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Abstract
Although autophagy is a type of programmed cell death, it is also essential for cell survival upon tolerable level of various stress events. For the cell to respond adequately to an external and/or internal stimulus induced by cellular stress, autophagy must be controlled in a highly regulated manner. By using systems biology techniques, here we explore the dynamical features of autophagy induction. We propose that the switch-like characteristic of autophagy induction is achieved by a control network, containing essential feedback loops of four components, so-called autophagy inducer, autophagy controller, mTORC1 and autophagy executor, respectively. We show how an autophagy inducer is capable to turn on autophagy in a cellular stress-specific way. The autophagy controller acts as a molecular switch and not only promotes autophagy but also blocks the permanent hyperactivation of the process via downregulating the autophagy inducer. In this theoretical analysis, we explore in detail the properties of all four proposed controlling elements and their connections. Here we also prove that the kinetic features of this control network can be considered accurate in various stress processes (such as starvation, endoplasmic reticulum stress and oxidative stress), even if the exact components may be different. The robust response of the resulting control network is essential during cellular stress.
Highlights
The Greek word ‘autophagy’ means ‘self-eating’, referring to the ability of the cells to digest their own components with respect to various external and internal signals
According to the already published scientific data, we propose that regulated autophagy induction can be described by a wiring diagram of four different regulators, called autophagy inducer (AUIN), autophagy controller (AUCO), mTORC1 and autophagy executors (AUEX), respectively (Fig. 1)
The proper behaviour of the model is proved upon three various stress events To confirm the accuracy of our autophagy regulation model, here we investigate the kinetic features of stresstype-specific autophagy controlling networks
Summary
The Greek word ‘autophagy’ means ‘self-eating’, referring to the ability of the cells to digest their own components with respect to various external and internal signals. Autophagy was classified as a cell death mechanism[4]; many scientific results have been revealed that autophagy has an essential role in cellular survival upon various stress events (such as starvation or endoplasmic reticulum (ER) stress)[5,6]. These data clearly suggest that the crucial function of autophagy is to maintain cellular homoeostasis, Due to the essential role of autophagy in regulating cellular homoeostasis and stress response, both the induction and the downregulation of the process are tightly controlled[10]. This complex can phosphorylate Beclin[1], the mammalian homologue of yeast Atg[617]
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