厦门大学林圣彩等研究人员合作发现，低糖代谢物3-磷酸甘油酸将PHGDH从丝氨酸合成转换为p53激活来控制细胞命运。该项研究成果于2023年9月19日在线发表在《细胞研究》杂志上。

研究人员发现低水平的糖酵解代谢物3-磷酸甘油酸（3-PGA）可以将磷酸甘油酸脱氢酶（PHGDH）从催化丝氨酸合成转换为促进凋亡的p53激活。PHGDH是一种p53结合蛋白，在未被3-PGA占位时会与支架蛋白AXIN和激酶HIPK2复合物相互作用，这两种蛋白也都是p53结合蛋白。这就形成了多价p53结合复合物，使HIPK2能够特异性地磷酸化p53-Ser46，从而促进细胞凋亡。

此外，研究人员还发现，能与3-PGA结合的PHGDH突变体（R135W和V261M）即使在低糖条件下也能抑制p53的激活，而不能与3-PGA结合的突变体（T57A和T78A）即使在高糖条件下也能导致肝细胞癌（HCC）细胞中p53的激活和凋亡。在体内，PHGDH-T57A会诱导凋亡并抑制亚硝胺诱导的小鼠HCC生长，而PHGDH-R135W则会阻止凋亡并促进HCC的生长，Trp53的敲除会消除上述影响。

重要的是，降低全身葡萄糖水平的热量限制会阻碍依赖PHGDH的HCC生长。这些结果共同揭示了葡萄糖可用性自主控制p53活性的机制，并为通过代谢底物可用性控制细胞命运提供了一个新范例。

据介绍，果糖-1,6-二磷酸等糖酵解中间代谢产物可以作为信号，控制能量代谢以外的代谢状态。然而，糖酵解代谢物是否也能在控制细胞命运方面发挥作用，这一点仍有待探索。

附：英文原文

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

Author: Wu, Yu-Qing, Zhang, Chen-Song, 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, Xiaoyan, Hu, Hui-Hui, Guo, Huiling, Yu, Yaxin, Ghafoor, Abdul, Xie, Changchuan, Wu, Yaying, Xu, Zheni, Zhang, Cixiong, Zhu, Mingxia, Huang, Xi, Sun, Xiufeng, Lin, Shu-Yong, Piao, Hai-Long, Zhou, Jianyin, Lin, Sheng-Cai

Issue&Volume: 2023-09-19

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.

DOI: 10.1038/s41422-023-00874-4

Source: https://www.nature.com/articles/s41422-023-00874-4