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  • The EMBO Journal (2001) 20, 6909 - 6918
  • doi:10.1093/emboj/20.23.6909

Heme-regulated eIF2alpha kinase (HRI) is required for translational regulation and survival of erythroid precursors in iron deficiency

An-Ping Han1, Channing Yu2, Linrong Lu1, Yuko Fujiwara2, Carol Browne2, Gregory Chin1, Mark Fleming3, Philippe Leboulch1,4, Stuart H. Orkin2,5 and Jane-Jane Chen1

  1. Harvard–MIT Division of Health Sciences and Technology, MIT, Cambridge, MA 02139, USA
  2. Division of Hematology and Oncology, Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
  3. Department of Pathology, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
  4. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
  5. Howard Hughes Medical Institute, Boston, MA 02115, USA

Correspondence to:

Jane-Jane Chen, E-mail: j-jchen@mit.edu

Received 27 April 2001; Accepted 10 October 2001; Revised 20 September 2001

Although the physiological role of tissue-specific translational control of gene expression in mammals has long been suspected on the basis of biochemical studies, direct evidence has been lacking. Here, we report on the targeted disruption of the gene encoding the heme-regulated eIF2alpha kinase (HRI) in mice. We establish that HRI, which is expressed predominantly in erythroid cells, regulates the synthesis of both alpha- and beta-globins in red blood cell (RBC) precursors by inhibiting the general translation initiation factor eIF2. This inhibition occurs when the intracellular concentration of heme declines, thereby preventing the synthesis of globin peptides in excess of heme. In iron-deficient HRI-/- mice, globins devoid of heme aggregated within the RBC and its precursors, resulting in a hyperchromic, normocytic anemia with decreased RBC counts, compensatory erythroid hyperplasia and accelerated apoptosis in bone marrow and spleen. Thus, HRI is a physiological regulator of gene expression and cell survival in the erythroid lineage.

  • Keywords:

    • apoptosis,
    • erythropoiesis,
    • heme-regulated eIF2alpha kinase,
    • iron deficiency,
    • translation