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Blood, 1 April 2007, Vol. 109, No. 7, pp. 2693-2699.
Prepublished online as a Blood First Edition Paper on November 16, 2006; DOI 10.1182/blood-2006-08-041830.
 Previous Article | Next Article 
Submitted August 15, 2006
Accepted November 9, 2006
Regulation of protein synthesis by the heme-regulated
eIF2 kinase: relevance to anemias
Jane-Jane Chen*
Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA
* Corresponding author; email: j-jchen{at}mit.edu.
During erythroid differentiation and maturation, it is critical that the three components of hemoglobin,  -globin,  -globin and heme, are made in proper stochiometry to form stable hemoglobin. Heme-regulated translation mediated by the heme-regulated inhibitor kinase (HRI) provides one major mechanism that ensures balanced synthesis of globins and heme. HRI phosphorylates the -subunit of eukaryotic translational initiation factor 2 (eIF2) in heme deficiency, thereby inhibiting protein synthesis globally. In this manner, HRI serves as a feedback inhibitor of globin synthesis by sensing the intracellular concentration of heme through its heme-binding domains. HRI is essential not only for the translational regulation of globins, but also for the survival of erythroid precursors in iron deficiency. Recently, the protective function of HRI has also been demonstrated in murine models of erythropoietic protoporphyria and -thalassemia. In these three anemias, HRI is essential in determining red blood cell size, number and hemoglobin content per cell. Translational regulation by HRI is critical to reduce excess synthesis of globin proteins or heme under non-optimal disease states, and thus reduces the severity of these diseases. The protective role of HRI may be more common among red cell disorders.
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