mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 11, 2021
- Source ID
- 10.1038/s41467-021-21841-w
Entities
People
- Bingliang Fang
- Boyi Gan
- Chao Mao
- Chao Wang
- Guang Lei
- Hyemin Lee
- Jie Zhang
- Junjie Chen
- Li Zhuang
- Litong Nie
- Pranavi Koppula
- Robert V. Swanda
- Shu-Bing Qian
- Weijie Cheng
- Xiaoguang Liu
- Yilei Zhang
- Zhenna Xiao
Organizations
- National Cancer Institute
- National Institute of General Medical Sciences
- United States Department of Defense
- United States Department of Health and Human Services