A Double Negative Feedback Loop between mTORC1 and AMPK Kinases Guarantees Precise Autophagy Induction upon Cellular Stress
A Double Negative Feedback Loop between mTORC1 and AMPK Kinases Guarantees Precise Autophagy Induction upon Cellular Stress
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DOI：
10.3390/ijms20225543
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发表时间：
2019-11-01
影响因子：
5.6
通讯作者：
Kapuy, Orsolya
中科院分区：
文献类型：
--
作者：
Holczer, Marianna;Hajdu, Bence;Kapuy, Orsolya
细胞内稳态是由一种进化保守的细胞消化过程控制的，称为自噬。这一机制受到两个传感器元件mTORC1和AMPK的严格调控。mTORC1是蛋白质稳态的主要调控因子之一，而AMPK维持细胞能量稳态。AMPK能够通过磷酸化自噬体形成的关键诱导剂ULK1来促进自噬，而mTORC1在营养丰富的条件下通过ULK1下调自噬过程。我们声称AMPK-mTORC1-ULK1调控三角的反馈回路保证了当营养和/或能量供应发生变化时适当的响应机制。我们认为在mTORC1和AMPK之间存在一个重要的双负反馈回路。也就是说，AMPK不仅下调mTORC1，而且mTORC1也抑制AMPK，这种抑制是在生理条件下保持AMPK失活所必需的。本研究的目的是探讨AMPK调控各种细胞应激事件的动态特性。我们通过结合理论和分子生物学技术，从系统生物学的角度进行科学分析。在本研究中，我们证实AMPK对促进自噬至关重要，但不足以维持自噬。AMPK激活之后是ULK1诱导，其中蛋白在保持自噬活性中起关键作用。ulk1控制的自噬总是在AMPK激活之前发生。在ULK1缺失和mTORC1超激活（即TSC1/2下调）的情况下，我们证明了AMPK和mTORC1之间的双负反馈回路对于控制网络的适当动态特征至关重要。我们的计算机模拟进一步证明了AMPK-mTORC1-ULK1控制细胞养分感知的动力学特性。
Cellular homeostasis is controlled by an evolutionary conserved cellular digestive process called autophagy. This mechanism is tightly regulated by the two sensor elements called mTORC1 and AMPK. mTORC1 is one of the master regulators of proteostasis, while AMPK maintains cellular energy homeostasis. AMPK is able to promote autophagy by phosphorylating ULK1, the key inducer of autophagosome formation, while mTORC1 downregulates the self-eating process via ULK1 under nutrient rich conditions. We claim that the feedback loops of the AMPK-mTORC1-ULK1 regulatory triangle guarantee the appropriate response mechanism when nutrient and/or energy supply changes. In our opinion, there is an essential double negative feedback loop between mTORC1 and AMPK. Namely, not only does AMPK downregulate mTORC1, but mTORC1 also inhibits AMPK and this inhibition is required to keep AMPK inactive at physiological conditions. The aim of the present study was to explore the dynamical characteristic of AMPK regulation upon various cellular stress events. We approached our scientific analysis from a systems biology perspective by incorporating both theoretical and molecular biological techniques. In this study, we confirmed that AMPK is essential to promote autophagy, but is not sufficient to maintain it. AMPK activation is followed by ULK1 induction, where protein has a key role in keeping autophagy active. ULK1-controlled autophagy is always preceded by AMPK activation. With both ULK1 depletion and mTORC1 hyper-activation (i.e., TSC1/2 downregulation), we demonstrate that a double negative feedback loop between AMPK and mTORC1 is crucial for the proper dynamic features of the control network. Our computer simulations have further proved the dynamical characteristic of AMPK-mTORC1-ULK1 controlled cellular nutrient sensing.