Cell
Volume 172, Issue 3, 25 January 2018, Pages 409-422.e21
Journal home page for Cell

Article
Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis

https://doi.org/10.1016/j.cell.2017.11.048Get rights and content
Under an Elsevier user license
open archive

Highlights

  • Selenium-containing GPX4 is necessary for full viability of mice

  • The GPX4-Cys variant is highly susceptible to hydroperoxide-induced inactivation

  • Hydroperoxide induces ferroptosis in Gpx4cys/cys cells

  • GPX4-Cys bypasses the requirement of selenoproteins for cell viability

Summary

Selenoproteins are rare proteins among all kingdoms of life containing the 21st amino acid, selenocysteine. Selenocysteine resembles cysteine, differing only by the substitution of selenium for sulfur. Yet the actual advantage of selenolate- versus thiolate-based catalysis has remained enigmatic, as most of the known selenoproteins also exist as cysteine-containing homologs. Here, we demonstrate that selenolate-based catalysis of the essential mammalian selenoprotein GPX4 is unexpectedly dispensable for normal embryogenesis. Yet the survival of a specific type of interneurons emerges to exclusively depend on selenocysteine-containing GPX4, thereby preventing fatal epileptic seizures. Mechanistically, selenocysteine utilization by GPX4 confers exquisite resistance to irreversible overoxidation as cells expressing a cysteine variant are highly sensitive toward peroxide-induced ferroptosis. Remarkably, concomitant deletion of all selenoproteins in Gpx4cys/cys cells revealed that selenoproteins are dispensable for cell viability provided partial GPX4 activity is retained. Conclusively, 200 years after its discovery, a specific and indispensable role for selenium is provided.

Keywords

ferroptosis
GPX4
selenoproteins
selenium
Trsp
selenocysteine
ACSL4
mouse genetics
glutathione peroxidase
lipid peroxidation

Cited by (0)

17

Present address: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, 97080 Würzburg, Germany

18

Lead Contact