Abstract
Ferroptosis is a form of regulated non-apoptotic cell death that has been implicated in several disease contexts. A better understanding of the ferroptotic death mechanism could lead to the development of new therapeutics for degenerative diseases, and a better understanding of how to induce ferroptosis in specific tumor contexts. We performed an unbiased genome-wide siRNA screen to find genetic suppressors of ferroptosis. We determined that loss of CARS, the cysteinyl-tRNA synthetase, suppresses ferroptosis induced by erastin, which inhibits the cystine–glutamate antiporter known as system xc−. Knockdown of CARS inhibited erastin-induced death by preventing the induction of lipid reactive oxygen species, without altering iron homeostasis. Knockdown of CARS led to the accumulation of cystathionine, a metabolite on the transsulfuration pathway, and upregulated genes associated with serine biosynthesis and transsulfuration. In addition, inhibition of the transsulfuration pathway resensitized cells to erastin, even after CARS knockdown. These studies demonstrate a new mechanism of resistance to ferroptosis and may lead to strategies for inducing and suppressing ferroptosis in diverse contexts.
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Abbreviations
- HD:
-
Huntington’s disease
- PVL:
-
periventricular leukomalacia
- GSH:
-
glutathione
- ROS:
-
reactive oxygen species
- GPX4:
-
glutathione peroxidase 4
- BSO:
-
bluthionine sulfoximine
- CARS:
-
cysteinyl-tRNA synthetase
- CSSG:
-
cysteine–glutathione disulfide
- PPG:
-
propargylglycine
- ATOC:
-
α-tocopherol
- DFOM:
-
deferoxamine
- CBS:
-
cystathionine β-synthase
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Acknowledgements
We acknowledge the assistance of Dr. Chi Yun and Janine Recio at the NYU RNAi core for advice and assistance with the RNAi screen, Dr. Jose Silva at Mount Sinai for reagents and assistance with LentiORF experiments and Dr. Christine Huang for help with mutagenesis experiments. The NYU RNAi core is supported by NIHA CI 5P30CA16087-31 and NYSTEM Contract C026719. MH was supported by NIH predoctoral training grant in cancer biology (CA009503). This research was funded by the Howard Hughes Medical Institute, National Institute of Health (5R01CA097061, 5R01GM085081, R01CA161061), and New York Stem Cell Science (C026715) to BRS. BRS is an Early Career Scientist of the Howard Hughes Medical Institute.
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Hayano, M., Yang, W., Corn, C. et al. Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ 23, 270–278 (2016). https://doi.org/10.1038/cdd.2015.93
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DOI: https://doi.org/10.1038/cdd.2015.93
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