Iron deficiency (ID) anemia is a prevalent disease, yet molecular mechanisms by which iron and heme regulate erythropoiesis are not completely understood. Heme-regulated eIF2α kinase (HRI) is a key hemoprotein in erythroid precursors that sense intracellular heme concentrations to balance globin synthesis with the amount of heme available for hemoglobin production. HRI is activated by heme deficiency and oxidative stress, and it phosphorylates eIF2α (eIF2αP), which inhibits the translation of globin messenger RNAs (mRNAs) and selectively enhances the translation of activating transcription factor 4 (ATF4) mRNA to induce stress response genes. Here, we generated a novel mouse model (eAA) with the erythroid-specific ablation of eIF2αP and demonstrated that eIF2αP is required for induction of ATF4 protein synthesis in vivo in erythroid cells during ID. We show for the first time that both eIF2αP and ATF4 are necessary to promote erythroid differentiation and to reduce oxidative stress in vivo during ID. Furthermore, the HRI-eIF2αP-ATF4 pathway suppresses mTORC1 signaling specifically in the erythroid lineage. Pharmacologic inhibition of mTORC1 significantly increased red blood cell counts and hemoglobin content in the blood, improved erythroid differentiation, and reduced splenomegaly of iron-deficient Hri-/- and eAA mice. However, globin inclusions and elevated oxidative stress remained, demonstrating the essential nonredundant role of HRI-eIF2αP in these processes. Dietary iron repletion completely reversed ID anemia and ineffective erythropoiesis of Hri-/- , eAA, and Atf4-/- mice by inhibiting both HRI and mTORC1 signaling. Thus, HRI coordinates 2 key translation-regulation pathways, eIF2αP and mTORC1, to circumvent ineffective erythropoiesis, highlighting heme and translation in the regulation of erythropoiesis.

中文翻译：

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HRI 协调 eIF2αP 和 mTORC1 的翻译，以减轻缺铁期间小鼠无效的红细胞生成

缺铁 (ID) 贫血是一种普遍的疾病，但尚未完全了解铁和血红素调节红细胞生成的分子机制。血红素调节的 eIF2α 激酶 (HRI) 是红细胞前体中的一种关键血红蛋白，可感知细胞内血红素浓度以平衡珠蛋白合成与可用于血红蛋白生成的血红素量。HRI 被血红素缺乏和氧化应激激活，它磷酸化 eIF2α (eIF2αP)，抑制珠蛋白信使 RNA (mRNA) 的翻译并选择性地增强激活转录因子 4 (ATF4) mRNA 的翻译以诱导应激反应基因。这里，我们使用 eIF2αP 的红细胞特异性消融生成了一种新的小鼠模型 (eAA)，并证明在 ID 期间，eIF2αP 是诱导红细胞体内 ATF4 蛋白合成所必需的。我们首次表明 eIF2αP 和 ATF4 都是促进红细胞分化和减少 ID 期间体内氧化应激所必需的。此外，HRI-eIF2αP-ATF4 通路在红细胞谱系中特异性地抑制 mTORC1 信号。mTORC1 的药理学抑制显着增加了血液中的红细胞计数和血红蛋白含量，改善了红细胞分化，并减少了缺铁 Hri-/- 和 eAA 小鼠的脾肿大。然而，珠蛋白内含物和升高的氧化应激仍然存在，证明了 HRI-eIF2αP 在这些过程中的重要非冗余作用。膳食铁补充通过抑制 HRI 和 mTORC1 信号传导，完全逆转了 Hri-/-、eAA 和 Atf4-/- 小鼠的 ID 贫血和无效的红细胞生成。因此，HRI 协调 2 个关键的翻译调节途径，eIF2αP 和 mTORC1，以规避无效的红细胞生成，突出血红素和翻译在红细胞生成的调节中。