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Translational regulation of glutathione peroxidase 4 expression through guanine-rich sequence-binding factor 1 is essential for embryonic brain development

¹ Institute of Biochemistry, University Medicine Berlin–Charité, D-10117 Berlin, F.R. Germany; ² School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, United Kingdom; ³ Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong; ⁴ Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin, Hong Kong; ⁵ Institute of Physiology, University Medicine Berlin–Charité, D-10117 Berlin, F.R. Germany

Phospholipid hydroperoxide glutathione peroxidase (GPx4) is a moonlighting selenoprotein, which has been implicated in basic cell functions such as anti-oxidative defense, apoptosis, and gene expression regulation. GPx4-null mice die in utero at midgestation, and developmental retardation of the brain appears to play a major role. We investigated post-transcriptional mechanisms of GPx4 expression regulation and found that the guanine-rich sequence-binding factor 1 (Grsf1) up-regulates GPx4 expression. Grsf1 binds to a defined target sequence in the 5'-untranslated region (UTR) of the mitochondrial GPx4 (m-GPx4) mRNA, up-regulates UTR-dependent reporter gene expression, recruits m-GPx4 mRNA to translationally active polysome fractions, and coimmunoprecipitates with GPx4 mRNA. During embryonic brain development, Grsf1 and m-GPx4 are coexpressed, and functional knockdown (siRNA) of Grsf1 prevents embryonic GPx4 expression. When compared with mock controls, Grsf1 knockdown embryos showed significant signs of developmental retardations that are paralleled by apoptotic alterations (TUNEL staining) and massive lipid peroxidation (isoprostane formation). Overexpression of m-GPx4 prevented the apoptotic alterations in Grsf1-deficient embryos and rescued them from developmental retardation. These data indicate that Grsf1 up-regulates translation of GPx4 mRNA and implicate the two proteins in embryonic brain development.

[Keywords: Glutathione peroxidase 4; guanine-rich sequence-binding factor 1; apoptosis; brain development; embryogenesis]

Received December 6, 2007; revised version accepted May 6, 2008.

⁷ Corresponding author.

E-MAIL hartmut.kuehn{at}charite.de; FAX 49-30-450-528905.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.466308.

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