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Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 3205-3211
Regulation of Intracellular Iron Metabolism in Human Erythroid
Precursors by Internalized Extracellular Ferritin
E.G. Meyron-Holtz,
B. Vaisman,
Z.I. Cabantchik,
E. Fibach,
T.A. Rouault,
C. Hershko, and
A.M. Konijn
From the Departments of Human Nutrition and Metabolism, and
Hematology, Faculty of Medicine; Department of Biological Chemistry,
Institute of Life Sciences, The Hebrew University of Jerusalem;
Department of Medicine, Shaare Zedek Medical Center, Jerusalem, Israel;
and Cell Biology and Metabolism Branch, National Institute of Child
Health and Human Development, National Institutes of Health, Bethesda,
MD.
Human erythroid precursors grown in culture possess membrane
receptors that bind and internalize acid isoferritin. These receptors are regulated by the iron status of the cell, implying that ferritin iron uptake may represent a normal physiologic pathway. The present studies describe the fate of internalized ferritin, the mechanisms involved in the release of its iron, and the recognition of this iron
by the cell. Normal human erythroid precursors were grown in a 2-phase
liquid culture that supports the proliferation, differentiation, and
maturation of erythroid precursors. At the stage of polychromatic normoblasts, cells were briefly incubated with 59Fe- and/or
125I-labeled acid isoferritin and chased. The
125I-labeled ferritin protein was rapidly degraded and only
50% of the label remained in intact ferritin protein after 3 to 4 hours. In parallel, 59Fe decreased in ferritin and
increased in hemoglobin. Extracellular holoferritin uptake elevated the
cellular labile iron pool (LIP) and reduced iron regulatory protein
(IRP) activity; this was inhibited by leupeptin or chloroquine.
Extracellular apoferritin taken up by the cell functioned as an iron
scavenger: it decreased the level of cellular LIP and increased IRP
activity. We suggest that the iron from extracellular is metabolized in
a similar fashion by developing erythroid cells as is intracellular
ferritin. Following its uptake, extracellular ferritin iron is released
by proteolytic degradation of the protein shell in an acid compartment.
The released iron induces an increase in the cellular LIP and
participates in heme synthesis and in intracellular iron regulatory pathways.
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