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

作　　者：Yu-Qing Wu Chen-Song Zhang Jinye Xiong Dong-Qi Cai Chen-Zhe 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 

机构地区：[1]State Key Laboratory of Cellular Stress Biology,Innovation Center for Cell Signaling Network,School of Life Sciences,Xiamen University,Xiamen,Fujian,China [2]Department of Hepatobiliary and Pancreatic Surgery,Zhongshan Hospital,Xiamen University,Xiamen,Fujian,China [3]Laboratory Animal Research Center,Xiamen University,Xiamen,Fujian,China [4]Fujian Provincial Key Laboratory of Tumor Biotherapy,Clinical Oncology School of Fujian Medical University,Fujian Cancer Hospital,Xiamen,Fujian,China [5]CAS Key Laboratory of Separation Science for Analytical Chemistry,Dalian Institute of Chemical Physics,Chinese Academy of Sciences,Dalian,Liaoning,China

出　　处：《Cell Research》2023年第11期835-850,共16页细胞研究（英文版）

基　　金：supported by grants from the National Key R&D Program of China (2022YFA0806501 and 2020YFA0803402);the National Natural Science Foundation of China (#82088102,#92057204,#92157001 and#81772818);the Fundamental Research Funds for the Central Universities (#20720200069);the Project“111”sponsored by the State Bureau of Foreign Experts and Ministry of Education of China (#BP2018017);the Joint Funds for the Innovation of Science and Technology,Fujian province (2021Y9232,2021Y9227);the Fujian provincial health technology project (2022ZD01005);the XMU Training Programme of Innovation and Entrepreneurship for Undergraduates (2020×908,2020Y1021 and 2021×1183);the Agilent Applications and Core Technology–University Research Grant (#4769).

摘　　要：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.

关 键 词：PHG ACTIVATION SYNTHESIS 

分 类 号：R329.2[医药卫生—人体解剖和组织胚胎学]