自噬和细胞凋亡受内质网和线粒体中AMBRA1对Bcl2的应激调节。

Q1 Mathematics
Bojie Yang, Quansheng Liu, Yuanhong Bi
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引用次数: 15

摘要

背景:自噬和细胞凋亡是决定细胞在不同应激信号下存活或死亡的两个重要生理过程。这两个过程的调节机制共享B细胞淋巴瘤-2家族蛋白和AMBRA1,它们存在于内质网和线粒体中。B细胞淋巴瘤-2家族蛋白感知不同的应激,并与AMBRA1相互作用以调节自噬和细胞凋亡,这分别由Beclin1和Caspase介导。因此,我们研究了在内质网和线粒体中与AMBRA1结合的B细胞淋巴瘤-2家族蛋白上不同水平的应激如何调节从自噬到凋亡的转变。方法:在本文中,我们在Kapuy等人最初提出的模型中考虑了在内质网和线粒体中与AMBRA1结合的B细胞淋巴瘤-2家族蛋白对两种不同应激水平的反应。我们研究了这两种应激水平如何影响从自噬到凋亡的转变,以及它们随着时间的推移对凋亡激活的影响。此外,我们分析了该模型中的反馈调节如何影响自噬和细胞凋亡之间两个水平的应激和细胞命运决定的分叉图。结果:无论内质网应激如何,线粒体中的轻微应激都会激活自噬,而线粒体中只有显著应激才会激活细胞凋亡。细胞凋亡只对线粒体应激敏感。在存在高AMBRA1水平和高内质网和线粒体应激的情况下,细胞凋亡激活前的持续时间更长。AMBRA1可以与B细胞淋巴瘤-2家族蛋白竞争,结合并激活Beclin1,从而在细胞凋亡前长时间促进自噬过程。此外,随着半胱天冬酶活性的增加、Beclin1-A的失活和半胱天冬蛋白酶的米氏常数的增加,细胞凋亡容易发生。结论:建立了一个新的数学模型来理解自噬和细胞凋亡的复杂调控机制。我们的模型可用于进一步的自噬-凋亡动态建模实验和模拟。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Autophagy and apoptosis are regulated by stress on Bcl2 by AMBRA1 in the endoplasmic reticulum and mitochondria.

Autophagy and apoptosis are regulated by stress on Bcl2 by AMBRA1 in the endoplasmic reticulum and mitochondria.

Autophagy and apoptosis are regulated by stress on Bcl2 by AMBRA1 in the endoplasmic reticulum and mitochondria.

Autophagy and apoptosis are regulated by stress on Bcl2 by AMBRA1 in the endoplasmic reticulum and mitochondria.

Background: Autophagy and apoptosis are two important physiological processes that determine cell survival or death in response to different stress signals. The regulatory mechanisms of these two processes share B-cell lymphoma-2 family proteins and AMBRA1, which are present in both the endoplasmic reticulum and mitochondria. B-cell lymphoma-2 family proteins sense different stresses and interact with AMBRA1 to regulate autophagy and apoptosis, which are respectively mediated by Beclin1 and Caspases. Therefore, we investigated how different levels of stress on B-cell lymphoma-2 family proteins that bind to AMBRA1 in the endoplasmic reticulum and mitochondria regulate the switch from autophagy to apoptosis.

Methods: In this paper, we considered the responses of B-cell lymphoma-2 family proteins, which bind to AMBRA1 in both the endoplasmic reticulum and mitochondria, to two different levels of stress in a model originally proposed by Kapuy et al. We investigated how these two stress levels affect the transition from autophagy to apoptosis and their effects on apoptosis activation over time. Additionally, we analyzed how the feedback regulation in this model affects the bifurcation diagrams of two levels of stress and cell fate decisions between autophagy and apoptosis.

Results: Autophagy is activated for minor stress in mitochondria regardless of endoplasmic reticulum stress, while apoptosis is activated for only significant stress in mitochondria. Apoptosis is only sensitive to mitochondria stress. The time duration before apoptosis activation is longer in the presence of high AMBRA1 levels with high endoplasmic reticulum and mitochondria stress. AMBRA1 can compete with B-cell lymphoma-2 family proteins to bind and activate Beclin1 and thus promote the autophagy process for a long time before apoptosis. Furthermore, apoptosis is prone to occur with increasing activation of Caspases, inactivation of Beclin1-A and the Michaelis constant of Caspases.

Conclusion: A novel mathematical model has been developed to understand the complex regulatory mechanisms of autophagy and apoptosis. Our model may be applied to further autophagy-apoptosis dynamic modeling experiments and simulations.

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来源期刊
Theoretical Biology and Medical Modelling
Theoretical Biology and Medical Modelling MATHEMATICAL & COMPUTATIONAL BIOLOGY-
自引率
0.00%
发文量
0
审稿时长
6-12 weeks
期刊介绍: Theoretical Biology and Medical Modelling is an open access peer-reviewed journal adopting a broad definition of "biology" and focusing on theoretical ideas and models associated with developments in biology and medicine. Mathematicians, biologists and clinicians of various specialisms, philosophers and historians of science are all contributing to the emergence of novel concepts in an age of systems biology, bioinformatics and computer modelling. This is the field in which Theoretical Biology and Medical Modelling operates. We welcome submissions that are technically sound and offering either improved understanding in biology and medicine or progress in theory or method.
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