ATF3 promotes erastin-induced ferroptosis by suppressing system Xc

Liyuan Wang, Yichen Liu, Tingting Du, Heng Yang, Lei Lei, Mengqi Guo, Hanfei Ding, Junran Zhang, Hongbo Wang, Xiaoguang Chen, Chunhong Yan

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalCell Death and Differentiation
DOIs
StatePublished - Jan 1 2019

Fingerprint

Activating Transcription Factor 3
Antiporters
Lipid Peroxidation
Glutathione
Cell Death
Iron
Light
Amino Acids
erastin
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

ATF3 promotes erastin-induced ferroptosis by suppressing system Xc. / Wang, Liyuan; Liu, Yichen; Du, Tingting; Yang, Heng; Lei, Lei; Guo, Mengqi; Ding, Hanfei; Zhang, Junran; Wang, Hongbo; Chen, Xiaoguang; Yan, Chunhong.

In: Cell Death and Differentiation, 01.01.2019.

Research output: Contribution to journalArticle

Wang, Liyuan ; Liu, Yichen ; Du, Tingting ; Yang, Heng ; Lei, Lei ; Guo, Mengqi ; Ding, Hanfei ; Zhang, Junran ; Wang, Hongbo ; Chen, Xiaoguang ; Yan, Chunhong. / ATF3 promotes erastin-induced ferroptosis by suppressing system Xc. In: Cell Death and Differentiation. 2019.
@article{d35ed5ecf71d46cfb16f7096d33405cd,
title = "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.",
author = "Liyuan Wang and Yichen Liu and Tingting Du and Heng Yang and Lei Lei and Mengqi Guo and Hanfei Ding and Junran Zhang and Hongbo Wang and Xiaoguang Chen and Chunhong Yan",
year = "2019",
month = "1",
day = "1",
doi = "10.1038/s41418-019-0380-z",
language = "English (US)",
journal = "Cell Death and Differentiation",
issn = "1350-9047",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - ATF3 promotes erastin-induced ferroptosis by suppressing system Xc–

AU - Wang, Liyuan

AU - Liu, Yichen

AU - Du, Tingting

AU - Yang, Heng

AU - Lei, Lei

AU - Guo, Mengqi

AU - Ding, Hanfei

AU - Zhang, Junran

AU - Wang, Hongbo

AU - Chen, Xiaoguang

AU - Yan, Chunhong

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85068578356&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068578356&partnerID=8YFLogxK

U2 - 10.1038/s41418-019-0380-z

DO - 10.1038/s41418-019-0380-z

M3 - Article

AN - SCOPUS:85068578356

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

SN - 1350-9047

ER -