Identification of interacting partners of the redox enzyme glutathione peroxidase 4 (GPx4), and evaluation of GPx4 as a mammalian redox sensor

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Glutathione peroxidase 4 (Gpx4) is emerging as one of the most significant mammalian redox enzymes. Gpx4 is evolutionary conserved and homologues are present in many organisms from bacteria to mammals. Unlike Cys-containing homologues, Gpx4 is a selenoenzyme in mouse and man; however, the reasons for selenothiol- versus thiol-based catalysis are still unclear. Systemic and neuron-specific disruption of Gpx4 causes early embryonic death and neurodegeneration in mice, thus highlighting the importance of Gpx4 for embryogenesis and neuroprotection. Gpx4 also controls an oxidative stress-induced cell death pathway, entailed of 12/15-lipoxygenase-induced lipid peroxidation and apoptosis inducing factor-mediated cell death. While the antioxidant role of Gpx4 has been well established, evidence for its putative role as a mammalian redox sensor, like that described for the yeast homologue, is still lacking. Initial proof that Gpx4 is able to introduce disulfide bridges in sperm proteins was provided by mice lacking either the nuclear or the mitochondrial Gpx4 isoforms. Hence, this application aims (i) to identify yet-unrecognized binding partners of Gpx4 in somatic cells, (ii) to address the role of selenothiol-based catalysis of Gpx4 in vivo and (iii) to investigate the molecular link between Gpx4 and redox-regulated growth factor receptor signaling.