Zaccarin Mattia, Bosello-Travain Valentina, Di Paolo Maria Luisa, Falda Marco, Maiorino Matilde, Miotto Giovanni, Piccolo Stefano, Roveri Antonella, Ursini Fulvio, Venerando Rina, Toppo Stefano
Department of Molecular Medicine, University of Padova, Viale G.Colombo 3, 35121 Padova, Italy.
Department of Molecular Medicine, University of Padova, Viale G.Colombo 3, 35121 Padova, Italy.
Arch Biochem Biophys. 2017 Mar 1;617:120-128. doi: 10.1016/j.abb.2016.09.002. Epub 2016 Sep 13.
Reversible oxidation of Cys residues is a crucial element of redox homeostasis and signaling. According to a popular concept in oxidative stress signaling, the oxidation of targets of signals can only take place following an overwhelming of the cellular antioxidant capacity. This concept, however, ignores the activation of feedback mechanisms possibly leading to a paradoxical effect. In a model of cancer stem cells (CSC), stably overexpressing the TAZ oncogene, we observed that the increased formation of oxidants is associated with a globally more reduced state of proteins. Redox proteomics revealed that several proteins, capable of undergoing reversible redox transitions, are indeed more reduced while just few are more oxidized. Among the proteins more oxidized, G6PDH emerges as both more expressed and activated by oxidation. This accounts for the observed more reduced state of the NADPH/NADP couple. The dynamic redox flux generating this apparently paradoxical effect is rationalized in a computational system biology model highlighting the crucial role of G6PDH activity on the rate of redox transitions eventually leading to the reduction of reversible redox switches.
半胱氨酸残基的可逆氧化是氧化还原稳态和信号传导的关键要素。根据氧化应激信号传导中的一个流行概念，信号靶点的氧化只能在细胞抗氧化能力不堪重负之后发生。然而，这一概念忽略了可能导致矛盾效应的反馈机制的激活。在一个稳定过表达TAZ致癌基因的癌症干细胞（CSC）模型中，我们观察到氧化剂形成的增加与蛋白质整体上更还原的状态相关。氧化还原蛋白质组学表明，几种能够经历可逆氧化还原转变的蛋白质确实更还原，而只有少数蛋白质更氧化。在氧化程度更高的蛋白质中，葡萄糖-6-磷酸脱氢酶（G6PDH）表现为表达量更高且被氧化激活。这就解释了所观察到的NADPH/NADP偶联更还原的状态。在一个计算系统生物学模型中，产生这种明显矛盾效应的动态氧化还原通量得到了合理的解释，该模型突出了G6PDH活性对氧化还原转变速率的关键作用，最终导致可逆氧化还原开关的还原。
