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

氧化还原酶谷胱甘肽过氧化物酶 4 (GPx4) 相互作用伙伴的鉴定以及 GPx4 作为哺乳动物氧化还原传感器的评估

• 批准号: 46138228
• 负责人: Dr. Marcus Conrad
• 金额: --
• 依托单位: Institut für Metabolismus und Zelltod (MCD)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/46138228?language=en
• 关键词: Identification; interacting; partners; redox; enzyme

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.

谷胱甘肽过氧化物酶4（Gpx 4）是哺乳动物最重要的氧化还原酶之一。gpx 4在进化上是保守的，并且同源物存在于从细菌到哺乳动物的许多生物体中。与含半胱氨酸的同源物不同，Gpx 4在小鼠和人类中是一种硒酶;然而，硒硫醇与硫醇基催化的原因仍不清楚。Gpx 4的系统性和神经元特异性破坏导致小鼠早期胚胎死亡和神经变性，从而突出了Gpx 4对胚胎发生和神经保护的重要性。Gpx 4还控制氧化应激诱导的细胞死亡途径，包括12/15-脂氧合酶诱导的脂质过氧化和凋亡诱导因子介导的细胞死亡。虽然Gpx 4的抗氧化作用已经得到很好的确立，但仍然缺乏其作为哺乳动物氧化还原传感器的假定作用的证据，如酵母同系物所描述的。Gpx 4能够在精子蛋白中引入二硫键的初步证据是由缺乏核或线粒体Gpx 4同种型的小鼠提供的。因此，本申请旨在（i）鉴定体细胞中Gpx 4的尚未识别的结合配偶体，（ii）解决体内Gpx 4的基于硒硫醇的催化作用，以及（iii）研究Gpx 4与氧化还原调节的生长因子受体信号传导之间的分子联系。