Abstract
The association of AMP-activated protein kinase (AMPK) with membranes plays a critical role in the regulation of AMPK activation and function. Protein lipid modification, including palmitoylation, myristoylation, and farnesyation, constitutes a crucial mechanism in the regulation of protein dynamic interactions with membranes. Among the three subunits of the AMPK heterotrimeric complex, the structural subunit AMPKβ is myristoylated and the catalytic subunit AMPKα is palmitoylated. Here, we report the characterization of AMPKα palmitoylation. We found that AMKPα was palmitoylated at Cys209 and Cys543, and this was required for AMPK activation and subcellular membrane compartmentalization. To understand the regulation of AMPKα palmitoylation, we have identified DHHC17 as a candidate palmitoyltransferase for AMPKα and found that DHHC17, by palmitoylating AMPKα, modulated AMPK membrane association and activation in response to energy stress. To determine the role of DHHC17 in cell function, we generated DHHC17 liver-specific knockout mice and found that inactivation of DHHC17 in the mouse liver impaired AMPK activation and hepatic autophagy and caused a type 2 diabetes-like syndrome. Overall, our studies demonstrate that AMPKα palmitoylation plays a critical role in AMPK activation and that DHHC17, through its modulation of AMPK signaling, constitutes a new regulator of hepatic metabolism.