ATF3 promotes erastin-induced ferroptosis by suppressing system Xc–

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.

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

“…Activating transcription factor (ATF)3 is a member of the ATF/cAMP response element binding protein (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. ATF3 achieved this activity through binding to the SLC7A11 promoter and repressing SLC7A11 expression in a p53independent manner (Wang et al, 2019b). ATP-binding cassette, sub-family C (CFTR/MRP), member 1 (ABCC1)/multidrug resistance protein 1 (MRP1) was confirmed to mediate GSH efflux from the cell (Cole, 2014).…”

Nuclear Factor Erythroid 2-Related Factor 2 in Regulating Cancer Metabolism

“…The SLC7A11 gene codes for xCT protein, a subunit of a membrane-localized cystine-glutamate antiporter (Xc -), which imports a cysteine dimer (cystine) in exchange for glutamate. SLC7A11 is a direct target of NRF2, activating transcription factor 4 (ATF4) (286), and ATF3 (298) and is also a prominent target of NRF2 signaling and ferroptosis in a number of malignancies.…”

Systematic identification of a nuclear receptor-enriched predictive signature for erastin-induced ferroptosis

“…GPX4 dependency on erastin induced ferroptic cell death occurs in cell-type-specific manner [10], though the strength of this vulnerability varies in a cell-specific manner. As such, a variety of cellular and molecular components and processes, such as metabolic heterogeneity [11], mesenchymal properties [9], differentiation status [12], p53 status [13], transcription factors [14,15], signaling pathways (e.g. MAPK [16], ATM [17] or YAP [18]), integrins [19], GSH regulators [20], and levels of monounsaturated fatty acid [21], have been examined as determinants of ferroptosis vulnerability in a diverse range of cell model systems.…”