Journal Article

Low glucose metabolite 3-phosphoglycerate switches PHGDH from serine synthesis to p53 activation to control cell fate

Zhu, Mingxia, Wu, Jian, Wu, Yaying, Wei, Xiaoyan, Huang, Xi, Zhou, Jianyin, Liu, Yan-Hui, Xie, Changchuan, Xiong, Jinye, Sun, Xiufeng, Piao, Hai-Long, Lan, Bin, Ghafoor, Abdul, Chen, Siwei, Li, Yiming, Xu, Zheni, Wang, Yu, Zhang, Cixiong, Cao, Xianglei, Lin, Shu-Yong, Wu, Jianfeng, Wang, Chen-Zhe, Guo, Huiling, Yu, Yaxin, Wang, Xuefeng, Zhang, Chen-Song, Wu, Yu-Qing, Hu, Hui-Hui, Cai, Dong-Qi, Lin, Sheng-Cai

2023

Overview

Glycolytic intermediary metabolites such as fructose-1,6-bisphosphate can serve as signals, controlling metabolic states beyond energy metabolism. However, whether glycolytic metabolites also play a role in controlling cell fate remains unexplored. Here, we find that low levels of glycolytic metabolite 3-phosphoglycerate (3-PGA) can switch phosphoglycerate dehydrogenase (PHGDH) from cataplerosis serine synthesis to pro-apoptotic activation of p53. PHGDH is a p53-binding protein, and when unoccupied by 3-PGA interacts with the scaffold protein AXIN in complex with the kinase HIPK2, both of which are also p53-binding proteins. This leads to the formation of a multivalent p53-binding complex that allows HIPK2 to specifically phosphorylate p53-Ser46 and thereby promote apoptosis. Furthermore, we show that PHGDH mutants (R135W and V261M) that are constitutively bound to 3-PGA abolish p53 activation even under low glucose conditions, while the mutants (T57A and T78A) unable to bind 3-PGA cause constitutive p53 activation and apoptosis in hepatocellular carcinoma (HCC) cells, even in the presence of high glucose. In vivo, PHGDH-T57A induces apoptosis and inhibits the growth of diethylnitrosamine-induced mouse HCC, whereas PHGDH-R135W prevents apoptosis and promotes HCC growth, and knockout of Trp53 abolishes these effects above. Importantly, caloric restriction that lowers whole-body glucose levels can impede HCC growth dependent on PHGDH. Together, these results unveil a mechanism by which glucose availability autonomously controls p53 activity, providing a new paradigm of cell fate control by metabolic substrate availability.

• Publisher: Springer Nature Singapore,Nature Publishing Group
• Subject: 13/1 / 13/109 / 13/2 / 13/31 / 13/89 / 14 / 14/19 / 631/67 / 631/80/82/23 / 631/80/86/2369 / 64/60 / 82/29 / 82/58 / Apoptosis / Availability / Biomedical and Life Sciences / Cell activation / Cell Biology / Cell fate / Dietary restrictions / Diethylnitrosamine / Energy metabolism / Fructose-1,6-bisphosphate / Glucose / Glycolysis / Hepatocellular carcinoma / HIPK2 protein / Kinases / Life Sciences / Liver cancer / Metabolism / Metabolites / Mutants / p53 Protein / Phosphoglycerate dehydrogenase / Proteins / Serine / Substrates / Synthesis