ZDHHC23

ZDHHC23 is a palmitoyl acyltransferase (S-acyltransferase) that regulates the trafficking, stability, and signaling activity of diverse substrates by catalyzing their S-acylation (PMID:22399288, PMID:37828054). At ion channels, it palmitoylates the intracellular S0-S1 loop of the BK channel α-subunit, an event required for efficient surface delivery from the trans-Golgi network (PMID:22399288) and, independently of surface expression, for functional coupling to regulatory β1-subunits in vascular smooth muscle, as shown by Zdhhc23 knockout (PMID:31213527). A recurrent theme is that ZDHHC23-mediated acylation drives substrate turnover: palmitoylation of the tumor suppressor PHF2 enhances its ubiquitin-dependent proteasomal degradation to promote SREBP1c-dependent lipogenesis in hepatocellular carcinoma (PMID:37828054), and S-acylation of the transcription factor T-bet promotes its degradation to limit Th1 differentiation (PMID:39989253). ZDHHC23 also acts on the RNA-binding protein TDP43 at Cys244, maintaining the liquid-like properties of TDP43 condensates by reducing aberrant interaction with PARP1 and preventing pathological aggregation, with this acylation decreased in ALS disease models (PMID:42127907). Beyond direct acylation, it palmitoylates the thioesterase APT1 to control H-Ras membrane localization and microglial proliferative signaling (PMID:33739454), modifies GFAP to promote astrocyte inflammatory signaling in cancer pain (PMID:38050183), drives nuclear export and exosomal secretion of NAT10 to promote liver fibrosis (PMID:42103688), and competes with ZDHHC18 for the RNF144A–BMI1 ubiquitination complex to regulate glioma stem cell plasticity (PMID:30658672).

1. 2012 High

   Established ZDHHC23 as a palmitoyl acyltransferase acting on an ion channel, defining a trafficking role: it was unknown which zDHHC enzymes control BK channel surface delivery.

   Evidence Heterologous zDHHC overexpression/knockdown with surface biotinylation and palmitoylation assays

   PMID:22399288

   Open questions at the time

   • Did not resolve catalytic site or stoichiometry on the α-subunit
   • Physiological relevance in native tissue not addressed
2. 2019 High

   Distinguished a function for BK α-subunit acylation beyond trafficking—regulatory subunit coupling—answering whether acylation has an electrophysiological role independent of surface expression.

   Evidence Zdhhc23 knockout mice, patch clamp electrophysiology, acyl-RAC, and non-acylatable mutant reconstitution

   PMID:31213527

   Open questions at the time

   • Mechanism by which acylation enables β1 coupling not defined
   • Restricted to vascular smooth muscle context
3. 2019 Medium

   Revealed a non-catalytic, competitive role: ZDHHC23 and ZDHHC18 compete for an E3 ligase complex, showing the enzyme can regulate ubiquitination machinery by protein interaction.

   Evidence Reciprocal Co-IP with LC-MS/MS, colony formation and xenograft assays in glioma stem cells

   PMID:30658672

   Open questions at the time

   • Whether acyltransferase activity is required for the RNF144A interaction unknown
   • Single lab; binding interface not mapped
4. 2021 Medium

   Identified APT1 as a ZDHHC23 (and ZDHHC5) substrate, linking the enzyme to H-Ras membrane localization and microglial signaling in a disease model.

   Evidence zDHHC overexpression palmitoylation assays plus Cln1−/− mouse fractionation and cytokine measurement

   PMID:33739454

   Open questions at the time

   • Relative contribution of ZDHHC23 vs ZDHHC5 not separated
   • Single lab
5. 2023 High

   Defined a palmitoylation→ubiquitination→degradation axis on PHF2, showing ZDHHC23 acylation can target substrates for proteasomal turnover to reprogram lipogenesis.

   Evidence Acyl-biotin exchange, Co-IP, ubiquitination assays, and siRNA in HepG2/Hep3B cells

   PMID:37828054

   Open questions at the time

   • Acylation site on PHF2 not pinpointed
   • In vivo tumor relevance not tested in this study
6. 2024 Medium

   Extended the inflammatory role by showing ZDHHC23 palmitoylates GFAP to drive astrocyte cytokine secretion, and that blocking this acylation is therapeutically tractable.

   Evidence ABE, ELISA, immunofluorescence, and competitive palmitoylation peptide rescue in a mouse cancer pain model

   PMID:38050183

   Open questions at the time

   • GFAP acylation site and direct enzyme-substrate kinetics not defined
   • Single lab
7. 2025 Medium

   Generalized the acylation-driven degradation theme to T-bet, connecting ZDHHC23 to Th1 differentiation control and dietary methionine sensing.

   Evidence ABE, cycloheximide chase, 2-BP inhibition, GPS-Palm prediction, and in vivo gastric cancer tumor model

   PMID:39989253

   Open questions at the time

   • ZDHHC23 assignment rests on computational prediction with pharmacological, not genetic, confirmation
   • T-bet acylation site not experimentally mapped
8. 2026 High

   Provided a mechanistic basis for ZDHHC23 in proteostasis of a phase-separating protein: Cys244 S-acylation of TDP43 preserves condensate fluidity and suppresses ALS-linked aggregation.

   Evidence Cys244 site-directed mutagenesis, S-acylation assays, PARP1 Co-IP, condensate assays, SOD1-G93A mice, and ALS iPSC neurons

   PMID:42127907

   Open questions at the time

   • Whether restoring TDP43 acylation is therapeutic in vivo untested
   • Single lab
9. 2026 Medium

   Showed ZDHHC23 controls intercellular signaling by palmitoylating NAT10 to drive its nuclear export and exosomal secretion, promoting hepatic fibrosis.

   Evidence Palmitoylation assays, exosome proteomics, hepatocyte-specific Nat10 knockout, and exosome transfer in MASH mouse models

   PMID:42103688

   Open questions at the time

   • NAT10 acylation site not defined
   • Genetic ZDHHC23 loss-of-function not tested in this system
10. 2025 Low

    Profiling implicated ZDHHC23 as a hypoxia-responsive node with altered ties to the proteasome and mitochondrial import machinery in neuroblastoma.

    Evidence Quantitative interactome profiling under varied oxygen and chick embryo xenograft (preprint)

    PMID:bio_10.1101_2025.11.03.686197

    Open questions at the time

    • Single-lab proteomic screen without mechanistic follow-up
    • Not peer-reviewed
    • Functional consequence of interactome remodelling unestablished

• The structural determinants and substrate-selection logic that allow one acyltransferase to act on channels, condensate proteins, transcription factors, and nuclear enzymes remain unresolved.
• No structure or catalytic-mechanism study in the corpus
• Acylation sites unmapped for most substrates
• Determinants of substrate specificity unknown