Regulation of ERK2 activity by dynamic S-acylation

The extracellular signal-regulated kinases (ERK1/2) are key effector proteins of the mitogen-activated protein kinase pathway, choreographing essential processes of cellular physiology. Critical in regulating these regulators are a patchwork of mechanisms, including post-translational modifications (PTMs) such as MEK-mediated phosphorylation. Here, we discover that ERK1/2 are subject to S-palmitoylation, a reversible lipid modification of cysteine residues, at C271/C254. Moreover, the levels of ERK1/2 S-acylation are modulated by epidermal growth factor (EGF) signaling, mirroring its phosphorylation dynamics, and palmitoylation-deficient ERK2 displays altered phosphorylation patterns at key sites. We find that chemical inhibition of either lipid addition or removal significantly alters ERK1/2’s EGF-triggered transcriptional program. We also identify a subset of “writer” protein acyl transferases (PATs) and an “eraser” acyl protein thioesterase (APT) that drive ERK1/2’s cycle of palmitoylation and depalmitoylation. Finally, we examine ERK1/2 S-acylation in a mouse model of metabolic syndrome, correlating changes in its lipidation levels with alterations in writer/eraser expression and solidifying the link between ERK1/2 activity, ERK1/2 lipidation, and organismal health. This study not only presents a previously undescribed mode of ERK1/2 regulation and a node to modulate MAPK pathway signaling in pathophysiological conditions, it also offers insight into the role of dynamic S-palmitoylation in cell signaling more generally.