A PPIX-binding probe facilitates discovery of PPIX-induced cell death modulation by peroxiredoxin.

Autor: Lynch J; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Wang Y; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Li Y; Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Kavdia K; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Fukuda Y; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Ranjit S; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Robinson CG; Cellular Imaging Shared Resource, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Grace CR; Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Xia Y; Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Peng J; Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Schuetz JD; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. john.schuetz@stjude.org.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2023 Jun 24; Vol. 6 (1), pp. 673. Date of Electronic Publication: 2023 Jun 24.
DOI: 10.1038/s42003-023-05024-5
Abstrakt: While heme synthesis requires the formation of a potentially lethal intermediate, protoporphyrin IX (PPIX), surprisingly little is known about the mechanism of its toxicity, aside from its phototoxicity. The cellular protein interactions of PPIX might provide insight into modulators of PPIX-induced cell death. Here we report the development of PPB, a biotin-conjugated, PPIX-probe that captures proteins capable of interacting with PPIX. Quantitative proteomics in a diverse panel of mammalian cell lines reveal a high degree of concordance for PPB-interacting proteins identified for each cell line. Most differences are quantitative, despite marked differences in PPIX formation and sensitivity. Pathway and quantitative difference analysis indicate that iron and heme metabolism proteins are prominent among PPB-bound proteins in fibroblasts, which undergo PPIX-mediated death determined to occur through ferroptosis. PPB proteomic data (available at PRIDE ProteomeXchange # PXD042631) reveal that redox proteins from PRDX family of glutathione peroxidases interact with PPIX. Targeted gene knockdown of the mitochondrial PRDX3, but not PRDX1 or 2, enhance PPIX-induced death in fibroblasts, an effect blocked by the radical-trapping antioxidant, ferrostatin-1. Increased PPIX formation and death was also observed in a T-lymphoblastoid ferrochelatase-deficient leukemia cell line, suggesting that PPIX elevation might serve as a potential strategy for killing certain leukemias.
(© 2023. The Author(s).)
Databáze: MEDLINE
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