Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
Pathobiochemistry Research Group of the Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
FEBS Lett. 2020 Mar;594(6):1112-1123. doi: 10.1002/1873-3468.13689. Epub 2019 Dec 11.
Scientific results have revealed that autophagy is able to promote cell survival in response to endoplasmic reticulum (ER) stress, while drastic events result in apoptotic cell death. Here, we analyse the important crosstalk of life-and-death decisions from a systems biological perspective by studying the regulatory modules of the unfolded protein response (UPR). While a double-negative loop between autophagy and apoptosis inducers is crucial for the switch-like characteristic of the stress response mechanism, a positive feedback loop between ER stress sensors is also essential. Corresponding to experimental data, here, we show the dynamical significance of Gadd34-CHOP connections inside the PERK branch of the UPR. The multiple system-level feedback loops seem to be crucial for managing a robust life-and-death decision depending on the level and durability of cellular stress.
科学研究表明，自噬能够促进细胞存活以应对内质网（ER）应激，而剧烈的事件则导致细胞凋亡。在这里，我们从系统生物学的角度分析了生与死决策的重要串扰，研究了未折叠蛋白反应（UPR）的调节模块。虽然自噬和凋亡诱导物之间的双负反馈环对于应激反应机制的开关特性至关重要，但 ER 应激传感器之间的正反馈环也是必不可少的。与实验数据相对应，我们在这里展示了 UPR 的 PERK 分支中 Gadd34-CHOP 连接的动态意义。多个系统级别的反馈环似乎对于根据细胞应激的水平和持久性做出稳健的生死决策至关重要。
