PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance

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Chen, Zhiyi ; Inague, Alex ; Kaushal, Kamini ; Fazeli, Gholamreza ; Schilling, Danny ; da Silva, Thamara N. Xavier ; dos Santos, Ancely Ferreira ; Cheytan, Tasneem ; Freitas, Florencio Porto ; Yildiz, Umut ; Viviani, Lucas Gasparello ; Lima, Rodrigo Santiago ; Pinz, Mikaela Peglow ; Medeiros, Isadora ; Iijima, Thais Satie ; Alegria, Thiago Geronimo Pires ; da Silva, Railmara Pereira ; Diniz, Larissa Regina ; Weinzweig, Simon ; Klein-Seetharaman, Judith ; Trumpp, Andreas ; Manas, Adriana ; Hondal, Robert ; Bartenhagen, Christoph ; Fischer, Matthias ; Shimada, Briana K. ; Seale, Lucia A. ; Chillon, Thilo Samson ; Fabiano, Marietta ; Schomburg, Lutz ; Schweizer, Ulrich ; Netto, Luis E. ; Meotti, Flavia C. ; Dick, Tobias P. ; Alborzina, Hamed ; Miyamoto, Sayuri ; Angeli, Jose Pedro Friedmann

• Document type: Journal article
• Source: MOLECULAR CELL; v. 84, n. 23, p. 25-pg., 2024-12-05.

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. (AU)

• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 18/14898-2 - Investigations of the redox processes in inflammatory response and associated pathologies
• Grantee: Flavia Carla Meotti
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 15/10411-3 - Multi-User Equipment, previously approved in grant 2015/08166-5: stopped-flow
• Grantee: Iolanda Midea Cuccovia
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 17/13804-1 - Mechanisms of detoxification and repair of oxidized biological membranes involving the action of the enzyme peroxiredoxin 6
• Grantee: Alex Inague
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)