Non-canonical Glutamate-Cysteine Ligase Activity Protects against Ferroptosis

  • Cell Metab. 2021 Jan 5;33(1):174-189.e7. doi: 10.1016/j.cmet.2020.12.007.
Yun Pyo Kang  1 ,  Andrea Mockabee-Macias  1 ,  Chang Jiang  1 ,  Aimee Falzone  1 ,  Nicolas Prieto-Farigua  1 ,  Everett Stone  2 ,  Isaac S Harris  3 ,  Gina M DeNicola  4
Affiliations
  • 1. Department of Cancer Physiology, H. Lee. Moffitt Cancer Center, Tampa, FL 33612, USA.
  • 2. Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
  • 3. University of Rochester Medical Center, Rochester, NY 14642, USA.
  • 4. Department of Cancer Physiology, H. Lee. Moffitt Cancer Center, Tampa, FL 33612, USA. Electronic address: [email protected].
PMID: 33357455 DOI: 10.1016/j.cmet.2020.12.007
Abstract

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 poorly characterized. Here, we find that cystine starvation of non-small-cell lung Cancer cell lines induces an unexpected accumulation of γ-glutamyl-peptides, which are produced due to a non-canonical activity of glutamate-cysteine Ligase catalytic subunit (GCLC). This activity is enriched in cell lines with high levels of NRF2, a key transcriptional regulator of GCLC, but is also inducible in healthy murine tissues following cysteine limitation. γ-glutamyl-peptide synthesis limits the accumulation of glutamate, thereby protecting against Ferroptosis. These results indicate that GCLC has a glutathione-independent, non-canonical role in the protection against Ferroptosis by maintaining glutamate homeostasis under cystine starvation.

Keywords
GCLC; NRF2; cysteine; cystine; ferroptosis; glutamate; γ-glutamyl.
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