Quantitative assessment of cell fate decision between autophagy and apoptosis.
Quantitative assessment of cell fate decision between autophagy and apoptosis.
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DOI：
10.1038/s41598-017-18001-w
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发表时间：
2017-12-14
影响因子：
4.6
通讯作者：
Bahar I
中科院分区：
文献类型：
--
作者：
Liu B;Oltvai ZN;Bayır H;Silverman GA;Pak SC;Perlmutter DH;Bahar I
自噬和凋亡是调节细胞存活和死亡的细胞过程，前者通过消除细胞中的功能失调成分，后者通过程序性细胞死亡。应激信号可以诱导这两种过程，目前还不清楚细胞如何“评估”细胞损伤，并在激活自噬或凋亡时做出“生”或“死”的决定。本文建立了细胞凋亡和自噬耦合的计算模型，以分析潜在的信号传导和调节网络动态。该模型解释了实验观察到的差异部署的自噬和凋亡响应于各种压力信号。自噬反应占主导地位，在低至中度的压力，而响应转移自噬（分级激活），凋亡（开关样激活），随着应力强度的增加。该模型表明，细胞质Ca 2+作为一个变阻器，微调自噬和凋亡反应。G蛋白信号传导介导的反馈环维持细胞质Ca 2+水平，这反过来又通过AMP激活的蛋白激酶（AMPK）介导的前馈环控制自噬反应。Ca 2 +/钙调素依赖性激酶激酶β（CaMKKβ）是细胞内Ca 2+在自噬调控中竞争作用的决定因素。该研究表明，所提出的模型可以有利地用于询问细胞调节事件和开发用于调节细胞决策的药理学策略。
Autophagy and apoptosis are cellular processes that regulate cell survival and death, the former by eliminating dysfunctional components in the cell, the latter by programmed cell death. Stress signals can induce either process, and it is unclear how cells ‘assess’ cellular damage and make a ‘life’ or ‘death’ decision upon activating autophagy or apoptosis. A computational model of coupled apoptosis and autophagy is built here to analyze the underlying signaling and regulatory network dynamics. The model explains the experimentally observed differential deployment of autophagy and apoptosis in response to various stress signals. Autophagic response dominates at low-to-moderate stress; whereas the response shifts from autophagy (graded activation) to apoptosis (switch-like activation) with increasing stress intensity. The model reveals that cytoplasmic Ca2+ acts as a rheostat that fine-tunes autophagic and apoptotic responses. A G-protein signaling-mediated feedback loop maintains cytoplasmic Ca2+ level, which in turn governs autophagic response through an AMP-activated protein kinase (AMPK)-mediated feedforward loop. Ca2+/calmodulin-dependent kinase kinase β (CaMKKβ) emerges as a determinant of the competing roles of cytoplasmic Ca2+ in autophagy regulation. The study demonstrates that the proposed model can be advantageously used for interrogating cell regulation events and developing pharmacological strategies for modulating cell decisions.
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11.1
作者：
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通讯作者：
Klionsky DJ
影响因子：
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作者：
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影响因子：
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作者：
Liu J;Xia H;Kim M;Xu L;Li Y;Zhang L;Cai Y;Norberg HV;Zhang T;Furuya T;Jin M;Zhu Z;Wang H;Yu J;Li Y;Hao Y;Choi A;Ke H;Ma D;Yuan J
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Yuan J
影响因子：
16
作者：
Kroemer G;Mariño G;Levine B
通讯作者：
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