增殖细胞在代谢上依赖谷氨酰胺提供能量来满足合成途径的需求，并重新填充线粒体的碳库。Hippo通路对于协调细胞的存活和生长与营养可用性至关重要，但目前尚未报道过它与缺乏谷氨酰胺的分子联系。在本研究中，我们发现了Hippo通路的一个非经典作用，即Hippo通路的关键效应器YAP在细胞对谷氨酰胺代谢紊乱的适应中起到重要作用。当营养物供应不足时，YAP被抑制，使细胞抑制增殖并保持能量平衡，而谷氨酰胺短缺引发迅速的YAP去磷酸化和激活。当谷氨酰胺解氨酶抑制时，增强的活性氧生成通过RhoA抑制LATS激酶，导致YAP去磷酸化。活化的YAP促进ATF4的转录诱导，进而诱导参与氨基酸稳态的基因表达，包括Sestrin2。我们发现，YAP介导的Sestrin2诱导在保护细胞在谷氨酰胺缺乏时的细胞活力方面至关重要，通过抑制mTORC1的活性。因此，我们的研究发现揭示了YAP、ATF4和mTORC1之间的重要关系。最后，我们的数据表明，通过靶向Hippo-YAP通路结合谷氨酰胺解氨酶抑制可能提供潜在的治疗肿瘤的方法。© 2023. 作者，Springer Nature Limited独家许可。

Proliferating cells have metabolic dependence on glutamine to fuel anabolic pathways and to refill the mitochondrial carbon pool. The Hippo pathway is essential for coordinating cell survival and growth with nutrient availability, but no molecular connection to glutamine deprivation has been reported. Here, we identify a non-canonical role of YAP, a key effector of the Hippo pathway, in cellular adaptation to perturbation of glutamine metabolism. Whereas YAP is inhibited by nutrient scarcity, enabling cells to restrain proliferation and to maintain energy homeostasis, glutamine shortage induces a rapid YAP dephosphorylation and activation. Upon glutaminolysis inhibition, an increased reactive oxygen species production inhibits LATS kinase via RhoA, leading to YAP dephosphorylation. Activated YAP promotes transcriptional induction of ATF4 to induce the expression of genes involved in amino acid homeostasis, including Sestrin2. We found that YAP-mediated Sestrin2 induction is crucial for cell viability during glutamine deprivation by suppressing mTORC1. Thus, a critical relationship between YAP, ATF4, and mTORC1 is uncovered by our findings. Finally, our data indicate that targeting the Hippo-YAP pathway in combination with glutaminolysis inhibition may provide potential therapeutic approaches to treat tumors.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.