Heme-regulated eIF2α kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and β-thalassemia
An-Ping Han, … , Mark D. Fleming, Jane-Jane Chen
An-Ping Han, … , Mark D. Fleming, Jane-Jane Chen
Published June 1, 2005
Citation Information: J Clin Invest. 2005;115(6):1562-1570. https://doi.org/10.1172/JCI24141.
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Research Article Hematology

Heme-regulated eIF2α kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and β-thalassemia

Abstract

Heme-regulated eIF2α kinase (HRI) controls protein synthesis by phosphorylating the α-subunit of eukaryotic translational initiation factor 2 (eIF2α). In heme deficiency, HRI is essential for translational regulation of α- and β-globins and for the survival of erythroid progenitors. HRI is also activated by a number of cytoplasmic stresses other than heme deficiency, including oxidative stress and heat shock. However, to date, HRI has not been implicated in the pathogenesis of any known human disease or mouse phenotype. Here we report the essential role of HRI in 2 mouse models of human rbc disorders, namely erythropoietic protoporphyria (EPP) and β-thalassemia. In both cases, lack of HRI adversely modifies the phenotype: HRI deficiency exacerbates EPP and renders β-thalassemia embryonically lethal. This study establishes the protective function of HRI in inherited rbc diseases in mice and suggests that HRI may be a significant modifier of many rbc disorders in humans. Our findings also demonstrate that translational regulation could play a critical role in the clinical manifestation of rbc diseases.

Authors

An-Ping Han, Mark D. Fleming, Jane-Jane Chen

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Figure 1

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HRI alters the hematological parameters of Fechm1Pas/m1Pas mice. (A) Act...
HRI alters the hematological parameters of Fechm1Pas/m1Pas mice. (A) Activation of HRI in the reticulocytes of Fech-deficient mice. Activation of HRI in the blood samples of 2-week-old mice from the same litter was analyzed by SDS-PAGE and Western blot analysis using anti-HRI antibody (top panel). The in vivo phosphorylation of eIF2α (eIF2αP) and the total eIF2α in the blood samples of various mice were determined by Western blot analysis using antibodies specifically against phosphorylated eIF2α (middle panel) and eIF2α (lower panel). (B) The complete blood analyses. Data are presented as mean ± SD. Retic, reticulocyte. Units of the hematological parameters: rbc, ×1012/l; Hb, g/dl; MCV, fl; MCH, pg; retic, %; PPIX, arbitrary units. (C) Examination of the blood smears by light microscopes. Original magnification, ×1,000. (D) Examination of the blood smears by electron microscopes. Original magnification, ×22,000. Arrow indicates intraerythroid inclusions. The blood samples from 12- to 16-week-old mice were used for these analyses.