Nrf2 and selenoproteins are essential for maintaining oxidative homeostasis in erythrocytes and protecting against hemolytic anemia
Nrf2 and selenoproteins are essential for maintaining oxidative homeostasis in erythrocytes and protecting against hemolytic anemia
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DOI：
10.1182/blood-2010-05-285817
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发表时间：
2011-01-20
期刊：
影响因子：
20.3
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
--
作者：
Kawatani, Yukie;Suzuki, Takafumi;Yamamoto, Masayuki
活性氧（ROS）对细胞大分子具有高度的破坏性。然而，中等水平的ROS可以促进正常的细胞过程，包括信号传导。在这里，我们评估的后果促氧化环境对造血稳态。NF-E2相关因子2（Nrf 2）转录因子调节与ROS清除和解毒相关的基因。Nrf 2响应于改变的细胞氧化还原状态，例如在硒代半胱氨酸-tRNA基因（Trsp）缺失后抗氧化剂硒蛋白的损失。条件敲除的Trsp基因使用Mx 1诱导的Cre重组酶导致硒蛋白缺乏症和贫血的野生型背景下，而Trsp：Nrf 2双缺陷显着加剧贫血，并增加细胞内过氧化氢水平在成红细胞。结果表明，当硒蛋白从红系细胞中丢失时，Nrf 2补偿有缺陷的ROS清除。我们还观察到胸腺萎缩的单Trsp条件敲除小鼠，表明在胸腺内的T细胞分化的硒蛋白功能的要求。令人惊讶的是，在骨髓单核细胞或巨核细胞群体中没有观察到变化。因此，我们的研究结果表明，硒蛋白的活性和Nrf 2基因电池是特别重要的氧化稳态在红细胞和预防溶血性贫血。（血。2011; 117（3）：986-996）
Reactive oxygen species (ROS) are highly destructive toward cellular macromolecules. However, moderate levels of ROS can contribute to normal cellular processes including signaling. Herein we evaluate the consequence of a pro-oxidant environment on hematopoietic homeostasis. The NF-E2 related factor 2 (Nrf2) transcription factor regulates genes related to ROS scavenging and detoxification. Nrf2 responds to altered cellular redox status, such as occurs with loss of antioxidant selenoproteins after deletion of the selenocysteine-tRNA gene (Trsp). Conditional knockout of the Trsp gene using Mx1-inducible Cre-recombinase leads to selenoprotein deficiency and anemia on a wild-type background, whereas Trsp: Nrf2 double deficiency dramatically exacerbates the anemia and increases intracellular hydrogen peroxide levels in erythroblasts. Results indicate that Nrf2 compensates for defective ROS scavenging when selenoproteins are lost from erythroid cells. We also observed thymus atrophy in single Trsp-conditional knockout mice, suggesting a requirement for selenoprotein function in T-cell differentiation within the thymus. Surprisingly, no changes were observed in the myelomonocytic or megakaryocytic populations. Therefore, our results show that selenoprotein activity and the Nrf2 gene battery are particularly important for oxidative homeostasis in erythrocytes and for the prevention of hemolytic anemia. (Blood. 2011; 117(3): 986-996)