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

Blood
Shuping ZhangJane-Jane Chen

Abstract

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, impro...Continue Reading

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Citations

Sep 27, 2018·American Journal of Hematology·Elisabetta BeneduceLucia De Franceschi
Nov 8, 2018·Blood·Clara Camaschella
Nov 8, 2018·Blood·Guenter WeissLawrence T Goodnough
Mar 12, 2019·Current Opinion in Hematology·Alessandro Matte, Lucia De Franceschi
Sep 27, 2019·Blood·Jane-Jane Chen, Shuping Zhang
Nov 8, 2019·Blood Advances·Steven HeshusiusEmile van den Akker
Sep 17, 2019·British Journal of Haematology·Shuping Zhang, Jane-Jane Chen
Jun 12, 2020·Blood·Jane-Jane Chen
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Dec 19, 2021·Nature Communications·Daniel HidalgoMerav Socolovsky

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