Heme-regulated eIF2α kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis

Heme-regulated eIF2 alpha kinase (Hri) is necessary for balanced synthesis of heme and globin. In addition, Hri deficiency exacerbates the phenotypic severity of beta-thalassemia intermedia in mice. Activation of Hri during heme deficiency and in beta-thalassemia increases eIF2 alpha phosphorylation and inhibits globin translation. Under endoplasmic reticulum stress and nutrient starvation, eIF2 alpha phosphorylation also induces the Atf4 signaling pathway to mitigate stress. Although the function of Hri in regulating globin translation is well established, its role in Atf4 signaling in erythroid precursors is not known. Here, we report the role of the Hri-activated Atf4 signaling pathway in reducing oxidative stress and in promoting erythroid differentiation during erythropoiesis. On acute oxidative stress, Hri(-/-) erythroblasts suffered from increased levels of reactive oxygen species (ROS) and apoptosis. During chronic iron deficiency in vivo, Hri is necessary both to reduce oxidative stress and to promote erythroid differentiation. Hri(-/-) mice developed inef fective erythropoiesis during iron deficiency with inhibition of differentiation at the basophilic erythroblast stage. This inhibition is recapitulated during ex vivo differentiation of Hri(-/-) fetal liver erythroid progenitors. Importantly, the Hri-eIF2 alpha P-Atf4 pathway was activated and required for erythroid differentiation. We further demonstrate the potential of modulating Hri-eIF2P-Atf4 signaling with chemical compounds as pharmaceutical therapies for beta-thalassemia. (Blood. 2012; 119(22): 5276-5284)