1. PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance.
- Author
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Chen Z, Inague A, Kaushal K, Fazeli G, Schilling D, Xavier da Silva TN, Dos Santos AF, Cheytan T, Freitas FP, Yildiz U, Viviani LG, Lima RS, Pinz MP, Medeiros I, Iijima TS, Alegria TGP, Pereira da Silva R, Diniz LR, Weinzweig S, Klein-Seetharaman J, Trumpp A, Mañas A, Hondal R, Bartenhagen C, Fischer M, Shimada BK, Seale LA, Chillon TS, Fabiano M, Schomburg L, Schweizer U, Netto LE, Meotti FC, Dick TP, Alborzinia H, Miyamoto S, and Friedmann Angeli JP
- Subjects
- Humans, Cell Line, Tumor, Neuroblastoma metabolism, Neuroblastoma pathology, Neuroblastoma genetics, HEK293 Cells, Animals, Ferroptosis genetics, Selenocysteine metabolism, Selenocysteine genetics, Peroxiredoxin VI metabolism, Peroxiredoxin VI genetics
- Abstract
Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and begins with the uptake of the Sec carrier, selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP is metabolized via selenocysteine lyase (SCLY), producing selenide, a substrate for selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor, selenophosphate (H
2 SePO3 - ), for the biosynthesis of the Sec-tRNA. Here, we discovered an alternative pathway in Sec metabolism mediated by peroxiredoxin 6 (PRDX6), independent of SCLY. Mechanistically, we demonstrate that PRDX6 can readily react with selenide and interact with SEPHS2, potentially acting as a selenium delivery system. Moreover, we demonstrate the functional significance of this alternative route in human cancer cells, revealing a notable association between elevated expression of PRDX6 and human MYCN-amplified neuroblastoma subtype. Our study sheds light on a previously unrecognized aspect of Sec metabolism and its implications in ferroptosis, offering further possibilities for therapeutic exploitation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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