YAP governs cellular adaptation to perturbation of glutamine metabolism by regulating ATF4-mediated stress response

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.