title: Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation.
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.
authors.affiliation: Department of Pharmacology, Columbia University, 550 West 120th Street, Northwest Corner Building, MC 4846, New York, NY 10027, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hayano
authors.affiliation: Department of Biological Sciences, Columbia University, 550 West 120th Street, Northwest Corner Building, MC 4846, New York, NY 10027, USA.
authors.forename: W S
authors.initials: WS
authors.lastname: Yang
authors.affiliation: Department of Biological Sciences, Columbia University, 550 West 120th Street, Northwest Corner Building, MC 4846, New York, NY 10027, USA.
authors.forename: C K
authors.initials: CK
authors.lastname: Corn
authors.affiliation: Department of Biological Sciences, Columbia University, 550 West 120th Street, Northwest Corner Building, MC 4846, New York, NY 10027, USA.
authors.forename: N C
authors.initials: NC
authors.lastname: Pagano
authors.affiliation: Department of Biological Sciences, Columbia University, 550 West 120th Street, Northwest Corner Building, MC 4846, New York, NY 10027, USA.|Department of Chemistry, Columbia University, 550 West 120th Street, Northwest Corner Building, MC 4846, New York, NY 10027, USA.|Howard Hughes Medical Institute, Columbia University, 550 West 120th Street, Northwest Corner Building, MC 4846, New York, NY 10027, USA.
authors.forename: B R
authors.initials: BR
authors.lastname: Stockwell
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D053898:Biosynthetic Pathways; D003553:Cystine / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D055785:Gene Knockdown Techniques; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D016716:PC12 Cells; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012694:Serine / Q000096:biosynthesis; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D017382:Reactive Oxygen Species; C477224:erastin; D018698:Glutamic Acid; D012694:Serine; D003553:Cystine; D000604:Amino Acyl-tRNA Synthetases; C019975:cysteinyl-tRNA synthetase