Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis
| Autor: | Martin Jastroch, Florencio Porto Freitas, Carsten Berndt, Daniel Lamp, Marcus Conrad, Antonella Roveri, Sabine Schmitt, Ulrich Schweizer, Lisa Mehr, Wolfgang Wurst, Fulvio Ursini, Axel Walch, Katalin Buday, Elias S.J. Arnér, Tobias Seibt, Xiaoxiao Peng, Sebastian Doll, José Pedro Friedmann Angeli, Noelia Fradejas-Villar, Michaela Aichler, Irina Ingold, Gereon Poschmann, Sayuri Miyamoto, Hans Zischka |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Apoptosis metabolism [Selenium] ACSL4 GPX4 Trsp ferroptosis glutathione peroxidase lipid peroxidation mouse genetics selenium selenocysteine selenoproteins glutathione peroxidase 4 mouse chemistry.chemical_compound Mice 0302 clinical medicine Acsl4 Ferroptosis Glutathione Peroxidase Gpx4 Lipid Peroxidation Mouse Genetics Selenium Selenocysteine Selenoproteins Cells Cultured metabolism [Interneurons] chemistry.chemical_classification integumentary system Glutathione peroxidase etiology [Seizures] Amino acid Biochemistry Female Cell Survival metabolism [Seizures] genetics [Glutathione Peroxidase] chemistry.chemical_element Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Interneurons Seizures Animals Humans Viability assay ddc:610 Hydrogen Peroxide toxicity [Hydrogen Peroxide] PROTEÍNAS Phospholipid Hydroperoxide Glutathione Peroxidase Mice Inbred C57BL metabolism [Glutathione Peroxidase] 030104 developmental biology HEK293 Cells chemistry Selenoprotein 030217 neurology & neurosurgery Cysteine |
| Zdroj: | Cell 172, 409–422.e21 (2018) Cell 172(3), 409-422.e21 (2018). doi:10.1016/j.cell.2017.11.048 Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| DOI: | 10.1016/j.cell.2017.11.048 |
| Popis: | Selenoproteins are rare proteins among all kingdoms of life containing the 21 st 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 Gpx4 cys/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. The trace element selenium protects a critical population of interneurons from ferroptotic cell death. |
| Databáze: | OpenAIRE |
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