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

Oncogene volume 42, pages 2828–2840 (2023)Cite this article

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Abstract

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.

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Fig. 1: YAP is activated by glutamine (Gln) metabolism inhibition.
Fig. 2: Gln metabolism regulates YAP activity through ROS.
Fig. 3: YAP transcriptionally up-regulates ATF4 upon glutaminolysis inhibition.
Fig. 4: The YAP-ATF4 pathway suppresses mTORC1 activity by inducing Sestrin2 upon glutaminolysis inhibition.
Fig. 5: YAP activation is required for cell survival upon glutaminolysis inhibition.
Fig. 6: YAP inhibition sensitizes tumor growth to glutaminolysis inhibitors in vivo.
Fig. 7: A proposed model for YAP-mediated cellular adaptation upon glutamine starvation.

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Data availability

The data generated and analyzed in the current study are available within the manuscript. Additional data are available from the corresponding author upon reasonable request.

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Acknowledgements

This research was supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Korean Government (2022R1F1A1066394 and RS-2023-00244737). M.K. was supported in part by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (2022R1A6A3A13068164).

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  1. Department of Biochemistry, Institute for Aging and Metabolic Diseases, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea

    Minjoong Kim, Sunsook Hwang, Byungjoo Kim, Seungmin Shin, Seungyeon Yang, Jihye Gwak & Seung Min Jeong

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Contributions

MK and SMJ prepared the concept. SMJ designed and supervised the study. MK, SH, BK, SS, SY, and JG performed the experiments. MK and SMJ analyzed the data. MK and SMJ acquired fundings. SMJ wrote the main manuscript.

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Correspondence to Seung Min Jeong.

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Kim, M., Hwang, S., Kim, B. et al. YAP governs cellular adaptation to perturbation of glutamine metabolism by regulating ATF4-mediated stress response. Oncogene 42, 2828–2840 (2023). https://doi.org/10.1038/s41388-023-02811-6

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