Volume 33, No 11, Nov 2023

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 33 Issue 11, November 2023: 835-850   |  Open Access

ORIGINAL ARTICLES

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

Yu-Qing Wu^1,† , Chen-Song Zhang^1,† , Jinye Xiong¹ , Dong-Qi Cai¹ , Chen-Zhe Wang¹ , Yu Wang^1,2 , Yan-Hui Liu¹ , Yiming Li² , Jian Wu² , Jianfeng Wu³ , Bin Lan⁴ , Xuefeng Wang⁴ , Siwei Chen¹ , Xianglei Cao¹ , Xiaoyan Wei¹ , Hui-Hui Hu¹ , Huiling Guo¹ , Yaxin Yu¹ , Shu-Yong Lin¹ , Hai-Long Piao⁵ , Jianyin Zhou² , Sheng-Cai Lin^1,*

¹State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
²Department of Hepatobiliary and Pancreatic Surgery, Zhongshan Hospital, Xiamen University, Xiamen, Fujian, China
³3 Laboratory Animal Research Center, Xiamen University, Xiamen, Fujian, China
⁴Fujian Provincial Key Laboratory of Tumor Biotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Xiamen, Fujian, China
⁵CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning, China
^†These authors contributed equally: Yu-Qing Wu, Chen-Song Zhang
Correspondence: Sheng-Cai Lin(linsc@xmu.edu.cn)

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.

https://doi.org/10.1038/s41422-023-00874-4

FULL TEXT | PDF

Browse 529