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. 2020 Feb;594(4):611-624.
doi: 10.1002/1873-3468.13631. Epub 2019 Oct 20.

Inactivation of the glutathione peroxidase GPx4 by the ferroptosis-inducing molecule RSL3 requires the adaptor protein 14-3-3ε

Ana-Marija Vučković  1 , Valentina Bosello Travain  1 , Luciana Bordin  1 , Giorgio Cozza  1 , Giovanni Miotto  1 , Monica Rossetto  1 , Stefano Toppo  1 , Rina Venerando  1 , Mattia Zaccarin  1 , Matilde Maiorino  1 , Fulvio Ursini  1 , Antonella Roveri  1
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Free article

Inactivation of the glutathione peroxidase GPx4 by the ferroptosis-inducing molecule RSL3 requires the adaptor protein 14-3-3ε

Ana-Marija Vučković et al. FEBS Lett. 2020 Feb.
Free article

Abstract

Ras-selective lethal small molecule 3 (RSL3), a drug candidate prototype for cancer chemotherapy, triggers ferroptosis by inactivating the glutathione peroxidase glutathione peroxidase 4 (GPx4). Here, we report the purification of the protein indispensable for GPx4 inactivation by RSL3. Mass spectrometric analysis identified 14-3-3 isoforms as candidates, and recombinant human 14-3-3ε confirms the identification. The function of 14-3-3ε is redox-regulated. Moreover, overexpression or silencing of the gene coding for 14-3-3ε consistently controls the inactivation of GPx4 by RSL3. The interaction of GPx4 with a redox-regulated adaptor protein operating in cell signaling further contributes to frame it within redox-regulated pathways of cell survival and death and opens new therapeutic perspectives.

Keywords: 14-3-3 proteins; RSL3; ferroptosis; glutathione peroxidase 4; protein; protein interaction; redox regulation.

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