem cell research & therapy 20 35927718
2017 DHHC5-mediated palmitoylation of S1P receptor subtype 1 determines G-protein coupling. Scientific reports 19 29185452
2017 LXR Activation Down-regulates Lipid Raft Markers FLOT2 and DHHC5 in MCF-7 Breast Cancer Cells. Anticancer research 15 28739689
2024 SMPDL3B is palmitoylated and stabilized by ZDHHC5, and its silencing aggravates diabetic retinopathy of db/db mice: Activation of NLRP3/NF-κB pathway. Cellular signalling 12 38266744
2025 Neonatal sevoflurane exposures inhibits DHHC5-mediated palmitoylation of TfR1 in oligodendrocytes, leading to hypomyelination and neurological impairments. Journal of advanced research 11 39929269
2022 Palmitoylation of the small GTPase Cdc42 by DHHC5 modulates spine formation and gene transcription. The Journal of biological chemistry 11 35597282
2020 miR-96-5p enhances cell proliferation and invasion via targeted regulation of ZDHHC5 in gastric cancer. Bioscience reports 9 32202303
2025 Protocatechuic Acid Reduces Liver Fatty Acid Uptake in HFD-Fed Mice Associated With the Inhibition of DHHC5-Mediated CD36 Palmitoylation. Molecular nutrition & food research 8 40109131
2023 Cell cycle-dependent palmitoylation of protocadherin 7 by ZDHHC5 promotes successful cytokinesis. Journal of cell science 7 36762613
2023 S-acylation of the Wnt receptor Frizzled-5 by zDHHC5 controls its cellular localization and synaptogenic activity in the rodent hippocampus. Developmental cell 6 37557176
2026 ZDHHC5-mediated BRAF palmitoylation activates the MAPK pathway and drives cholangiocarcinoma progression. Cancer letters 1 42134490
2025 DHHC5 regulates lacteal function and intestinal lipid absorption by maintaining VEGFR2 localization in lipid rafts. Life metabolism 1 40589731
2025 ZDHHC5 Mediates Immune Dysregulation Driving Generalized Anxiety Disorder Risk. Brain and behavior 1 40898659
2025 The emerging role of palmitoyl acyltransferase zDHHC5 in health and disease: A review. International journal of biological macromolecules 1 41086885
2025 ZDHHC5 deficiency impairs spermatogenesis and causes male infertility in mice. Reproduction (Cambridge, England) 1 41182177
2026 Metabolic orchestration of NOD1 signaling by AMPK-mediated phosphorylation of ZDHHC5. iScience 0 41890956
2026 DNA methylation-regulated ZDHHC5 and PPT1 in the pathogenesis of osteoporosis. Medicine 0 42071838
2026 ZDHHC5: a pivotal palmitoyltransferase orchestrating signaling networks - unraveling mechanisms and therapeutic horizons. Biomarker research 0 42098785
2026 miR-130a-3p regulates the occurrence and progression of lung squamous cell carcinoma by activating ZDHHC5 and immune cell-related pathways. Medicine 0 42260863
2025 Amelioration of intervertebral disc degeneration using engineered extracellular vesicle-delivered ZDHHC5 via inhibiting PANoptosis. Journal of tissue engineering 0 41179831
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

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