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HRI coordinates translation by eIF2αP and mTORC1 to mitigate ineffective erythropoiesis in mice during iron deficiency

Shuping Zhang, Alejandra Macias-Garcia, Jason Velazquez, Elena Paltrinieri, Randal J. Kaufman and Jane-Jane Chen

Key points

  • Erythroid eIF2aP and ATF4 are essential for iron-restricted erythropoiesis. HRI-eIF2aP is responsible for microcytic hypochromic anemia.

  • HRI activates integrated stress response and represses mTORC1 signaling in iron deficiency to mitigate ineffective erythropoiesis.

Abstract

Iron deficiency anemia is a prevalent disease, yet molecular mechanisms by which iron and heme regulate erythropoiesis are not completely understood. HRI, heme-regulated eIF2α kinase, is a key hemoprotein in erythroid precursors sensing 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 phosphorylates eIF2α (eIF2αP), which inhibits the translation of globin mRNAs as well as enhances selectively 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 demonstrate that eIF2αP is required for induction of ATF4 protein synthesis in vivo in erythroid cells during iron deficiency (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, HRI-eIF2αP-ATF4 pathway suppresses mTORC1 signaling specifically in the erythroid lineage. Pharmacological inhibition of mTORC1 significantly increased RBC 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 non-redundant 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 two key translation-regulation pathways, eIF2αP and mTORC1, to circumvent ineffective erythropoiesis, highlighting heme and translation in the regulation of erythropoiesis.

  • Submitted August 2, 2017.
  • Accepted November 1, 2017.