Molecular chaperones and hemoglobin synthesis. (A) Hsp90 and Hsp70 are required for the biogenesis of functional heme regulated inhibitor kinase (HRI), a protein that regulates globin synthesis according to heme availability. In the absence of heme or during other erythroid stresses, HRI phosphorylates translational initiation factor eIF2a, which blocks globin synthesis. Hsc70 may also negatively regulate HRI activity during heme deficiency. (B) Activities of alpha hemoglobin stabilizing protein (AHSP). AHSP binds nascent apo α globin, facilitates its folding, and promotes its incorporation into hemoglobin A (HbA). During β globin deficiency, exposure to ROS or hypoxia, AHSP generates a more stable “bis-histidyl” form of α globin in which the heme iron is oxidized and liganded by 2 histidines within the globin polypeptide (Figure 2). The biologic functions of the AHSP-bis-histidyl α globin complex are unknown. Professional illustration by Paulette Dennis.