The p53 tumor suppressor protein is a transcription factor and master stress response mediator, and it is subject to reduction-oxidation (redox)-dependent regulation. The P47S variant of TP53, which exists primarily in African-descent populations, associates with an elevated abundance of low molecular weight (LMW) thiols, including glutathione (GSH) and coenzyme A (CoA). Here we show that S47 and P47 cells exhibit distinct metabolic profiles, controlled by their different redox states and expression of Activating Transcription Factor-4 (ATF4). We find that S47 cells exhibit decreased catabolic glycolysis but increased use of the pentose phosphate pathway (PPP), and an enhanced abundance of the antioxidant, NADPH. We identify ATF4 as differentially expressed in P47 and S47 cells and show that ATF4 can reverse the redox status and rescue metabolism of S47 cells, as well as increase sensitivity to ferroptosis. This adaptive metabolic switch is rapid, reversible, and accompanied by thiol-mediated changes in the structures and activities of key glycolytic signaling pathway proteins, including GAPDH and G6PD. The results presented here unveil the important functional interplay among pathways regulating thiol-redox status, metabolic adaptation, and cellular responses to oxidative stress.

p53肿瘤抑制蛋白是转录因子和主要的应激反应介质，并且受到还原氧化（redox）依赖性调节。TP53的P47S变体，主要存在于非洲人后裔中，与低分子量（LMW）硫醇（包括谷胱甘肽（GSH）和辅酶A（CoA））的含量升高有关。在这里，我们显示S47和P47细胞表现出不同的代谢特征，受其不同的氧化还原状态和激活转录因子4（ATF4）的表达控制。我们发现S47细胞表现出降低的分解代谢糖酵解，但增加了戊糖磷酸途径（PPP）的使用，并增加了抗氧化剂NADPH的丰度。我们确定ATF4在P47和S47细胞中差异表达，并显示ATF4可以逆转氧化还原状态并拯救S47细胞的新陈代谢，并增加对肥大症的敏感性。这种适应性新陈代谢转换是快速，可逆的，并伴随着巯基介导的关键糖酵解信号通路蛋白（包括GAPDH和G6PD）的结构和活性发生变化。本文介绍的结果揭示了调节硫醇-氧化还原状态，代谢适应和细胞对氧化应激反应的途径之间重要的功能相互作用。