AMPK Activates Autophagy by Phosphorylating ULK1

Abstract

### Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy Egan et al Science . 2011;331:456–461. In eukaryotes, macroautophagy (hereafter, autophagy) functions as a highly conserved catabolic mechanism in which cytoplasm, including damaged organelles and protein aggregates, is sequestered into autophagosomes, double-membrane vesicles, for ultimate degradation and recycling in lysosomes. Autophagy has attracted increasing attention in recent years because of its significance in various aspects of cell physiology, including survival during nutrient or energy limitation, and in the clearance of excess or dysfunctional proteins and organelles. In addition, autophagy is associated with a range of human pathophysiologies, including cancer, neurodegeneration, and cardiomyopathies. Autophagy is tightly regulated because either too much or too little can be detrimental to cell physiology. The ULK1 (mammalian homolog of yeast Atg1) kinase complex plays a central role in autophagy induction; the mTORC1 kinase complex, one of the primary negative regulators of autophagy, functions, in part, by phosphorylating and inhibiting ULK1. In contrast, AMPK is a positive regulator that stimulates autophagy in response to energy depletion. Two recent studies suggest that AMPK directly regulates autophagy through phosphorylating and activating ULK1.1,2 mTORC1-dependent phosphorylation appears to work antagonistically to …