A schematic illustration of Hri-eIF2αP-Atf4 signaling pathway in mitigating stress and during erythropoiesis. (A) Inhibition of general protein synthesis and enhancement of Atf4 translation by eIF2α. On various stress conditions, eIF2α kinases are activated and phosphorylate eIF2α. The first order of action by eIF2α is to inhibit protein synthesis to prevent proteotoxicity resulted from accumulation of excessive unfolded proteins. In the erythroid precursors, Hri is necessary to inhibit globin synthesis in heme deficiency to prevent accumulation of denatured heme-free globins. The second action by eIF2α is to selectively enhance the translation of some mRNAs with open reading frames in their 5′-UTR. At present, Atf4 mRNA is the only known target of this regulation. However, Atf4 is not the only target; there are yet to be identified mRNAs. Induction of Atf4 leads to a signaling pathway for adaptive gene expression as described in the “Introduction.” (B) Dual roles of Hri in erythropoiesis. Expression of Hri is increased during erythropoiesis from basophilic erythroblasts to reticulocytes. Both roles of Hri in inhibition of globin translation and in activation of Atf4 during erythroid differentiation contribute to reduced anemic phenotypes.