mTORC1 regulates the pyrimidine salvage pathway by controlling UCK2 turnover via the CTLH-WDR26 E3 ligase

作     者：Pham, Brittany Q. Yi, Sang Ah Ordureau, Alban An, Heeseon 

作者机构：Weill Cornell Grad Sch Med Sci Dept Pharmacol New York NY 10065 USA Mem Sloan Kettering Canc Ctr Sloan Kettering Inst Chem Biol Program New York NY 10065 USA Mem Sloan Kettering Canc Ctr Sloan Kettering Inst Cell Biol Program New York NY USA Mem Sloan Kettering Canc Ctr Triinst PhD Program New York NY 10065 USA 

出 版 物：《CELL REPORTS》 (Cell Rep.)

年 卷 期：2025年第44卷第1期

页      面：115179页

核心收录：

学科分类：0710[理学-生物学] 07[理学] 071009[理学-细胞生物学] 09[农学] 0901[农学-作物学] 090102[农学-作物遗传育种] 

基　　金：NIH [1R01GM152667] MSKCC Josie Robertson Foundation Geoffrey Beene Grant Memorial Sloan Kettering Cancer Center Support Grant [P30CA008748] 

主　　题：pyrimidine UCK2 mTOR mTORC1 CTLH WDR26 pyrimidine salvage degradomics ubiquitin YPEL5 

摘      要：One critical aspect of cell proliferation is increased nucleotide synthesis, including pyrimidines. Pyrimidines are synthesized through de novo and salvage pathways. Prior studies established that the mammalian target of rapamycin complex 1 (mTORC1) promotes pyrimidine synthesis by activating the de novo pathway for cell proliferation. However, the involvement of mTORC1 in regulating the salvage pathway remains unclear. Here, we report that mTORC1 controls the half-life of uridine cytidine kinase 2 (UCK2), the rate-limiting enzyme in the salvage pathway. Specifically, UCK2 is degraded via the CTLH-WDR26 E3 complex during mTORC1 inhibition, which is prevented when mTORC1 is active. We also find that UCK1, an isoform of UCK2, affects the turnover of UCK2 by influencing its cellular localization. Importantly, altered UCK2 levels through the mTORC1-CTLH E3 pathway affect pyrimidine salvage and the efficacy of pyrimidine analog prodrugs. Therefore, mTORC1-CTLH E3-mediated degradation of UCK2 adds another layer of complexity to mTORC1 s role in regulating pyrimidine metabolism.