ULK1（hATG1）的磷酸化由 AMP 激活的蛋白激酶介导，将能量感应与线粒体自噬连接起来。
Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy.
机构信息
Molecular and Cell Biology Laboratory, Dulbecco Center for Cancer Research, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
出版信息
Science. 2011 Jan 28;331(6016):456-61. doi: 10.1126/science.1196371. Epub 2010 Dec 23.
Abstract
Adenosine monophosphate-activated protein kinase (AMPK) is a conserved sensor of intracellular energy activated in response to low nutrient availability and environmental stress. In a screen for conserved substrates of AMPK, we identified ULK1 and ULK2, mammalian orthologs of the yeast protein kinase Atg1, which is required for autophagy. Genetic analysis of AMPK or ULK1 in mammalian liver and Caenorhabditis elegans revealed a requirement for these kinases in autophagy. In mammals, loss of AMPK or ULK1 resulted in aberrant accumulation of the autophagy adaptor p62 and defective mitophagy. Reconstitution of ULK1-deficient cells with a mutant ULK1 that cannot be phosphorylated by AMPK revealed that such phosphorylation is required for mitochondrial homeostasis and cell survival during starvation. These findings uncover a conserved biochemical mechanism coupling nutrient status with autophagy and cell survival.
摘要
腺苷酸单磷酸活化蛋白激酶（AMPK）是一种细胞内能量的保守感受器，在响应低营养可用性和环境应激时被激活。在 AMPK 的保守底物筛选中，我们鉴定了 ULK1 和 ULK2，这是酵母蛋白激酶 Atg1 的哺乳动物同源物，该蛋白对于自噬是必需的。在哺乳动物的肝脏和秀丽隐杆线虫中对 AMPK 或 ULK1 的遗传分析揭示了这些激酶在自噬中的必需性。在哺乳动物中，AMPK 或 ULK1 的缺失导致自噬衔接蛋白 p62 的异常积累和有缺陷的线粒体自噬。用不能被 AMPK 磷酸化的突变型 ULK1 重建 ULK1 缺陷细胞揭示了这种磷酸化对于饥饿期间线粒体的动态平衡和细胞存活是必需的。这些发现揭示了一种将营养状态与自噬和细胞存活相偶联的保守生化机制。
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