mTORC1是机械靶向雷帕霉素复合物1，它通过调节氨基酸和葡萄糖水平来控制细胞生长。然而，mTORC1如何感知葡萄糖的可用性以调节下游信号通路仍然不清楚。在这里，我们报告了AMP激活蛋白激酶（AMPK）介导的WDR24的磷酸化，在mTORC1的葡萄糖感知功能中发挥作用。机制上，葡萄糖匮乏会激活AMPK，直接在S155上磷酸化WDR24，随后破坏GATOR2复合物的完整性，抑制mTORC1的激活。磷酸模拟的Wdr24S155D敲入小鼠表现出早期胚胎致死和降低的mTORC1活性。另一方面，与野生型小鼠相比，磷酸缺陷的Wdr24S155A敲入小鼠对禁食更有抵抗力，并显示出升高的mTORC1活性。我们的发现揭示了AMPK介导的WDR24磷酸化如何调节葡萄糖诱导的mTORC1激活，从而提供了将AMPK-WDR24信号作为潜在治疗手段来微调mTORC1激活，以对抗包括癌症在内的异常mTORC1信号的人类疾病的合理基础。©2023年。作者及其专利人独家授权Springer Nature Limited。

The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth in response to amino acid and glucose levels. However, how mTORC1 senses glucose availability to regulate various downstream signalling pathways remains largely elusive. Here we report that AMP-activated protein kinase (AMPK)-mediated phosphorylation of WDR24, a core component of the GATOR2 complex, has a role in the glucose-sensing capability of mTORC1. Mechanistically, glucose deprivation activates AMPK, which directly phosphorylates WDR24 on S155, subsequently disrupting the integrity of the GATOR2 complex to suppress mTORC1 activation. Phosphomimetic Wdr24S155D knock-in mice exhibit early embryonic lethality and reduced mTORC1 activity. On the other hand, compared to wild-type littermates, phospho-deficient Wdr24S155A knock-in mice are more resistant to fasting and display elevated mTORC1 activity. Our findings reveal that AMPK-mediated phosphorylation of WDR24 modulates glucose-induced mTORC1 activation, thereby providing a rationale for targeting AMPK-WDR24 signalling to fine-tune mTORC1 activation as a potential therapeutic means to combat human diseases with aberrant activation of mTORC1 signalling including cancer.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.