Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation

• Published in: Cell death and differentiation Vol. 23; no. 2; pp. 270 - 278
• Main Authors: Hayano, M, Yang, W S, Corn, C K, Pagano, N C, Stockwell, B R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2016; Nature Publishing Group
• Subjects: 13; 13/106; 13/109; 13/89; 13/95; 38/89; 38/90; 631/337; Amino Acyl-tRNA Synthetases - genetics; Amino Acyl-tRNA Synthetases - metabolism; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Biochemistry; Biomedical and Life Sciences; Biosynthetic Pathways; Cell Biology; Cell Cycle Analysis; Cystine - metabolism; Drug Resistance, Neoplasm; Ferroptosis; Gene Knockdown Techniques; Glutamic Acid - pharmacology; Humans; Life Sciences; Original Paper; PC12 Cells; Piperazines - pharmacology; Rats; Reactive Oxygen Species - metabolism; Serine - biosynthesis; Signal Transduction; Stem Cells
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2015.93

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 x c − . 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.