ZDHHC18

ZDHHC18 is a DHHC-family protein palmitoyltransferase that controls innate immune signaling, mitochondrial metabolism, and pro-fibrotic signal transduction by S-palmitoylating distinct substrate cysteines (PMID:35438208, PMID:35366151, PMID:39913299). In the cGAS DNA-sensing pathway it palmitoylates cGAS at C474, weakening cGAS binding to double-stranded DNA and blocking its dimerization, so that ZDHHC18 acts as a negative regulator of antiviral signaling—an activity reflected in enhanced resistance to DNA virus infection in Zdhhc18-deficient mice (PMID:35438208). In metabolism, it palmitoylates MDH2 at C138 to raise malate dehydrogenase activity and sustain mitochondrial respiration, a modification engaged under glutamine deprivation and required for ovarian cancer cell growth (PMID:35366151). In epithelial cells it palmitoylates HRAS to drive its plasma-membrane translocation and activation, feeding MEK/ERK and RREB1/SMAD signaling that promotes partial EMT and renal fibrosis, with tubule-specific deletion attenuating fibrosis in vivo (PMID:39913299). A recurring theme is that ZDHHC18-mediated palmitoylation antagonizes ubiquitin-dependent turnover of its targets: it stabilizes MDH2 by preventing its ubiquitination (PMID:38973363) and stabilizes SARS-CoV-2 ORF3a at Cys130/Cys133 by competitively blocking TRIM16-dependent K27-linked polyubiquitination, thereby enhancing viral replication (PMID:42107085). Independently of its enzymatic activity, ZDHHC18 competes with the E3 ligase RNF144A to regulate BMI1 polyubiquitination and accumulation in glioma stem cells (PMID:30658672). Loss-of-function reduces viability across Burkitt lymphoma and ccRCC tumor cells, indicating a broad pro-tumorigenic role (PMID:40645243).

1. 2022 High

   Established ZDHHC18 as a negative regulator of cytosolic DNA sensing by defining cGAS as a direct palmitoylation substrate, answering how an enzymatic modification restrains cGAS activity.

   Evidence Palmitoylation assays, C474 substrate mutagenesis, reciprocal Co-IP, immune reporter assays, and a Zdhhc18 knockout mouse with antiviral phenotype

   PMID:35438208

   Open questions at the time

   • Does not define how ZDHHC18 itself is regulated to time cGAS suppression
   • Structural basis of how C474 palmitoylation blocks DNA binding/dimerization not resolved
2. 2022 High

   Extended ZDHHC18 function to metabolism by showing it palmitoylates MDH2 at C138 to boost enzyme activity and respiration, linking the enzyme to nutrient-responsive cancer growth.

   Evidence Palmitoylation assay, C138S rescue experiments, siRNA knockdown, and in vitro/in vivo respiration and proliferation assays in ovarian cancer

   PMID:35366151

   Open questions at the time

   • Mechanism by which glutamine deprivation enhances the ZDHHC18-MDH2 interaction unknown
   • Whether MDH2 palmitoylation is reversed by a specific thioesterase not addressed
3. 2019 Medium

   Revealed a non-catalytic role: ZDHHC18 (with ZDHHC23) competes with the E3 ligase RNF144A to control BMI1 ubiquitination, governing glioma stem cell plasticity.

   Evidence Reciprocal Co-IP, LC-MS/MS complex identification, xenograft, colony formation and flow cytometry

   PMID:30658672

   Open questions at the time

   • Whether palmitoyltransferase activity contributes to RNF144A competition not determined
   • BMI1 itself not shown to be a palmitoylation substrate
4. 2024 High

   Showed palmitoylation can directly antagonize ubiquitin-dependent degradation, with ZDHHC18 stabilizing SARS-CoV-2 ORF3a by masking a degron and blocking TRIM16-dependent ubiquitination.

   Evidence Palmitoylation and ubiquitination assays, Cys130/133 mutagenesis, Co-IP of competing modifications, OPIP peptide inhibition, viral replication assays

   PMID:42107085

   Open questions at the time

   • Whether host substrates are similarly protected from degradation via the same mechanism not generalized here
   • In vivo therapeutic window of OPIP not defined
5. 2024 Medium

   Connected ZDHHC18-MDH2 palmitoylation to protein stability and drug resistance, showing the modification prevents MDH2 ubiquitination in GIST.

   Evidence Proteome-ubiquitinome mass spectrometry, palmitoylation assay, Co-IP, Western blot

   PMID:38973363

   Open questions at the time

   • Ubiquitin ligase acting on MDH2 not identified
   • Whether the stability effect is separable from the earlier activity-enhancing effect unclear
6. 2025 High

   Defined a pro-fibrotic signaling axis in which ZDHHC18 palmitoylates HRAS to enable membrane localization and MEK/ERK-RREB1/SMAD-driven EMT.

   Evidence Palmitoylation and membrane-localization assays, tubule-specific conditional KO (UUO, folic acid), signaling Western blots

   PMID:39913299

   Open questions at the time

   • Whether ZDHHC18 selectively targets HRAS over other RAS isoforms not resolved
   • Upstream signals controlling ZDHHC18 in tubular epithelium unknown
7. 2025 Medium

   Proposed a phase-separation mechanism whereby ZDHHC18's intrinsically disordered region recruits cGAS and dsDNA to Golgi-associated condensates to suppress immune signaling, complementing the earlier palmitoylation model.

   Evidence Subcellular localization imaging, phase-separation and IDR analysis, dsDNA challenge (preprint)

   PMID:bio_10.1101_2025.08.01.668185

   Open questions at the time

   • Preprint, not peer-reviewed
   • Relationship between condensate formation and C474 palmitoylation of cGAS not integrated
8. 2025 Medium

   Demonstrated a broad tumor-supportive dependency on ZDHHC18 in B-cell lymphoma without defining the responsible substrate.

   Evidence shRNA/siRNA knockdown across four Burkitt lymphoma cell lines with viability readout

   PMID:40645243

   Open questions at the time

   • No substrate or pathway mechanism identified in lymphoma
   • No in vivo validation
9. 2025 Low

   Nominated LYPLA2 as an additional ZDHHC18 substrate in ccRCC linked to proliferation and invasion.

   Evidence Bioinformatics, molecular docking, implied palmitoylation/Co-IP assays, knockdown in 786-O and Caki-1 cells

   PMID:42218414

   Open questions at the time

   • Substrate assignment rests largely on bioinformatics/docking with limited experimental validation
   • Palmitoylation site on LYPLA2 not defined

• How ZDHHC18 substrate selectivity is achieved and how its own activity, localization, and IDR-driven condensation are regulated across immune, metabolic, and fibrotic contexts remains unresolved.
• No structural model of the enzyme or its substrate-recognition determinants
• Regulators and depalmitoylases counteracting ZDHHC18 not identified
• Mechanism coupling palmitoylation to blockade of ubiquitination not generalized