Regulation of ERK2 activity by dynamic S-acylation

Extracellular signal-regulated kinases (ERK1/2) are key effector proteins of the mitogen-activated protein kinase pathway, choreographing essential processes of cellular physiology. Here, we discover that ERK1/2 are subject to S-acylation, a reversible lipid modification of cysteine residues, at C271/C254. The levels of ERK1/2 S-acylation are modulated by epidermal growth factor (EGF) signaling, mirroring its phosphorylation dynamics, and acylation-deficient ERK2 displays altered phosphorylation patterns. We show that ERK1/2 S-acylation is mediated by “writer” protein acyl transferases (PATs) and “eraser” acyl protein thioesterases (APTs) and that chemical inhibition of either lipid addition or removal alters ERK1/2’s EGF-triggered transcriptional program. Finally, in a mouse model of metabolic syndrome, we find that ERK1/2 lipidation levels correlate with alterations in ERK1/2 lipidation writer/eraser expression, solidifying a link between ERK1/2 activity, ERK1/2 lipidation, and organismal health. This study describes how lipidation regulates ERK1/2 and offers insight into the role of dynamic S-acylation in cell signaling more broadly. [Display omitted] •S-acylation of ERK1/2 occurs at C271/C254 and responds to EGF stimulation•Perturbation of S-acylation alters ERK2 activation and transcriptional program•A panel of DHHC-family proteins increases ERK1/2 S-acylation•ERK1/2 S-acylation is altered in a mouse model of metabolic disease Azizi et al. introduce S-acylation as an EGF-responsive post-translational modification of ERK1/2. Further studies highlight its impact on ERK2 activation and the consequences for downstream signaling. Moreover, a mouse model of metabolic disease reveals organ-specific changes in the levels of ERK1/2 S-acylation.