Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Tűzoltó utca 37-47, Budapest, 1094, Hungary.
Laboratory of Biochemistry and Molecular Biology, Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Budapest, Hungary.
Sci Rep. 2020 Oct 20;10(1):17803. doi: 10.1038/s41598-020-75030-8.
Autophagy is an intracellular digestive process, which has a crucial role in maintaining cellular homeostasis by self-eating the unnecessary and/or damaged components of the cell at various stress events. ULK1, one of the key elements of autophagy activator complex, together with the two sensors of nutrient and energy conditions, called mTORC1 and AMPK kinases, guarantee the precise function of cell response mechanism. We claim that the feedback loops of AMPK-mTORC1-ULK1 regulatory triangle determine an accurate dynamical characteristic of autophagic process upon cellular stress. By using both molecular and theoretical biological techniques, here we reveal that a delayed negative feedback loop between active AMPK and ULK1 is essential to manage a proper cellular answer after prolonged starvation or rapamycin addition. AMPK kinase quickly gets induced followed by AMPK-P-dependent ULK1 activation, whereas active ULK1 has a rapid negative effect on AMPK-P resulting in a delayed inhibition of ULK1. The AMPK-P → ULK1 ˧ AMPK-P negative feedback loop results in a periodic repeat of their activation and inactivation and an oscillatory activation of autophagy, as well. We demonstrate that the periodic induction of self-cannibalism is necessary for the proper dynamical behaviour of the control network when mTORC1 is inhibited with respect to various stress events. By computational simulations we also suggest various scenario to introduce "delay" on AMPK-P-dependent ULK1 activation (i.e. extra regulatory element in the wiring diagram or multi-phosphorylation of ULK1).
自噬是一种细胞内消化过程，通过在各种应激事件中自噬细胞内不必要和/或受损的成分，对维持细胞内稳态起着至关重要的作用。ULK1 是自噬激活复合物的关键要素之一，与两种营养和能量条件传感器（称为 mTORC1 和 AMPK 激酶）一起，保证了细胞反应机制的精确功能。我们声称，AMPK-mTORC1-ULK1 调节三角的反馈回路决定了细胞应激时自噬过程的准确动态特征。通过使用分子和理论生物学技术，我们在这里揭示了活跃的 AMPK 和 ULK1 之间的延迟负反馈回路对于在长期饥饿或雷帕霉素添加后管理适当的细胞反应是必不可少的。AMPK 激酶迅速被诱导，随后是 AMPK-P 依赖性 ULK1 的激活，而活跃的 ULK1 对 AMPK-P 有快速的负效应，导致 ULK1 的延迟抑制。AMPK-P → ULK1˧AMPK-P 负反馈回路导致它们的激活和失活的周期性重复，以及自噬的振荡激活。我们证明，当 mTORC1 被抑制时，对于各种应激事件，自我吞噬的周期性诱导对于控制网络的适当动态行为是必要的。通过计算模拟，我们还提出了各种方案来在 AMPK-P 依赖性 ULK1 激活（即在接线图中引入额外的调节元件或 ULK1 的多磷酸化）上引入“延迟”。
