Sha Nannan, Zhou Bei, Hou Guofang, Xi Zhifeng, Wang Wang, Yan Man, He Jing, Zhou Yue, Xia Qiang, Jiang Yuhui, Zhao Qin
Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
Oncogene. 2025 May;44(16):1078-1092. doi: 10.1038/s41388-025-03274-7. Epub 2025 Jan 26.
Overexpression of uridine-cytidine kinase 2 (UCK2), a key enzyme in the pyrimidine salvage pathway, is implicated in human cancer development, while its regulation under nutrient stress remains to be investigated. Here, we show that under glucose limitation, AMPK phosphorylates glycinamide ribonucleotide formyltransferase (GART) at Ser440, and this modification facilitates its interaction with UCK2. Through its binding to UCK2, GART generates tetrahydrofolate (THF) and thus inhibits the activity of integrin-linked kinase associated phosphatase (ILKAP) for removing AKT1-mediated UCK2-Ser254 phosphorylation under glucose limitation, in which dephosphorylation of UCK2-Ser254 tends to cause Trim21-mediated UCK2 polyubiquitination and degradation. In this way, both UCK2 binding ability and THF producing catalytic activity of GART protect protein stability of UCK2 and pyrimidine salvage synthesis, and sustain tumor cell growth under glucose limitation. In addition, UCK2-Ser254 phosphorylation level displays a positive relationship with GART-Ser440 phosphorylation level and its enhancement is correlated with poor prognosis of human hepatocellular carcinoma (HCC) patients. These findings reveal a non-canonical role of GART in regulating pyrimidine salvage synthesis under nutrient stress, and raise the potential for alternative treatments in targeting pyrimidine salvage-dependent tumor growth.
尿苷 - 胞苷激酶2（UCK2）是嘧啶补救途径中的关键酶，其过表达与人类癌症发展有关，而其在营养应激下的调节机制仍有待研究。在此，我们表明在葡萄糖限制条件下，AMPK使甘氨酰胺核糖核苷酸甲酰基转移酶（GART）在Ser440位点磷酸化，这种修饰促进了它与UCK2的相互作用。通过与UCK2结合，GART生成四氢叶酸（THF），从而抑制整合素连接激酶相关磷酸酶（ILKAP）的活性，以在葡萄糖限制条件下去除AKT1介导的UCK2 - Ser254磷酸化，其中UCK2 - Ser254的去磷酸化倾向于导致Trim21介导的UCK2多聚泛素化和降解。通过这种方式，GART的UCK2结合能力和THF产生催化活性都保护了UCK2的蛋白质稳定性和嘧啶补救合成，并在葡萄糖限制条件下维持肿瘤细胞生长。此外，UCK2 - Ser254磷酸化水平与GART - Ser440磷酸化水平呈正相关，其增强与人类肝细胞癌（HCC）患者的不良预后相关。这些发现揭示了GART在营养应激下调节嘧啶补救合成中的非经典作用，并提高了针对嘧啶补救依赖性肿瘤生长进行替代治疗的潜力。
