HRI balances heme and globin synthesis by sensing intracellular heme concentrations. During the synthesis of hemoglobin, one molecule of heme is incorporated into each globin chain. When heme concentration is high, heme binds to the second heme-binding domain of HRI and keeps HRI in inactive state, thereby permitting globin protein synthesis and the formation of stable hemoglobin. In heme deficiency, HRI is activated by autophosphorylation. Activated HRI phosphorylates eIF2α and inhibits globin protein synthesis by the mechanism illustrated in Figure 2. HRI, therefore, acts as a feedback inhibitor of globin synthesis to ensure no globin is translated in excess of the heme available for assembly of stable hemoglobin.