Abstract
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.
Highlights
System Xc− is an amino acid antiporter that mediates the exchange of extracellular cystine and intracellularEdited by E
A recent finding that the activating transcription factor 3 (ATF3) mRNA level was increased during erastin-induced ferroptosis [4] prompted us to hypothesize that ATF3 may play a role in the regulation of this important form of cell death
While ATF3 expression can be induced by the endoplasmic reticulum (ER) stress via the PERK/ATF4-mediated pathway [35], ATF3 induction by erastin was impaired when the cells were pretreated with an PERK inhibitor GSK 2606414 (Fig. 1f), suggesting that erastin-induced ER stress [4] might contribute to ATF3 induction as well
Summary
System Xc− is an amino acid antiporter that mediates the exchange of extracellular cystine and intracellular. Because cysteine reduced from cystine is the rate-limiting substrate for the synthesis of the antioxidant glutathione (GSH) [2], inhibition of system Xc−-mediated cystine import by small molecules (e.g., erastin) causes depletion of intracellular GSH and subsequent iron-dependent lipid peroxidation, which in turn leads to a form of nonapoptotic, iron-dependent cell death referred to as ferroptosis [3, 4]. Activation transcription factor 3 (ATF3) is a member of the ATF/CREB family of transcription factors, and its expression is rapidly induced by a wide range of cellular stresses, including DNA damage, oxidative stress, and cell injury [13]. ATF3 contains a basic-region leucinezipper (bZIP) domain that binds to the ATF/CREB cisregulatory element or the AP-1 element [14], and as a result, can either repress or activate transcription depending on cell context. We report that ATF3 could suppress system Xc− and predispose cells to ferroptosis by repressing SLC7A11 expression
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