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 Sacylation is mediated by writerprotein acyl transferases (PATs) and eraseracyl 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.

Automated summary

This study reveals that extracellular signal-regulated kinases (ERK1/2) are regulated by S-acylation, and their levels of S-acylation are modulated by epidermal growth factor (EGF) signaling. ERK1/2 S-acylation is mediated by writerprotein acyl transferases (PATs) and eraseracyl protein thioesterases (APTs). Inhibition of lipid addition or removal alters ERK1/2's activity and transcriptional program triggered by EGF. In a mouse model of metabolic syndrome, ERK1/2 lipidation levels correlate with the expression of ERK1/2 lipidation writer/eraser.