The essential iron-sulfur protein Rli1 is an important target accounting for inhibition of cell growth by reactive oxygen species.
The essential iron-sulfur protein Rli1 is an important target accounting for inhibition of cell growth by reactive oxygen species.
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DOI：
10.1091/mbc.e12-05-0413
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发表时间：
2012-09
影响因子：
3.3
通讯作者：
Avery SV
中科院分区：
文献类型：
--
作者：
Alhebshi A;Sideri TC;Holland SL;Avery SV
活性氧（ROS）与各种退行性疾病有关，但目前尚不清楚哪些分子靶点可能是细胞的主要“阿喀琉斯之踵”，解释了ROS的抑制作用。我们的研究结果表明，FeS蛋白Rli 1 p，在蛋白质合成中具有必要的和保守的功能，是ROS毒性的重要靶点。由活性氧（ROS）介导的氧化应激与人类退行性疾病和一系列细胞成分的损伤有关。然而，目前还不清楚哪些分子靶标可能是生物体的主要“阿喀琉斯之踵”，解释ROS的抑制作用。Rli 1 p（ABCE 1）是真核生物和古生菌中一种重要的高度保守蛋白质，在蛋白质合成中需要ROS不稳定的辅助因子（Fe-S簇）来发挥作用。在这项研究中，我们测试了ROS毒性是由Rli 1 p功能障碍引起的假设。除了是必不可少的，Rli 1 p活性（在核核糖体亚基输出）被证明是由酵母中的轻度氧化应激受损。此外，促氧化剂抗性降低RLI 1抑制和增加RLI 1过表达。这种Rlip 1依赖性在厌氧期间被废除，并在表达FeS簇缺陷型Rli 1 p构建体的细胞中加重。该蛋白的FeS簇在体外孵育期间出现ROS不稳定，但在体内则不太稳定。相反，它主要是55 FeS-簇供应Rli 1 p是有缺陷的促氧化剂暴露的细胞。这些数据表明，由于其基本性质，但依赖于ROS不稳定的FeS簇，Rli 1 p功能是ROS作用的主要目标。这种见解可以帮助为对抗氧化应激相关疾病的新方法提供信息。
Reactive oxygen species (ROS) are linked to various degenerative conditions, but it is unclear which molecular target(s) may be the cell's primary “Achilles’ heel,” accounting for inhibition by ROS. Our results indicate that the FeS protein Rli1p, with essential and conserved functions in protein synthesis, is an important target of ROS toxicity. Oxidative stress mediated by reactive oxygen species (ROS) is linked to degenerative conditions in humans and damage to an array of cellular components. However, it is unclear which molecular target(s) may be the primary “Achilles’ heel” of organisms, accounting for the inhibitory action of ROS. Rli1p (ABCE1) is an essential and highly conserved protein of eukaryotes and archaea that requires notoriously ROS-labile cofactors (Fe-S clusters) for its functions in protein synthesis. In this study, we tested the hypothesis that ROS toxicity is caused by Rli1p dysfunction. In addition to being essential, Rli1p activity (in nuclear ribosomal-subunit export) was shown to be impaired by mild oxidative stress in yeast. Furthermore, prooxidant resistance was decreased by RLI1 repression and increased by RLI1 overexpression. This Rlip1 dependency was abolished during anaerobicity and accentuated in cells expressing a FeS cluster–defective Rli1p construct. The protein's FeS clusters appeared ROS labile during in vitro incubations, but less so in vivo. Instead, it was primarily 55FeS-cluster supply to Rli1p that was defective in prooxidant-exposed cells. The data indicate that, owing to its essential nature but dependency on ROS-labile FeS clusters, Rli1p function is a primary target of ROS action. Such insight could help inform new approaches for combating oxidative stress–related disease.