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

Abstract

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.

Regulatory effects of protein S-acylation on insulin secretion and insulin action

“…Protein S-acylation dynamics have been previously shown to be affected by insulin treatment in human umbilical vein endothelial cells (with 35 of 375 high royalsocietypublishing.org/journal/rsob Open Biol. 11: 210017 confidence S-acylated proteins showing altered S-acylation following insulin treatment) [130], and indeed a 10-min insulin stimulation of 3T3-L1 adipocytes led to a 3-fold increase in GLUT4 S-acylation [124]. This was accompanied by a corresponding 3-fold increase in autoacylation of zDHHC7 [124].…”

“…As autoacylation is often used as a measure of zDHHC enzyme activity [ 2 ], this led to the suggestion that insulin activates zDHHC7, which then increases S-acylation of GLUT4. It is unclear how insulin treatment leads to an elevation in zDHHC7 activity but it is worth noting that zDHHC enzymes are regulated by a variety of different PTMs [ 131 ] and indeed zDHHC20 was shown to display increased tyrosine phosphorylation in insulin-stimulated 3T3-L1 adipocytes [ 132 ]. Thus, a similar phosphorylation event (or other PTM) could underlie the effects of insulin on zDHHC7 activity and GLUT4 S-acylation.…”

Protein cysteine palmitoylation in immunity and inflammation

“…This is important as too much palmitoylation may lead to uncontrollable inflammation while too little palmitoylation may lead Accepted Article to immune deficiency. Although some regulatory mechanisms are known [142], such as the regulation of ZDHHC13 by phosphorylation [134], the regulation of ZDHHC6 [143] and APT1/APT2 [24] by palmitoylation, much more needs to be learned. Understanding the regulatory mechanisms of palmitoyltransferases and depalmitoylases is another challenge that future research should address.…”

Protein S -palmitoylation in immunity

“…PATs were first discovered in yeast and are conserved across all eukaryotes, though their numbers and specificities can differ between species [9,10]. Regulation at transcriptional, translational and posttranslational levels, as well as PAT variable domains, determine localization, specific substrate profiles and functionality of individual enzymes [11]. Recent structural studies of PAT family members have provided key understanding of reaction mechanism, substrate recognition, interaction, binding and fatty acyl chain selectivity and PAT substrates in many patho-physiological conditions including cancer and schizophrenia [14,15].…”