Transient APC/C inactivation by mTOR boosts glycolysis during cell cycle entry
- Debasish Paul
- Derek L. Bolhuis
- Hualong Yan
- Sudipto Das
- Xia Xu
- Christina C. Abbate
- Lisa M. M. Jenkins
- Michael J. Emanuele
- Thorkell Andresson
- Jing Huang
- John G. Albeck
- Nicholas G. Brown
- Steven D. Cappell
2025-07-30
Mammalian cells entering the cell cycle favour glycolysis to rapidly generate ATP and produce the biosynthetic intermediates that are required for rapid biomass accumulation 1 . Simultaneously, the ubiquitin-ligase anaphase-promoting complex/cyclosome and its coactivator CDH1 (APC/C CDH1 ) remains active, allowing origin licensing and blocking premature DNA replication. Paradoxically, glycolysis is reduced by APC/C CDH1 through the degradation of key glycolytic enzymes 2 , 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.