Palmitoyltransferase ZDHHC9

ZDHHC9 is a palmitoyltransferase that catalyzes the addition of palmitate to protein substrates including HRAS, NRAS, ADRB2, GSDMD, and CGAS (UniProt: Q9Y397). Through these modifications, it regulates G protein-coupled receptor signaling, innate immunity via CGAS-mediated cyclic GMP-AMP synthesis, and pyroptosis through GSDMD-dependent pore formation. ZDHHC9 also palmitoylates the SARS-CoV-2 spike protein to promote viral biogenesis.

ZDHHC9 is associated with X-linked intellectual developmental disorder, Raymond type (MRXSR, MIM 300799), characterized by intellectual disability, facial dysmorphism, hypotonia, and behavioral problems (UniProt: Q9Y397). The protein functions across multiple cellular compartments and signaling contexts.

In Alzheimer's disease, ZDHHC9 is significantly downregulated in post-mortem AD brain tissue compared to age-matched controls, with a mean log2 fold-change of −1.074 in a TMT-labeled proteomics study of subcellular fractions (Chaparral AD proteomics). This reduced expression may impact palmitoylation-dependent signaling in neuroinflammation and cell death pathways relevant to neurodegeneration.