作者
Irina Ingold,Carsten Berndt,Sabine Schmitt,Sebastian Doll,Gereon Poschmann,Katalin Buday,Antonella Roveri,Xiaoxiao Peng,Florêncio P. Freitas,Tobias Seibt,Lisa Mehr,Michaela Aichler,Axel Walch,Daniel Lamp,Martin Jastroch,Sayuri Miyamoto,Wolfgang Wurst,Fulvio Ursini,Elias S.J. Arnér,Noelia Fradejas‐Villar,Ulrich Schweizer,Hans Zischka,José Pedro Friedmann Angeli,Marcus Conrad
摘要
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.