ZDHHC8

ZDHHC8 is a transmembrane palmitoyl acyltransferase that S-palmitoylates a diverse set of substrates to control neuronal signaling, synaptic plasticity, and cancer-cell survival (PMID:24068808, PMID:38211651). In the nervous system it palmitoylates PICK1 at a cysteine essential for cerebellar long-term depression (PMID:24068808), drives GluA1/AMPA-receptor surface trafficking and seizure susceptibility (PMID:30038264), stabilizes the dendritic-spine localization of the 190 kDa ankyrin-G isoform at Cys70 in a lithium-inhibited reaction (PMID:36969554), and—together with ZDHHC5—palmitoylates Gp130 to sustain its surface expression and JAK/STAT3 retrograde axonal signaling in DRG neurons (PMID:32958558). Consistent with these palmitoylation-dependent neuronal roles, a splice-regulatory SNP and Zdhhc8 knockout produce psychiatric-relevant behavioral deficits in mice (PMID:15184899). In tumors ZDHHC8 promotes ferroptosis resistance by palmitoylating SLC7A11 at Cys327 to reduce its ubiquitination and stabilize the protein—an interaction strengthened by AMPKα1 phosphorylation of ZDHHC8 at Ser299—and by palmitoylating GPX4 at Cys75 to maintain GPX4 stability, with the inhibitor PF-670462 reversing both to sensitize tumors to ferroptosis and immunotherapy (PMID:38211651, PMID:40108413). ZDHHC8 expression is directly driven by KLF5, defining a KLF5–ZDHHC8–β-catenin axis that confers chemoresistance in ovarian cancer (PMID:40681764).

1. 2004 Medium

   Established ZDHHC8 as a candidate neuronal palmitoyltransferase whose expression is splice-regulated and whose loss produces psychiatric-relevant behavioral phenotypes, linking palmitoylation to brain function.

   Evidence SNP genotyping/splice analysis and Zdhhc8-knockout mouse behavioral phenotyping

   PMID:15184899

   Open questions at the time

   • No direct neuronal substrate identified at this stage
   • Mechanism connecting palmitoyltransferase activity to behavior unresolved
2. 2011 Medium

   Showed ZDHHC8 supports the G2/M checkpoint and genomic stability, providing the first evidence of a role in cancer-cell survival independent of any identified substrate.

   Evidence siRNA knockdown in mesothelioma with cell-cycle, micronuclei, apoptosis, and xenograft readouts

   PMID:22017350

   Open questions at the time

   • No palmitoylation substrate linking ZDHHC8 to checkpoint control
   • Catalytic dependence not tested
3. 2013 High

   Identified PICK1 as a direct ZDHHC8 substrate and connected its palmitoylation to a defined form of synaptic plasticity, moving from candidate enzyme to mechanistic substrate-function chain.

   Evidence Co-IP/palmitoylation assays, PICK1 cysteine mutagenesis, and LTD electrophysiology in cerebellar Purkinje neurons

   PMID:24068808

   Open questions at the time

   • Whether other synaptic substrates contribute to plasticity not addressed
   • In vivo requirement not tested
4. 2018 Medium

   Extended ZDHHC8's synaptic role to AMPA-receptor trafficking, linking it bidirectionally to neuronal excitability and seizure susceptibility.

   Evidence rAAV knockdown/overexpression in mice, patch-clamp, GluA1 surface biochemistry, and seizure models

   PMID:30038264

   Open questions at the time

   • Direct palmitoylation of GluA1 versus indirect trafficking effect not fully resolved
   • Single lab
5. 2020 High

   Demonstrated axonal enrichment of ZDHHC8 and its requirement, with ZDHHC5, for Gp130 palmitoylation and retrograde JAK/STAT3 signaling, defining pathway specificity.

   Evidence PAT localization in DRG neurons, shRNA knockdown, Gp130 palmitoylation assay, STAT3 signaling and surface-expression readouts

   PMID:32958558

   Open questions at the time

   • Relative contribution of ZDHHC8 versus ZDHHC5 not dissected
   • Palmitoylation site on Gp130 not mapped
6. 2023 Medium

   Mapped ankyrin-G-190 Cys70 as a ZDHHC8 site controlling dendritic-spine nanodomain stability and showed lithium acts as a ZDHHC8 inhibitor, providing a pharmacological handle.

   Evidence Palmitoylation assays, Cys70 mutagenesis, FRAP imaging, and lithium treatment in neurons

   PMID:36969554

   Open questions at the time

   • Mechanism of lithium inhibition of ZDHHC8 unknown
   • Direct versus indirect lithium effect not separated
7. 2024 High

   Defined a ferroptosis-protective axis in which ZDHHC8 palmitoylates SLC7A11 at Cys327 to block ubiquitination, with AMPKα1 phosphorylation at Ser299 tuning the interaction, integrating ZDHHC8 into metabolic-stress signaling.

   Evidence Palmitoylation and ubiquitination assays, substrate (Cys327) and enzyme (Ser299) mutagenesis, Co-IP, and ferroptosis rescue in glioblastoma cells

   PMID:38211651

   Open questions at the time

   • No structural basis for phospho-regulated substrate binding
   • Generalizability beyond GBM not tested
8. 2025 High

   Identified GPX4 Cys75 as a second ferroptosis-relevant ZDHHC8 substrate and validated PF-670462 as a ZDHHC8 inhibitor that sensitizes tumors to ferroptosis and immunotherapy.

   Evidence Palmitoylation assays, GPX4 Cys75 mutagenesis, small-molecule screening, and B16-F10 xenograft immunotherapy models

   PMID:40108413

   Open questions at the time

   • Inhibitor selectivity against other ZDHHC enzymes not exhaustively defined
   • Whether SLC7A11 and GPX4 palmitoylation are co-regulated unclear
9. 2025 Medium

   Placed ZDHHC8 downstream of KLF5 transcriptional control in a β-catenin chemoresistance axis, connecting its regulation to ovarian cancer drug response.

   Evidence ChIP, luciferase reporter, knockdown/overexpression with cisplatin sensitivity and β-catenin rescue, animal models

   PMID:40681764

   Open questions at the time

   • Palmitoylation substrate linking ZDHHC8 to β-catenin not identified
   • Catalytic requirement for chemoresistance untested
10. 2025 Medium

    Established Gαq as a conserved ZDHHC8 substrate required for GPCR membrane localization and signaling using unbiased genetic screening in Drosophila.

    Evidence Genome-wide CRISPR screen and Gαq palmitoylation/localization/signaling assays in Drosophila (preprint)

    PMID:bio_10.1101_2025.08.06.668953

    Open questions at the time

    • Not peer-reviewed
    • Conservation of human ZDHHC8-Gαq interaction not demonstrated

• How ZDHHC8 selects among its diverse substrates across neuronal and tumor contexts, and whether a single catalytic mechanism is differentially regulated by phosphorylation, transcription, and pharmacology, remains unresolved.
• No structural model of substrate recognition
• Tissue-specific substrate prioritization mechanism unknown
• Whether neuronal and oncogenic functions share regulatory inputs untested