Heme-regulated eIF2α kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis
Heme-regulated eIF2α kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis
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DOI：
10.1182/blood-2011-10-388132
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发表时间：
2012-05-31
期刊：
影响因子：
20.3
通讯作者：
Chen, Jane-Jane
中科院分区：
文献类型：
--
作者：
Suragani, Rajasekhar N. V. S.;Zachariah, Roshini S.;Chen, Jane-Jane
血红素调节的eIF2α激酶(HRI)是血红素和珠蛋白平衡合成所必需的。此外，HRI缺乏加剧了小鼠中间型β地中海贫血的表型严重程度。在血红素缺乏和β-地中海贫血期间，HRI的激活增加了eIF2α的磷酸化，并抑制了珠蛋白的翻译。在内质网应激和营养饥饿条件下，eIF2α的磷酸化也诱导ATF4信号通路减轻应激。虽然HRI在调节珠蛋白翻译中的功能已被证实，但其在红系前体ATF4信号转导中的作用尚不清楚。在这里，我们报告了HRI激活的ATF4信号通路在减少氧化应激和促进红系分化中的作用。在急性氧化应激中，HRI(-/-)红细胞的活性氧簇(ROS)水平升高和细胞凋亡。在体内慢性缺铁时，HRI对于减少氧化应激和促进红系分化是必要的。HRI(-/-)小鼠在缺铁期间出现有效的红细胞生成，在嗜碱性红细胞阶段分化受到抑制。这种抑制在HRI(-/-)胎肝红系祖细胞的体外分化过程中被重复。重要的是，HRI-eIF2αP-ATF4通路被激活，是红系分化所必需的。我们进一步证明了用化合物调节HRI-eIF2P-ATF4信号作为治疗β-地中海贫血的药物的可能性。(血。2012年；119(22)：5276-5284)
Heme-regulated eIF2 alpha kinase (Hri) is necessary for balanced synthesis of heme and globin. In addition, Hri deficiency exacerbates the phenotypic severity of beta-thalassemia intermedia in mice. Activation of Hri during heme deficiency and in beta-thalassemia increases eIF2 alpha phosphorylation and inhibits globin translation. Under endoplasmic reticulum stress and nutrient starvation, eIF2 alpha phosphorylation also induces the Atf4 signaling pathway to mitigate stress. Although the function of Hri in regulating globin translation is well established, its role in Atf4 signaling in erythroid precursors is not known. Here, we report the role of the Hri-activated Atf4 signaling pathway in reducing oxidative stress and in promoting erythroid differentiation during erythropoiesis. On acute oxidative stress, Hri(-/-) erythroblasts suffered from increased levels of reactive oxygen species (ROS) and apoptosis. During chronic iron deficiency in vivo, Hri is necessary both to reduce oxidative stress and to promote erythroid differentiation. Hri(-/-) mice developed inef fective erythropoiesis during iron deficiency with inhibition of differentiation at the basophilic erythroblast stage. This inhibition is recapitulated during ex vivo differentiation of Hri(-/-) fetal liver erythroid progenitors. Importantly, the Hri-eIF2 alpha P-Atf4 pathway was activated and required for erythroid differentiation. We further demonstrate the potential of modulating Hri-eIF2P-Atf4 signaling with chemical compounds as pharmaceutical therapies for beta-thalassemia. (Blood. 2012; 119(22): 5276-5284)