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We also showed that autophagy-dependent survival has an important antiapoptotic effect in the presence of various ER stressors and achieves this by directly influencing the threshold for apoptosis activation (Figure 5). We observed that inhibition of autophagy with 3-methyladenine leads to activation of apoptosis even at low stress levels, while hyperactivation of autophagy with metyrapone pretreatment delays the activation of apoptosis at severe ER stress. These results undoubtedly suggest that the activation threshold of self-killing mechanism is sensitive to autophagy. Antiapoptotic role of autophagy under ER stress suggests that apoptosis activation also depends on autophagy inactivation. Since autophagy gets rapidly downregulated when apoptosis switches on (Figures 2, 3, S5, and S6) we claim that a mutual antagonism between autophagy and apoptosis inducers has a crucial role in controlling the decision-making process with respect to various ER stressors.
We observed that the threshold for the activation of apoptosis is influenced by the stochasticity of cell population (Figures 4 and 5). Therefore, individual cells have different activation threshold, which in turn influences the time of activation of apoptosis. We think this is due to the critical slowing down phenomenon near the activation threshold of apoptosis. Therefore, apoptosis gets activated with a time lag in the cells with activation threshold closer to the actual stress level while time lag is decreased in cells with activation threshold further away from the actual stress level. However the sigmoid characteristic of autophagy induction is the same in both single cell and cell population simulations. These results suggest that experiments studying cell population (i.e., immunoblotting) are sufficient to give a good description about the dynamical characteristic of autophagy induction with respect to ER stress. However, single cell experiments would be essential to carry out for the analysis of apoptosis induction in the future. 点击翻译
We observed that the threshold for the activation of apoptosis is influenced by the stochasticity of cell population (Figures 4 and 5). Therefore, individual cells have different activation threshold, which in turn influences the time of activation of apoptosis. We think this is due to the critical slowing down phenomenon near the activation threshold of apoptosis. Therefore, apoptosis gets activated with a time lag in the cells with activation threshold closer to the actual stress level while time lag is decreased in cells with activation threshold further away from the actual stress level. However the sigmoid characteristic of autophagy induction is the same in both single cell and cell population simulations. These results suggest that experiments studying cell population (i.e., immunoblotting) are sufficient to give a good description about the dynamical characteristic of autophagy induction with respect to ER stress. However, single cell experiments would be essential to carry out for the analysis of apoptosis induction in the future. 点击翻译
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