Evolutionary and functional analyses demonstrate conserved ferroptosis protection by Arabidopsis GPXs in mammalian cells
Evolutionary and functional analyses demonstrate conserved ferroptosis protection by Arabidopsis GPXs in mammalian cells
复制标题
进化和功能分析证明拟南芥 GPX 在哺乳动物细胞中具有保守的铁死亡保护作用
DOI：
10.1096/fj.202000856r
复制
发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Xiang Jin
中科院分区：
文献类型：
--
作者：
Wangyang Song;Shan Xin;Meng He;Susanne Pfeiffer;Aiping Cao;Hongbin Li;Joel A. Schick;Xiang Jin
物种已经进化出独特的机制来对抗细胞内氧化应激的影响。在铁的存在下，膜脂质的不受阻碍的氧化的特别破坏性的后果导致细胞死亡，称为铁凋亡。包括多不饱和脂肪酸的过氧化作用在内的铁凋亡的标志在动物和植物中是保守的，然而，祖先哺乳动物GPX 4（mGPX 4）的早期分歧使我们对物种之间的机制相似性的理解变得复杂。为此，我们进行了一个全面的系统发育分析，并确定orthologousamphopsisGPXs（AtGPXs）是更高度相关的mGPX 4比mGPX 4是其他哺乳动物GPXs。这种高度的保守性表明，实验替代是可能的。因此，我们在铁凋亡敏感的小鼠成纤维细胞中异位表达AtGPX 1 - 8。该替代实验显示，AtGPX 5对铁凋亡诱导的保护作用最高，AtGPX 2、-7和-8的保护作用中等。对这些细胞的进一步分析显示，响应于药理学挑战，脂质过氧化反应显著减轻。这些结果表明，祖先GPX 4的存在导致了植物中GPXs后来的功能分化和专业化。这些结果也挑战了对硒代半胱氨酸活性的严格要求，并表明硫氧还蛋白在植物和哺乳动物中是一种有效的平行抗氧化系统。
Species have evolved unique mechanisms to combat the effects of oxidative stress inside cells. A particularly devastating consequence of an unhindered oxidation of membrane lipids in the presence of iron results in cell death, known as ferroptosis. Hallmarks of ferroptosis, including peroxidation of polyunsaturated fatty acids, are conserved among animals and plants, however, early divergence of an ancestral mammalian GPX4 (mGPX4) has complicated our understanding of mechanistic similarities between species. To this end, we performed a comprehensive phylogenetic analysis and identified that orthologousArabidopsisGPXs (AtGPXs) are more highly related to mGPX4 than mGPX4 is to other mammalian GPXs. This high degree of conservation suggested that experimental substitution may be possible. We, therefore, ectopically expressed AtGPX1‐8 in ferroptosis‐sensitive mouse fibroblasts. This substitution experiment revealed highest protection against ferroptosis induction by AtGPX5, as well as moderate protection by AtGPX2, −7, and −8. Further analysis of these cells revealed substantial abatement of lipid peroxidation in response to pharmacological challenge. The results suggest that the presence of ancestral GPX4 resulted in later functional divergence and specialization of GPXs in plants. The results also challenge a strict requirement for selenocysteine activity and suggest thioredoxin as a potent parallel antioxidant system in both plants and mammals.