The DOI matches its Crossref record; 74 of the 74 references it cites were found in a registry or an index.
mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation
Open accessAbstract
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.
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Cites
Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death
Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.042 · Cited by 18,691
Regulation of Ferroptotic Cancer Cell Death by GPX4
Yang, W. S., SriRamaratnam, R., Welsch, M. E., Shimada, K., Skouta, R., Viswanathan, V. S., Cheah, J. H., Clemons, P. A., Shamji, A. F., Clish, C. B., et al. (2014) · Cell · doi:10.1016/j.cell.2013.12.010 · Cited by 7,713
Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease
Stockwell, B. R., Friedmann Angeli, J. P., Bayir, H., Bush, A. I., Conrad, M., Dixon, S. J., Fulda, S., Gascón, S., Hatzios, S. K., Kagan, V. E., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.021 · Cited by 7,695
mTOR Signaling in Growth, Metabolism, and Disease
Saxton, R. A., & Sabatini, D. M. (2017) · Cell · doi:10.1016/j.cell.2017.02.004 · Cited by 7,555
TOR signaling in growth and metabolism
Wullschleger, S., Loewith, R., & Hall, M. N. (2006) · Cell · doi:10.1016/j.cell.2006.01.016 · Cited by 5,787
ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition
Doll, S., Proneth, B., Tyurina, Y. Y., Panzilius, E., Kobayashi, S., Ingold, I., Irmler, M., Beckers, J., Aichler, M., Walch, A., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2239 · Cited by 4,293
TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival
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Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice
Friedmann Angeli, J. P., Schneider, M., Proneth, B., Tyurina, Y. Y., Tyurin, V. A., Hammond, V. J., Herbach, N., Aichler, M., Walch, A., Eggenhofer, E., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb3064 · Cited by 3,732
The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis
Bersuker, K., Hendricks, J. M., Li, Z., Magtanong, L., Ford, B., Tang, P. H., Roberts, M. A., Tong, B., Maimone, T. J., Zoncu, R., et al. (2019) · Nature · doi:10.1038/s41586-019-1705-2 · Cited by 3,703
FSP1 is a glutathione-independent ferroptosis suppressor
Doll, S., Freitas, F. P., Shah, R., Aldrovandi, M., da Silva, M. C., Ingold, I., Goya Grocin, A., Xavier da Silva, T. N., Panzilius, E., Scheel, C. H., et al. (2019) · Nature · doi:10.1038/s41586-019-1707-0 · Cited by 3,341
Cited by
Targeting Ferroptosis as a Vulnerability in Cancer
Lei, G., Zhuang, L., & Gan, B. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-022-00459-0 · Cited by 2,252
Self-citationThe Cell Biology of Ferroptosis
Dixon, S. J., & Olzmann, J. A. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00703-5 · Cited by 1,596
GPX4 in cell death, autophagy, and disease
Xie, Y., Kang, R., Klionsky, D. J., & Tang, D. (2023) · Autophagy · doi:10.1080/15548627.2023.2218764 · Cited by 623
Mitochondrial regulation of ferroptosis
Gan, B. (2021) · Journal of Cell Biology · doi:10.1083/jcb.202105043 · Cited by 601
Self-citationGPX4: The hub of lipid oxidation, ferroptosis, disease and treatment
Liu, Y., Wan, Y., Jiang, Y., Zhang, L., & Cheng, W. (2023) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2023.188890 · Cited by 528
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Metadata
- Authors
- Zhang, Y., Swanda, R. V., Nie, L., Liu, X., Wang, C., Lee, H., Lei, G., Mao, C., Koppula, P., Cheng, W., Zhang, J., Xiao, Z., Zhuang, L., Fang, B., Chen, J., Qian, S.-B., & Gan, B.
- Venue
- Nature Communications
- Published
- 2021-03-11
- Volume
- 12
- Issue
- 1
- Pages
- 1589-1589
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W3133823534
- Cited by
- 698
- References
- 74
- FWCI
- 70.35
- Type
- journal article
- Language
- en
- Open access
- gold
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- Zhang, Y., Swanda, R. V., Nie, L., Liu, X., Wang, C., Lee, H., Lei, G., Mao, C., Koppula, P., Cheng, W., Zhang, J., Xiao, Z., Zhuang, L., Fang, B., Chen, J., Qian, S.-B., & Gan, B. (2021). mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation. Nature Communications. https://doi.org/10.1038/s41467-021-21841-w
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