Abstract
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).
Highlights
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
In this study we directly focus on AMPK-P → ULK1-P ┤ AMPK-P negative feedback loop to try to understand the dynamical features of this feedback loop in details by applying both molecular and theoretical biological techniques
Our previously published mathematical model was used for describing mTORC1–AMPK-P–ULK1-P controlled a utophagy[23], first direct positive AMPKP → ULK1-P and negative ULK1-P ┤ AMPK-P connections are assumed
Summary
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. While AMPK enhances autophagy, mTORC1 keeps the self-cannibalism inactive at physiological conditions It is well-known that mTORC1 has a key role in controlling cell growth and cellular metabolism by integrating different external and internal signals, such as growth factors, amino acids, glucose and energy status. At physiological conditions mTORC1 is kept active, inactivation of mTORC1 leads to a general inhibition of protein translation in the cell, autophagy-dependent self-digestive process becomes fully active. AMPK tightly controls ATP-consuming mechanisms, such as glycogen or protein syntheses; fatty acids and cholesterol syntheses due to Ser/Thr phosphorylation of key regulatory enzymes and up-regulates processes that increase ATP level (i.e. glycolysis, β-oxidation) in the c ell[10,11]
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