Heme-regulated eIF2 alpha kinase (HRI) is required for translational regulation and survival of erythroid precursors in iron deficiency

Although the physiological role of tissue-specific translational control of gene expression in mammals has long been suspected on the basis of biochem ical studies, direct evidence has been lacking. Here, we report on the targ eted disruption of the gene encoding the heme-regulated eIF2 alpha kinase ( HRI) in mice. We establish that HRI, which is expressed predominantly in er ythroid cells, regulates the synthesis of both alpha -and beta -globins in red blood cell (RBC) precursors by inhibiting the general translation initi ation factor eIF2. This inhibition occurs when the intracellular concentrat ion of heme declines, thereby preventing the synthesis of globin peptides i n excess of heme. In iron-deficient HRI-/- mice, globins devoid of heme agg regated within the RBC and its precursors, resulting in a hyperchromic, nor mocytic anemia with decreased RBC counts, compensatory erythroid hyperplasi a and accelerated apoptosis in bone marrow and spleen. Thus, HRI is a physi ological regulator of gene expression and cell survival in the erythroid li neage.