PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance.

作者：Zhiyi Chen, Alex Inague, Kamini Kaushal, Gholamreza Fazeli, Danny Schilling, Thamara Nishida Xavier da Silva, A. F. dos Santos, Tasneem Cheytan, F. Freitas, Umut Yildiz, L. Viviani, R. Lima, M. Pinz, I. Medeiros, T. S. Iijima, T. Alegria, Railmara Pereira da Silva, L. Diniz, Simon Weinzweig, Judith Klein-Seetharaman, A. Trumpp, Adriana Mañas, R. Hondal, C. Bartenhagen, Matthias Fischer, Briana K. Shimada, Lucia A. Seale, T. Chillon, M. Fabiano, L. Schomburg, Ulrich Schweizer, Luis E Netto, F. Meotti, T. Dick, Hamed Alborzinia, Sayuri Miyamoto, J. P. Friedmann Angeli · 发表于：Molecules and Cells · 年份：2024 · DOI：10.1016/j.molcel.2024.10.027 · 被引用次数：68 · 研究领域：Medicine

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 (H2SePO3-), 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.