Post-transcriptional Defects of Antioxidant Selenoenzymes Cause Oxidative Stress under Methylmercury Exposure
Post-transcriptional Defects of Antioxidant Selenoenzymes Cause Oxidative Stress under Methylmercury Exposure
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DOI：
10.1074/jbc.m110.168872
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发表时间：
2011-02-25
影响因子：
4.8
通讯作者：
Fujimura, Masatake
中科院分区：
文献类型：
--
作者：
Usuki, Fusako;Yamashita, Akio;Fujimura, Masatake
甲基汞（MeHg）毒性是一个持续危害人类健康的环境问题。氧化应激在甲基汞细胞毒性发病机制中的关键作用已被阐明，但甲基汞介导的氧化应激的分子机制仍有待阐明。在这里，我们证明了一个转录后的甲基汞对抗氧化硒酶的影响，通过使用甲基汞敏感的细胞系。甲基汞诱导的硒缺乏导致硒代半胱氨酸的UGA密码子重新编码失败，并导致主要抗氧化剂谷胱甘肽过氧化物酶1（GPx 1）mRNA通过无义介导的mRNA衰变（NMD）降解，这是一种细胞机制，可检测位于最后一个外显子-外显子连接5 '上游的提前终止密码子（PTC）并降解含PTC的mRNA。相比之下，硫氧还蛋白还原酶1（TrxR 1），硫氧还蛋白系统的另一种抗氧化硒酶，可能是跳过NMD，因为在最后一个外显子的UGA密码子。然而，TrxR 1活性下降，尽管mRNA的上调，这可能是由于合成异常的TrxR 1蛋白没有硒代半胱氨酸。硒酶GPx 1和TrxR 1 mRNA的变化早于氧化应激和其他抗氧化酶mRNA上调的发生。结果表明，甲基汞诱导的相对缺硒条件通过转录后效应影响主要的抗氧化硒酶GPx 1和TrxR 1，导致细胞氧化还原系统的紊乱和氧化应激的发生。治疗与依布硒，硒的有机化合物，有效地抑制氧化应激和保护细胞对甲基汞诱导的相对硒缺乏症和细胞毒性。
Methylmercury (MeHg) toxicity is a continuous environmental problem to human health. The critical role of oxidative stress in the pathogenesis of MeHg cytotoxicity has been clarified, but the molecular mechanisms underlying MeHg-mediated oxidative stress remain to be elucidated. Here we demonstrate a post-transcriptional effect of MeHg on antioxidant selenoenzymes by using a MeHg-susceptible cell line. MeHg-induced selenium deficiency leads to failure of the recoding of a UGA codon for selenocysteine and results in degradation of the major antioxidant selenoenzyme glutathione peroxidase 1 (GPx1) mRNA by nonsense-mediated mRNA decay (NMD), a cellular mechanism that detects the premature termination codon (PTC) located 5'-upstream of the last exon-exon junction and degrades PTC-containing mRNAs. In contrast, thioredoxin reductase 1 (TrxR1), another antioxidant selenoenzyme of the thioredoxin system, was likely skipped by NMD because of a UGA codon in the last exon. However, TrxR1 activity was decreased despite mRNA up-regulation, which was probably due to the synthesis of aberrant TrxR1 protein without selenocysteine. Changes in selenoenzyme GPx1 and TrxR1 mRNAs were observed earlier than was the incidence of oxidative stress and up-regulation of other antioxidant enzyme mRNAs. Results indicated that the MeHg-induced relative selenium-deficient condition affects the major antioxidant selenoenzymes GPx1 and TrxR1 through a post-transcriptional effect, resulting in the disturbance of cellular redox systems and the incidence of oxidative stress. Treatment with ebselen, a seleno-organic compound, effectively suppressed oxidative stress and protected cells against MeHg-induced relative selenium deficiency and cytotoxicity.