PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance
Zhiyi Chen, Alex Inague, Kamini Kaushal, Gholamreza Fazeli, Danny Schilling, Thamara N. Xavier da Silva, Ancély Ferreira dos Santos, Tasneem Cheytan, Florêncio Porto Freitas, Umut Yildiz, Lucas Gasparello Viviani, Rodrigo Santiago Lima, Mikaela P. Pinz, Isadora Medeiros, T. Iijima, Thiago Gerônimo Pires Alegria, Railmara Pereira da Silva, Larissa Regina Diniz, Simon Weinzweig, Judith Klein‐Seetharaman, Andreas Trumpp, Adriana Mañas, Robert J. Hondal, Christoph Bartenhagen, Matthias Fischer, Briana K. Shimada, Lucia A. Seale, Thilo Samson Chillon, Marietta Fabiano, Lutz Schomburg, Ulrich Schweizer, Luís Eduardo Soares Netto, Flávia Carla Meotti, Tobias P. Dick, Hamed Alborzinia, Sayuri Miyamoto, José Pedro Friedmann Angeli
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 SePO 3 − ), 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.