美国国家癌症研究所Steven D. Cappell课题组宣布他们的最新研究提出了mTOR对APC/C的瞬时失活促进了细胞周期进入期间的糖酵解。2025年7月30日出版的《自然》发表了这项成果。

在这里，该课题组人员表明细胞通过在细胞周期进入期间暂时失活APC/C来解决这一矛盾，这允许有利于糖酵解的短暂代谢转变。在有丝分裂原刺激后，mTOR介导的APC/C适配蛋白CDH1在氨基末端的快速磷酸化使其与APC/C部分分离。APC/C的部分失活导致PFKFB3的积累，PFKFB3是糖酵解的限速酶，促进糖酵解的代谢转变。磷酸酶活性的延迟积累随后会消除CDH1磷酸化，恢复APC/C的全部活性，并使细胞回到有利于氧化磷酸化的状态。因此，细胞通过一个不连贯的前馈循环协调细胞周期进程和代谢的同时需求，该循环短暂地抑制APC/C活性以产生糖酵解脉冲，这是哺乳动物细胞周期进入所必需的。

据悉，进入细胞周期的哺乳动物细胞倾向于糖酵解以快速生成ATP和产生快速生物量积累所需的生物合成中间体。同时，泛素连接酶后期促进复合体/环体及其辅助激活因子CDH1 （APC/C^CDH1）保持活性，允许起始许可并阻止过早的DNA复制。矛盾的是，APC/C^CDH1通过降解关键的糖酵解酶来减少糖酵解，这就提出了细胞如何协调这些相互排斥的事件以确保适当的细胞分裂的问题。

附：英文原文

Title: Transient APC/C inactivation by mTOR boosts glycolysis during cell cycle entry

Author: Paul, Debasish, Bolhuis, Derek L., Yan, Hualong, Das, Sudipto, Xu, Xia, Abbate, Christina C., Jenkins, Lisa M. M., Emanuele, Michael J., Andresson, Thorkell, Huang, Jing, Albeck, John G., Brown, Nicholas G., Cappell, Steven D.

Issue&Volume: 2025-07-30

Abstract: Mammalian cells entering the cell cycle favour glycolysis to rapidly generate ATP and produce the biosynthetic intermediates that are required for rapid biomass accumulation1. Simultaneously, the ubiquitin-ligase anaphase-promoting complex/cyclosome and its coactivator CDH1 (APC/CCDH1) remains active, allowing origin licensing and blocking premature DNA replication. Paradoxically, glycolysis is reduced by APC/CCDH1 through the degradation of key glycolytic enzymes2, raising the question of how cells coordinate these mutually exclusive events to ensure proper cell division. Here we show that cells resolve this paradox by transiently inactivating the APC/C during cell cycle entry, which allows a transient metabolic shift favouring glycolysis. After mitogen stimulation, rapid mTOR-mediated phosphorylation of the APC/C adapter protein CDH1 at the amino terminus causes it to partially dissociate from the APC/C. This partial inactivation of the APC/C leads to the accumulation of PFKFB3, a rate-limiting enzyme for glycolysis, promoting a metabolic shift towards glycolysis. Delayed accumulation of phosphatase activity later removes CDH1 phosphorylation, restoring full APC/C activity, and shifting cells back to favouring oxidative phosphorylation. Thus, cells coordinate the simultaneous demands of cell cycle progression and metabolism through an incoherent feedforward loop, which transiently inhibits APC/C activity to generate a pulse of glycolysis that is required for mammalian cell cycle entry.

DOI: 10.1038/s41586-025-09328-w

Source: https://www.nature.com/articles/s41586-025-09328-w