mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation

Yilei Zhang, Robert V. Swanda, Litong Nie, Xiaoguang Liu, Chao Wang, Hyemin Lee, Guang Lei, Chao Mao, Pranavi Koppula, Weijie Cheng, Jie Zhang, Zhenna Xiao, Li Zhuang, Bingliang Fang, Junjie Chen, Shu-Bing Qian and Boyi Gan ()
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Yilei Zhang: the University of Texas MD Anderson Cancer Center
Robert V. Swanda: Cornell University
Litong Nie: the University of Texas MD Anderson Cancer Center
Xiaoguang Liu: the University of Texas MD Anderson Cancer Center
Chao Wang: the University of Texas MD Anderson Cancer Center
Hyemin Lee: the University of Texas MD Anderson Cancer Center
Guang Lei: the University of Texas MD Anderson Cancer Center
Chao Mao: the University of Texas MD Anderson Cancer Center
Pranavi Koppula: the University of Texas MD Anderson Cancer Center
Weijie Cheng: the University of Texas MD Anderson Cancer Center
Jie Zhang: the University of Texas MD Anderson Cancer Center
Zhenna Xiao: the University of Texas MD Anderson Cancer Center
Li Zhuang: the University of Texas MD Anderson Cancer Center
Bingliang Fang: the University of Texas MD Anderson Cancer Center
Junjie Chen: the University of Texas MD Anderson Cancer Center
Shu-Bing Qian: Cornell University
Boyi Gan: the University of Texas MD Anderson Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and plays an essential role in inhibiting ferroptosis. As a selenoprotein, GPX4 protein synthesis is highly inefficient and energetically costly. How cells coordinate GPX4 synthesis with nutrient availability remains unclear. In this study, we perform integrated proteomic and functional analyses to reveal that SLC7A11-mediated cystine uptake promotes not only GSH synthesis, but also GPX4 protein synthesis. Mechanistically, we find that cyst(e)ine activates mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and promotes GPX4 protein synthesis at least partly through the Rag-mTORC1-4EBP signaling axis. We show that pharmacologic inhibition of mTORC1 decreases GPX4 protein levels, sensitizes cancer cells to ferroptosis, and synergizes with ferroptosis inducers to suppress patient-derived xenograft tumor growth in vivo. Together, our results reveal a regulatory mechanism to coordinate GPX4 protein synthesis with cyst(e)ine availability and suggest using combinatorial therapy of mTORC1 inhibitors and ferroptosis inducers in cancer treatment.

Date: 2021
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DOI: 10.1038/s41467-021-21841-w

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