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ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase

2013; Nature Portfolio; Volume: 15; Issue: 7 Linguagem: Inglês

10.1038/ncb2757

1476-4679

Ryan C. Russell, Ye Tian, Hai‐Xin Yuan, Hyun Woo Park, Yu-Yun Chang, Joungmok Kim, Haerin Kim, Thomas P. Neufeld, Andrew Dillin, Kun‐Liang Guan,

Endoplasmic Reticulum Stress and Disease

Autophagy is the primary cellular catabolic program activated in response to nutrient starvation. Initiation of autophagy, particularly by amino-acid withdrawal, requires the ULK kinases. Despite its pivotal role in autophagy initiation, little is known about the mechanisms by which ULK promotes autophagy. Here we describe a molecular mechanism linking ULK to the pro-autophagic lipid kinase VPS34. Following amino-acid starvation or mTOR inhibition, the activated ULK1 phosphorylates Beclin-1 on Ser 14, thereby enhancing the activity of the ATG14L-containing VPS34 complexes. The Beclin-1 Ser 14 phosphorylation by ULK is required for full autophagic induction in mammals and this requirement is conserved in Caenorhabditis elegans. Our study reveals a molecular link from ULK1 to activation of the autophagy-specific VPS34 complex and autophagy induction. The protein kinase ULK1 regulates autophagy induction but its mode of action is poorly understood. Guan and colleagues show that following nutrient starvation, ULK1-mediated phosphorylation of Beclin-1 is required for the activation of VPS34 lipid kinase within the autophagy complex ATG1–VPS34–Beclin-1. They also find that during starvation, the inhibitory effect of mTOR on ULK1 is relieved to increase the phosphorylation of Beclin-1.