Regulation of intracellular iron metabolism in human erythroid precursors by internalized extracellular ferritin.
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 (59)Fe- and/or (125)I-labeled acid isoferritin and chased. The (125)I-labeled ferritin protein was rapidly degraded and only 50% of the label remained in intact ferritin protein after 3 to 4 hours. In parallel, (59)Fe 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.
Meyron-Holtz
E G
EG
Department of Human Nutrition and Metabolism, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
Vaisman
B
B
Cabantchik
Z I
ZI
Fibach
E
E
Rouault
T A
TA
Hershko
C
C
Konijn
A M
AM
D002454:Cell Differentiation; D002478:Cells, Cultured; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism*; D005293:Ferritins / Q000378:metabolism*; D006418:Heme / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*
D006418:Heme; D005293:Ferritins; D007501:Iron