PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance

IF 14.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell Pub Date : 2024-11-14 DOI:10.1016/j.molcel.2024.10.027

Zhiyi Chen, Alex Inague, Kamini Kaushal, Gholamreza Fazeli, Danny Schilling, Thamara N. Xavier da Silva, Ancely Ferreira dos Santos, Tasneem Cheytan, Florencio Porto Freitas, Umut Yildiz, Lucas Gasparello Viviani, Rodrigo Santiago Lima, Mikaela Peglow Pinz, Isadora Medeiros, Thais Satie Iijima, Thiago Geronimo Pires Alegria, Railmara Pereira da Silva, Larissa Regina Diniz, Simon Weinzweig, Judith Klein-Seetharaman, José Pedro Friedmann Angeli

{"title":"PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance","authors":"Zhiyi Chen, Alex Inague, Kamini Kaushal, Gholamreza Fazeli, Danny Schilling, Thamara N. Xavier da Silva, Ancely Ferreira dos Santos, Tasneem Cheytan, Florencio Porto Freitas, Umut Yildiz, Lucas Gasparello Viviani, Rodrigo Santiago Lima, Mikaela Peglow Pinz, Isadora Medeiros, Thais Satie Iijima, Thiago Geronimo Pires Alegria, Railmara Pereira da Silva, Larissa Regina Diniz, Simon Weinzweig, Judith Klein-Seetharaman, José Pedro Friedmann Angeli","doi":"10.1016/j.molcel.2024.10.027","DOIUrl":null,"url":null,"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 (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.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"98 1","pages":""},"PeriodicalIF":14.5000,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cell","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.molcel.2024.10.027","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

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 (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.

Abstract Image

查看原文本刊更多论文

PRDX6 促进硒代半胱氨酸代谢和抗铁病能力

硒代半胱氨酸（Sec）代谢对细胞功能和预防铁变态反应至关重要，它始于硒代半胱氨酸载体硒蛋白 P（SELENOP）的吸收。摄取后，从 SELENOP 释放的 Sec 通过硒半胱氨酸裂解酶（SCLY）进行代谢，产生硒化物，硒化物是硒磷酸盐合成酶 2（SEPHS2）的底物，后者为 Sec-tRNA 的生物合成提供必要的硒供体硒磷酸盐（H2SePO3-）。在这里，我们发现了由过氧化物歧化酶 6（PRDX6）介导的独立于 SCLY 的 Sec 代谢的另一条途径。从机理上讲，我们证明了 PRDX6 很容易与硒化物发生反应，并与 SEPHS2 相互作用，从而可能充当硒传递系统。此外，我们还证明了这一替代途径在人类癌细胞中的功能意义，揭示了 PRDX6 表达升高与人类 MYCN 扩增神经母细胞瘤亚型之间的显著关联。我们的研究揭示了 Sec 代谢中以前未被认识到的一个方面及其在铁跃迁中的影响，为治疗提供了更多可能性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Molecular Cell 生物-生化与分子生物学

CiteScore

26.00

自引率

3.80%

发文量

389

审稿时长

1 months

期刊介绍： Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.