Regulatory effects of post-translational modifications on zDHHC S-acyltransferases

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The human zDHHC S-acyltransferase family comprises 23 enzymes that mediate the S-acylation of a multitude of cellular proteins, including channels, receptors, transporters, signalling molecules, scaffolds and chaperones. This reversible post-transitional modification (PTM) involves the attachment of a fatty acyl chain, usually derived from palmitoyl-CoA, to specific cysteine residues on target proteins, which affects their stability, localisation and function. These outcomes are essential to control many processes, including synaptic transmission and plasticity, cell growth and differentiation, and infectivity of viruses and other pathogens. Given the physiological importance of S-acylation, it is unsurprising that perturbations in this process, including mutations in ZDHHC genes, have been linked to different neurological pathologies and cancers, and there is growing interest in zDHHC enzymes as novel drug targets. Although zDHHC enzymes control a diverse array of cellular processes and are associated with major disorders, our understanding of these enzymes is surprisingly incomplete, particularly in regards to the regulatory mechanisms controlling these enzymes. However, there is growing evidence highlighting the role of different PTMs in this process. In this review, we discuss how PTMs including phosphorylation, S-acylation and ubiquitination affect the stability, localisation and function of zDHHC enzymes and speculate on possible effects of PTMs that have emerged from larger screening studies. Developing a better understanding of the regulatory effects of PTMs on zDHHC enzymes will provide new insight into the intracellular dynamics of S-acylation and may also highlight novel approaches to modulate S-acylation for clinical gain.
Original languageEnglish
JournalJournal of Biological Chemistry
Early online date17 Aug 2020
Publication statusE-pub ahead of print - 17 Aug 2020


  • protein acylation
  • post-translational modification (PTM)
  • protein palmitoylation
  • protein chemical modification
  • S-acylation
  • zDHHC enzyme
  • phosphorylation
  • ubiquitination
  • acetylation
  • methylation

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