Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92130, USA.
Nat Cell Biol. 2011 Feb;13(2):132-41. doi: 10.1038/ncb2152. Epub 2011 Jan 23.
Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling.
自噬是一种细胞成分降解的过程，以维持在营养限制下的基本活性和生存能力。广泛的遗传研究表明，酵母 ATG1 激酶在自噬诱导中具有必需的作用。此外，自噬还受到 AMP 激活的蛋白激酶（AMPK）的促进，AMPK 是一种关键的能量传感器，调节细胞代谢以维持能量平衡。相反，哺乳动物雷帕霉素靶蛋白（mTOR）抑制自噬，mTOR 是一种中央细胞生长调节剂，整合生长因子和营养信号。在这里，我们展示了一种调节哺乳动物自噬起始激酶 Ulk1 的分子机制，Ulk1 是酵母 ATG1 的同源物。在葡萄糖饥饿下，AMPK 通过磷酸化 Ser 317 和 Ser 777 直接激活 Ulk1 来促进自噬。在营养充足的情况下，高 mTOR 活性通过磷酸化 Ulk1 Ser 757 和破坏 Ulk1 与 AMPK 之间的相互作用来阻止 Ulk1 的激活。这种协调的磷酸化对 Ulk1 诱导自噬非常重要。我们的研究揭示了一种信号机制，用于响应营养信号调节 Ulk1 并诱导自噬。
