Wang Shengyuan, Li Hongyan, Yuan Minghao, Fan Haixia, Cai Zhiyou
Chongqing Medical University, Chongqing, China.
Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, China.
Front Physiol. 2022 Nov 25;13:1015500. doi: 10.3389/fphys.2022.1015500. eCollection 2022.
Adenosine monophosphate-activated protein kinase (AMPK) is a significant energy sensor in the maintenance of cellular energy homeostasis. Autophagy is a highly conserved catabolic process that involves an intracellular degradation system in which cytoplasmic components, such as protein aggregates, organelles, and other macromolecules, are directed to the lysosome through the self-degradative process to maintain cellular homeostasis. Given the triggered autophagy process in various situations including the nutrient deficit, AMPK is potentially linked with different stages of autophagy. Above all, AMPK increases ULK1 activity by directly phosphorylating Ser467, Ser555, Thr574, and Ser637 at least four sites, which increases the recruitment of autophagy-relevant proteins (ATG proteins) to the membrane domains which affects autophagy at the initiation stage. Secondly, AMPK inhibits VPS34 complexes that do not contain pro-autophagic factors and are thus involved in isolation membrane forming processes, by direct phosphorylation of VPS34 on Thr163 and Ser165. After phosphorylation, AMPK can govern autophagosome formation through recruiting downstream autophagy-related proteins to the autophagosome formation site. Finally, the AMPK-SIRT1 signaling pathway can be activated by upregulating the transcription of autophagy-related genes, thereby enhancing autophagosome-lysosome fusion. This review provides an introduction to the role of AMPK in different stages of autophagy.
腺苷单磷酸激活的蛋白激酶（AMPK）是维持细胞能量稳态的重要能量传感器。自噬是一种高度保守的分解代谢过程，涉及细胞内降解系统，在该系统中，细胞质成分，如蛋白质聚集体、细胞器和其他大分子，通过自我降解过程被导向溶酶体以维持细胞稳态。鉴于在包括营养缺乏在内的各种情况下自噬过程都会被触发，AMPK可能与自噬的不同阶段相关联。首先，AMPK通过直接磷酸化至少四个位点的Ser467、Ser555、Thr574和Ser637来增加ULK1活性，这增加了自噬相关蛋白（ATG蛋白）向膜结构域的募集，从而在起始阶段影响自噬。其次，AMPK通过直接磷酸化VPS34的Thr163和Ser165来抑制不含促自噬因子且因此参与隔离膜形成过程的VPS34复合物。磷酸化后，AMPK可通过将下游自噬相关蛋白募集到自噬体形成位点来调控自噬体的形成。最后，AMPK-SIRT1信号通路可通过上调自噬相关基因的转录被激活，从而增强自噬体-溶酶体融合。本综述介绍了AMPK在自噬不同阶段的作用。
