PT  - JOURNAL ARTICLE
AU  - Yun Pyo Kang
AU  - Andrea Mockabee-Macias
AU  - Chang Jiang
AU  - Isaac S. Harris
AU  - Gina M. DeNicola
TI  - Non-canonical glutamate-cysteine ligase activity protects against ferroptosis
AID  - 10.1101/2020.05.29.123802
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.29.123802
4099  - http://biorxiv.org/content/early/2020/05/30/2020.05.29.123802.short
4100  - http://biorxiv.org/content/early/2020/05/30/2020.05.29.123802.full
AB  - Cysteine is required for maintaining cellular redox homeostasis in both normal and transformed cells. Deprivation of cysteine induces the iron-dependent form of cell death known as ferroptosis; however, the metabolic consequences of cysteine starvation beyond impairment of glutathione synthesis are uncharacterized. Here, we find that cystine starvation promotes ferroptosis not only through the inhibition of glutathione (GSH) synthesis, but also through the accumulation of glutamate. Surprisingly, we find that glutamate-cysteine ligase catalytic subunit (GCLC) prevents glutamate accumulation through the generation of alternative γ-glutamyl peptides. Further, inhibition of GCLC accelerates ferroptosis under cystine starvation in a GSH-independent manner. These results indicate that GCLC has an additional, non-canonical role in the protection against ferroptosis to maintain glutamate homeostasis under cystine starvation.Competing Interest StatementThe authors declare no competing financial interests. I.S.H. is a consultant for Ono Pharma USA, who had no role in funding or design of this study.