Journal
BLOOD
Volume 131, Issue 4, Pages 450-461Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-08-799908
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Funding
- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [RO1 DK087984]
- NIDDK [DK042394, DK103185, DK110973]
- National Institutes of Health, National Cancer Institute [CA198103]
- Consejo Nacional de Ciencia y Tecnologia in Mexico
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Iron deficiency (ID) anemia is a prevalent disease, yet molecular mechanisms by which iron and heme regulate erythropoiesis are not completely understood. Heme-regulated eIF2 alpha 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 eIF2 alpha (eIF2 alpha P), 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 eIF2 alpha P and demonstrated that eIF2 alpha P is required for induction of ATF4 protein synthesis in vivo in erythroid cells during ID. We show for the first time that both eIF2 alpha P and ATF4 are necessary to promote erythroid differentiation and to reduce oxidative stress in vivo during ID. Furthermore, the HRI-eIF2 alpha P-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-eIF2 alpha P 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 translationregulation pathways, eIF2 alpha P and mTORC1, to circumvent ineffective erythropoiesis, highlighting heme and translation in the regulation of erythropoiesis.
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