S-acylation is a reversible post-translational modification of free cysteine residues with fatty acids, predominantly palmitic acid; this modification targets peripheral proteins to membranes and also regulates protein trafficking and turnover. Among the proteins that are lipidated in this way are the SNAREs, which are involved in intracellular membrane fusion. Syntaxin 19 (STX19), one of the least-characterised SNAREs, has been found to be S-acylated; however, the role of S-acylation in regulating STX19 trafficking and function is unclear. In this study (Ampah et al., 2018), Andrew Peden and co-workers thus investigate the localisation and function of STX19 in more detail and first observe that a pool of endogenous STX19 is found at tubular recycling endosomes. Interestingly, S-acylation is important for this targeting because its inhibition alters the localisation of STX19. Furthermore, the authors show that several cysteine residues within the cysteine-rich domain of STX19 are a substrate for Golgi-localised S-acyltransferases, indicating that STX19 is first S-acylated in the Golgi prior to trafficking to the cell membrane and recycling endosomes. In addition, S-acylation also regulates the stability of STX19 by protecting it from proteosomal degradation, suggesting that its cysteine-rich domain, when not S-acylated, might be a novel degron. Taken together, the findings presented here point to an important and previously unappreciated role of S-acylation in protein sorting to recycling endosomes.
