Heme-regulated eIF2α kinase in erythropoiesis and hemoglobinopathies

摘要: As essential components of hemoglobin, iron and heme play central roles in terminal erythropoiesis. The impairment this process iron/heme deficiency results 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 concentrations to balance globin synthesis with amount available for hemoglobin production. HRI activated during phosphorylate (eIF2αP), which simultaneously inhibits translation messenger RNAs (mRNAs) selectively enhances activating transcription factor 4 (ATF4) mRNA induce stress response genes. This coordinated translational regulation universal hallmark across kinase family under various conditions termed integrated (ISR). Inhibition general by HRI-eIF2αP erythroblasts necessary prevent proteotoxicity maintain homeostasis cytoplasm mitochondria. Additionally, HRI-eIF2αP-ATF4 pathway represses mechanistic target rapamycin complex 1 (mTORC1) signaling, specifically erythroid lineage feedback mechanism erythropoietin-stimulated erythropoiesis deficiency. Furthermore, ATF4 genes are highly mitochondrial function redox homeostasis, well enable differentiation. Thus, regulate through 2 signaling pathways, ISR mTORC1, circumvent ineffective (IE). HRI-ISR reduce severity β-thalassemia intermedia Hbbth1/th1 murine model. Recently, has been implicated human fetal Therefore, emerged potential therapeutic hemoglobinopathies.