Blood. 2019 Nov 14;134(20):1697-1707. doi: 10.1182/blood.2019001915.
As essential components of hemoglobin, iron and heme play central roles in terminal erythropoiesis. The impairment of this process in iron/heme deficiency results in microcytic hypochromic anemia, the most prevalent anemia globally. Heme-regulated eIF2α kinase, also known as heme-regulated inhibitor (HRI), is a key heme-binding protein that senses intracellular heme concentrations to balance globin protein synthesis with the amount of heme available for hemoglobin production. HRI is activated during heme deficiency to phosphorylate eIF2α (eIF2αP), which simultaneously 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. This coordinated translational regulation is a universal hallmark across the eIF2α kinase family under various stress conditions and is termed the integrated stress response (ISR). Inhibition of general protein synthesis by HRI-eIF2αP in erythroblasts is necessary to prevent proteotoxicity and maintain protein homeostasis in the cytoplasm and mitochondria. Additionally, the HRI-eIF2αP-ATF4 pathway represses mechanistic target of rapamycin complex 1 (mTORC1) signaling, specifically in the erythroid lineage as a feedback mechanism of erythropoietin-stimulated erythropoiesis during iron/heme deficiency. Furthermore, ATF4 target genes are most highly activated during iron deficiency to maintain mitochondrial function and redox homeostasis, as well as to enable erythroid differentiation. Thus, heme and translation regulate erythropoiesis through 2 key signaling pathways, ISR and mTORC1, which are coordinated by HRI to circumvent ineffective erythropoiesis (IE). HRI-ISR is also activated to reduce the severity of β-thalassemia intermedia in the Hbbth1/th1 murine model. Recently, HRI has been implicated in the regulation of human fetal hemoglobin production. Therefore, HRI-ISR has emerged as a potential therapeutic target for hemoglobinopathies.
作为血红蛋白的重要组成部分，铁和血红素在终末红细胞生成中发挥核心作用。在铁/血红素缺乏时，这一过程受损会导致小细胞低色素性贫血，这是全球最常见的贫血症。血红素调节的真核起始因子 2α 激酶，也称为血红素调节抑制剂（HRI），是一种关键的血红素结合蛋白，可感知细胞内血红素浓度，以平衡球蛋白蛋白合成与血红蛋白生成可用的血红素量。在血红素缺乏时，HRI 被激活，使真核起始因子 2α（eIF2α）磷酸化（eIF2αP），同时抑制球蛋白信使 RNA（mRNA）的翻译，并选择性增强激活转录因子 4（ATF4）mRNA 的翻译，从而诱导应激反应基因。这种协调的翻译调控是各种应激条件下 eIF2α 激酶家族的普遍特征，被称为综合应激反应（ISR）。在红细胞中，HRI-eIF2αP 抑制一般蛋白质合成是防止细胞质和线粒体中蛋白质毒性和维持蛋白质内稳所必需的。此外，HRI-eIF2αP-ATF4 途径抑制雷帕霉素靶蛋白复合物 1（mTORC1）信号，特别是在红系谱系中，作为铁/血红素缺乏时促红细胞生成素刺激的红细胞生成的反馈机制。此外，ATF4 靶基因在铁缺乏时被高度激活，以维持线粒体功能和氧化还原稳态，并促进红细胞分化。因此，血红素和翻译通过 2 个关键信号通路调节红细胞生成，即 ISR 和 mTORC1，HRI 协调这两个信号通路以避免无效的红细胞生成（IE）。HRI-ISR 也被激活以减轻 Hbbth1/th1 小鼠模型中中间型 β-地中海贫血的严重程度。最近，HRI 被牵涉到人类胎儿血红蛋白产生的调节中。因此，HRI-ISR 已成为血红蛋白病的潜在治疗靶点。
