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

By Yilei Zhang, Robert V. Swanda, Litong Nie, Xiaoguang Liu, Chao Wang, Hyemin Lee, Guang Lei, Chao Mao, Pranavi Koppula, Weijie Cheng and 7 more. Nature Communications, 2021

635 citations recorded by the source corpus.

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. Glutathione peroxidase 4 (GPX4) inhibits ferroptosis, but protein synthesis is inefficient and costly. Here, the authors reveal that cystine uptake promotes GPX4 synthesis by activating mTORC1 and show that cancer cells are sensitized to ferroptosis by mTORC1 inhibition.

Subfields: Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/135b6aa357d97459e3f1da5f440a4bdcf754e523

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Citations in the corpus

Ferroptosis in infection, inflammation, and immunity (2021, background): “Ferroptosis may be further doubly regulated by an amino acid sensor: mechanistic target of rapamycin kinase (Baba et al., 2018; Conlon et al., 2021; Liu et al., 2021; Yi et al., 2020; Zhang et al., 2021) or an energy sensor: adenosine monophosphate–activated protein kinase (AMPK; Lee et al.”
The cell biology of ferroptosis (2024, positive): “In other cells, active mTORC1 inhibits ferroptosis by stimulating the translation of GPX4 or the activation of SREBP1, which, as noted above, promotes anti-ferroptotic MUFA synthesis 125,159 .”
Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. (2022, positive): “The mTOR pathway promotes resistance to ferroptosis through increased GPX4 protein synthesis (Zhang et al., 2021) and increased sterol response element binding protein (SREBP)-mediated lipogenesis (Yi et al., 2020).”