Nutrient-Regulated Phosphorylation of ATG13 Inhibits Starvation-Induced Autophagy [Membrane Biology]

January 22nd, 2016 by Puente, C., Hendrickson, R. C., Jiang, X.

Autophagy is a conserved catabolic process that utilizes a defined series of membrane trafficking events to generate a de novo double-membrane vesicle termed the autophagosome, which matures by fusing to the lysosome. Subsequently, the lysosome facilitates the degradation and recycling of the cytoplasmic cargo. In yeast, the upstream signals that regulate the induction of starvation-induced autophagy are clearly defined. The nutrient-sensing kinase Tor inhibits the activation of autophagy by regulating the formation of the Atg1-Atg13-Atg17 complex, through hyperphosphorylation of Atg13. However, in mammals, the ortholog complex ULK1-ATG13-FIP200 is constitutively formed. As such, the molecular mechanism by which mTOR regulates mammalian autophagy is unknown. Here we report the identification and characterization of novel nutrient-regulated phosphorylation sites on ATG13: Ser224 and Ser258. mTOR directly phosphorylates ATG13 on Ser258 while Ser224 is a putative AMPK phosphorylation site. In ATG13 knockout cells reconstituted with an unphosphorylatable mutant of ATG13, ULK1 kinase activity is more potent, and amino acid starvation induced more rapid ULK1 translocation and autophagy. Therefore, ATG13 phosphorylation plays a crucial role in autophagy regulation.