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

AbstractRas ‐selective lethal small molecule 3 (RSL3), a drug candidate prototype for cancer chemotherapy, triggers ferroptosis by inactivating the glutathione peroxidase GPx4. Here, we report the purification of the protein indispensable for GPx4 inactivation by RSL3. Mass spectrometric analysis identified 1 4‐3‐3 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 GP x4 with a redox‐regulated adaptor protein operating in cell signalling further contributes to frame it within redox‐regulated pathways of cell survival and death and opens new therapeutic perspectives.
Source: FEBS Letters - Category: Biochemistry Authors: Tags: Research Articles Source Type: research