AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.
AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.
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DOI：
10.1038/ncb2152
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发表时间：
2011-02
影响因子：
21.3
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中科院分区：
文献类型：
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自噬是细胞的组分被降解以维持响应营养限制的基本活性和存活力的过程。广泛的遗传学研究表明，酵母ATG1激酶在自噬诱导中具有重要作用。此外，AMP活化的蛋白激酶（AMPK）促进自噬，AMPK是关键的能量传感器并调节细胞代谢以维持能量稳态。相反，自噬被哺乳动物雷帕霉素靶蛋白（mTOR）抑制，mTOR是一种整合生长因子和营养信号的中央细胞生长调节剂。在这里，我们展示了一种调节哺乳动物自噬起始激酶Ulk1（酵母ATG 1的同源物）的分子机制。在葡萄糖饥饿下，AMPK通过Ser 317和Ser 777的磷酸化直接激活Ulk 1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并破坏Ulk1和AMPK之间的相互作用来防止Ulk1活化。这种协调的磷酸化对于Ulk1在自噬诱导中是重要的。我们的研究揭示了Ulk1调节和自噬诱导响应营养信号的信号传导机制。
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.