Low glucose metabolite 3-phosphoglycerate switches PHGDH from serine synthesis to p53 activation to control cell fate
Yuqing Wu, Chen‐Song Zhang, Jinye Xiong, Dongrui Cai, C.-Y. Wang, Yu Wang, Yan‐Hui Liu, Yu Wang, Yiming Li, Jian Wu, Jianfeng Wu, Bin Lan, Xuefeng Wang, Siwei Chen, Xianglei Cao, Xiaoyan Wei, Hui-Hui Hu, Huiling Guo, Yaxin Yu, Abdul Ghafoor, Changchuan Xie, Yaying Wu, Zheni Xu, Cixiong Zhang, Mingxia Zhu, Xi Huang, Xiufeng Sun, Shu‐Yong Lin, Hai‐long Piao, Jianyin Zhou, Sheng‐Cai Lin, Sheng‐Cai Lin, Sheng‐Cai Lin
Abstract
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.