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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More severe pathology in HRI-deficient Fechm1Pas/m1Pas mice. (A) Increas...
More severe pathology in HRI-deficient Fechm1Pas/m1Pas mice. (A) Increased protoporphyrin level in the reticulocytes and rbcs of Fechm1Pas/m1Pas mice deficient in HRI. The fluorescent porphyrin levels in blood cells were analyzed by FACS analysis (left panels). The numbers inside the peak represent the arbitrary mean values of PPIX in each genotype. FACS analyses of the fluorescent porphyrin in reticulocytes were performed after staining with thiazole orange (right panels). The values on the right upper quadrant are percentages of reticulocytes. Left panels: x axes are arbitrary units of fluorescent intensity. Right panels: x and y axes are arbitrary units of fluorescent intensity. (B) Liver pathology. The liver sections were stained with H&E. (C) Skin photosensitivity. The HRI–/–Fechm1Pas/m1Pas mice were extremely jaundiced, as can be seen by the yellow color in their ears, and were dead 6 hours after exposure to mercury vapor lamp. Photos were taken 4 days after exposure to the mercury vapor lamp for the HRI+/– Fechm1Pas/m1Pas mice and HRI+/+Fechm1Pas/m1Pas mice. Twelve- to sixteen-week-old mice were used for these experiments.