Low glucose metabolite 3-phosphoglycerate switches PHGDH from serine synthesis to p53 activation to control cell fate
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Published:2023-09-19
Issue:11
Volume:33
Page:835-850
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ISSN:1748-7838
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Container-title:Cell Research
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language:en
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Short-container-title:Cell Res
Author:
Wu Yu-Qing, Zhang Chen-SongORCID, Xiong Jinye, Cai Dong-Qi, Wang Chen-Zhe, Wang Yu, Liu Yan-Hui, Wang Yu, Li Yiming, Wu Jian, Wu Jianfeng, Lan Bin, Wang Xuefeng, Chen Siwei, Cao Xianglei, Wei XiaoyanORCID, Hu Hui-Hui, Guo Huiling, Yu Yaxin, Ghafoor Abdul, Xie ChangchuanORCID, Wu Yaying, Xu Zheni, Zhang Cixiong, Zhu Mingxia, Huang Xi, Sun Xiufeng, Lin Shu-YongORCID, Piao Hai-LongORCID, Zhou Jianyin, Lin Sheng-CaiORCID
Abstract
AbstractGlycolytic 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.
Funder
National Natural Science Foundation of China Ministry of Science and Technology of the People's Republic of China Ministry of Education of the People's Republic of China Xiamen University Agilent Technologies
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Molecular Biology
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