Journal
CELL DEATH AND DIFFERENTIATION
Volume 27, Issue 2, Pages 662-675Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41418-019-0380-z
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Funding
- NCI NIH HHS [R01 CA190429, R01 CA139107] Funding Source: Medline
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The amino acid antiporter system Xc(-) is important for the synthesis of glutathione (GSH) that functions to prevent lipid peroxidation and protect cells from nonapoptotic, iron-dependent death (i.e., ferroptosis). While the activity of system Xc(-) often positively correlates with the expression level of its light chain encoded by SLC7A11, inhibition of system Xc(-) activity by small molecules (e.g., erastin) causes a decrease in the intracellular GSH level, leading to ferroptotic cell death. How system Xc(-) is regulated during ferroptosis remains largely unknown. Here we report that activating transcription factor 3 (ATF3), a common stress sensor, can promote ferroptosis induced by erastin. ATF3 suppressed system Xc(-), depleted intracellular GSH, and thereby promoted lipid peroxidation induced by erastin. ATF3 achieved this activity through binding to the SLC7A11 promoter and repressing SLC7A11 expression in a p53-independent manner. These findings thus add ATF3 to a short list of proteins that can regulate system Xc(-) and promote ferroptosis repressed by this antiporter.
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