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A Genome-wide Haploid Genetic Screen Identifies Regulators of Glutathione Abundance and Ferroptosis Sensitivity

Authors :
Jennifer Yinuo Cao
Aunoy Poddar
Leslie Magtanong
Jennifer H. Lumb
Trevor R. Mileur
Michael A. Reid
Cole M. Dovey
Jin Wang
Jason W. Locasale
Everett Stone
Susan P.C. Cole
Jan E. Carette
Scott J. Dixon
Source :
Cell Reports, Vol 26, Iss 6, Pp 1544-1556.e8 (2019)
Publication Year :
2019
Publisher :
Elsevier, 2019.

Abstract

Summary: The tripeptide glutathione suppresses the iron-dependent, non-apoptotic cell death process of ferroptosis. How glutathione abundance is regulated in the cell and how this regulation alters ferroptosis sensitivity is poorly understood. Using genome-wide human haploid genetic screening technology coupled to fluorescence-activated cell sorting (FACS), we directly identify genes that regulate intracellular glutathione abundance and characterize their role in ferroptosis regulation. Disruption of the ATP binding cassette (ABC)-family transporter multidrug resistance protein 1 (MRP1) prevents glutathione efflux from the cell and strongly inhibits ferroptosis. High levels of MRP1 expression decrease sensitivity to certain pro-apoptotic chemotherapeutic drugs, while collaterally sensitizing to all tested pro-ferroptotic agents. By contrast, disruption of KEAP1 and NAA38, leading to the stabilization of the transcription factor NRF2, increases glutathione levels but only weakly protects from ferroptosis. This is due in part to concomitant NRF2-mediated upregulation of MRP1. These results pinpoint glutathione efflux as an unanticipated regulator of ferroptosis sensitivity. : Glutathione suppresses the non-apoptotic cell death process of ferroptosis. Using genome-wide human haploid cell mutagenesis and FACS-based detection, Cao et al. identify negative regulators of intracellular glutathione abundance that affect glutathione efflux and NRF2 protein levels, altering ferroptosis sensitivity. Keywords: ROS, metabolite efflux, multidrug resistance, ferroptosis, necrosis, cancer, glutathione, iron, collateral sensitivity

Subjects

Subjects :
Biology (General)
QH301-705.5

Details

Language :
English
ISSN :
22111247
Volume :
26
Issue :
6
Database :
Directory of Open Access Journals
Journal :
Cell Reports
Publication Type :
Academic Journal
Accession number :
edsdoj.62f1fcca97a4f38a038ca65ecfdfe8f
Document Type :
article
Full Text :
https://doi.org/10.1016/j.celrep.2019.01.043