The protein structure and integrated stress response of HRI in erythropoiesis. (A) Heme and kinase domains of HRI. The 2 heme-binding domains in the N terminus and kinase insert (V) are marked and shaded in red, whereas the conserved kinase domains I-IV in the small lobe and VI-XI in the large lobe of protein kinase are shaded in blue. The N terminus, kinase insert, and C terminus are unique to HRI. (B) ISR of HRI during erythropoiesis. Expression of HRI and Hb intensify during terminal erythropoiesis from Baso, polychromatic (Poly), and orthochromatic (Ortho) erythroblasts to reticulocytes (Ret). Both arms of HRI-ISR, inhibition of globin synthesis and induction of ATF4 target gene expression, are operative in nucleated erythroblasts. In the enucleated reticulocytes, the role of HRI is limited to inhibit protein synthesis and, thus, prevent proteotoxicity of globin inclusions in heme deficiency.