HRI-mediated integrated stress response in HbF expression. HRI is activated in heme deficiency, oxidative stress, heat shock, and pathological conditions of β-thalassemia. Activated HRI phosphorylates its substrate eIF2α, and the phosphorylated eIF2α (eIF2αP) inhibits protein synthesis globally to prevent proteotoxicity incurred during stress. This inhibition of global protein synthesis permits the selective enhancement of the translation of Atf4 mRNA to induce stress response genes for adaptation to stress. The coordinated translational regulation is a universal hallmark across the eIF2α kinase family under various stress conditions and is termed the integrated stress response. Huang et al demonstrated that ATF4 binds to the +55 enhancer of the Bcl11a gene to increase transcription of BCL11A, which represses γ-globin transcription.