S‐acylation: an orchestrator of the life cycle and function of membrane proteins

Abstract

S‐acylation is a covalent post‐translational modification of proteins with fatty acids, achieved by enzymatic attachment via a labile thioester bond. This modification allows for dynamic control of protein properties and functions in association with cell membranes. This lipid modification regulates a substantial portion of the human proteome and plays an increasingly recognized role throughout the lifespan of affected proteins. Recent technical advancements have propelled the S‐acylation field into a ‘molecular era’, unveiling new insights into its mechanistic intricacies and far‐reaching implications. With a striking increase in the number of studies on this modification, new concepts are indeed emerging on the roles of S‐acylation in specific cell biology processes and features. After a brief overview of the enzymes involved in S‐acylation, this viewpoint focuses on the importance of S‐acylation in the homeostasis, function, and coordination of integral membrane proteins. In particular, we put forward the hypotheses that S‐acylation is a gatekeeper of membrane protein folding and turnover and a regulator of the formation and dynamics of membrane contact sites.