HRI-eIF2αP signaling in mitigating stress and induction of γ-globin expression. Among the family of eIF2α kinases, heme-regulated eIF2α kinase (HRI) is most predominant in the erythroid precursors. In heme deficiency, HRI is activated and phosphorylates eIF2α to balance globin synthesis with the intracellular heme concentrations ensuring that no globin is translated in excess of heme during erythroid maturation. HRI is also activated by oxidative stress and environmental stress, such as heat shock and osmotic shock. Under these stress conditions, the first action of eIF2αP is to inhibit general protein synthesis, especially globin to prevent proteotoxicity. Second, eIF2αP also increases translation of selective mRNAs, such as ATF4 mRNA to reprogram gene expression for adaptation to stress. GADD34 is a downstream target of ATF4 signaling, and it is responsible for bringing eIF2αP to type 1 phosphatase (PPase 1) for dephosphorylation to regenerate active eIF2, which is necessary for the recovery of protein synthesis of stress-induced gene expression that occurs late in the stress response. CReP has the same function as GADD34, except that it is constitutively expressed. Salubrinal, a selective inhibitor of eIF2αP dephosphorylation, interferes with the recruitment of eIF2αP to PPase1 through GADD34 and CReP, thus preventing eIF2αP dephosphorylation. Inhibiting eIF2αP dephosphorylation by salubrinal or by the knockdown of GAAD34 and CReP in differentiating human CD34⁺ cells induces γ-globin expression, leading to an increase in HbF production.