Lobe specificity of iron binding to transferrin modulates murine erythropoiesis and iron homeostasis

Transferrin, the major plasma iron-binding molecule, interacts with cell-surface receptors to deliver iron, modulates hepcidin expression, and regulates erythropoiesis. Transferrin binds and releases iron via either or both of 2 homologous lobes (N and C). To test the hypothesis that the specificity...

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Veröffentlicht in:Blood 2019-10, Vol.134 (17), p.1373-1384
Hauptverfasser: Parrow, Nermi L., Li, Yihang, Feola, Maria, Guerra, Amaliris, Casu, Carla, Prasad, Princy, Mammen, Luke, Ali, Faris, Vaicikauskas, Edvinas, Rivella, Stefano, Ginzburg, Yelena Z., Fleming, Robert E.
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container_end_page 1384
container_issue 17
container_start_page 1373
container_title Blood
container_volume 134
creator Parrow, Nermi L.
Li, Yihang
Feola, Maria
Guerra, Amaliris
Casu, Carla
Prasad, Princy
Mammen, Luke
Ali, Faris
Vaicikauskas, Edvinas
Rivella, Stefano
Ginzburg, Yelena Z.
Fleming, Robert E.
description Transferrin, the major plasma iron-binding molecule, interacts with cell-surface receptors to deliver iron, modulates hepcidin expression, and regulates erythropoiesis. Transferrin binds and releases iron via either or both of 2 homologous lobes (N and C). To test the hypothesis that the specificity of iron occupancy in the N vs C lobe influences transferrin function, we generated mice with mutations to abrogate iron binding in either lobe (TfN-bl or TfC-bl). Mice homozygous for either mutation had hepatocellular iron loading and decreased liver hepcidin expression (relative to iron concentration), although to different magnitudes. Both mouse models demonstrated some aspects of iron-restricted erythropoiesis, including increased zinc protoporphyrin levels, decreased hemoglobin levels, and microcytosis. Moreover, the TfN-bl/N-bl mice demonstrated the anticipated effect of iron restriction on red cell production (ie, no increase in red blood cell [RBC] count despite elevated erythropoietin levels), along with a poor response to exogenous erythropoietin. In contrast, the TfC-bl/C-bl mice had elevated RBC counts and an exaggerated response to exogenous erythropoietin sufficient to ameliorate the anemia. Observations in heterozygous mice further support a role for relative N vs C lobe iron occupancy in transferrin-mediated regulation of iron homeostasis and erythropoiesis. •Iron occupancy of the N compared with C lobe of transferrin confers functionally distinct properties.•The monoferric forms of transferrin influence hepcidin expression and erythropoietin responsiveness. [Display omitted]
doi_str_mv 10.1182/blood.2018893099
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Transferrin binds and releases iron via either or both of 2 homologous lobes (N and C). To test the hypothesis that the specificity of iron occupancy in the N vs C lobe influences transferrin function, we generated mice with mutations to abrogate iron binding in either lobe (TfN-bl or TfC-bl). Mice homozygous for either mutation had hepatocellular iron loading and decreased liver hepcidin expression (relative to iron concentration), although to different magnitudes. Both mouse models demonstrated some aspects of iron-restricted erythropoiesis, including increased zinc protoporphyrin levels, decreased hemoglobin levels, and microcytosis. Moreover, the TfN-bl/N-bl mice demonstrated the anticipated effect of iron restriction on red cell production (ie, no increase in red blood cell [RBC] count despite elevated erythropoietin levels), along with a poor response to exogenous erythropoietin. In contrast, the TfC-bl/C-bl mice had elevated RBC counts and an exaggerated response to exogenous erythropoietin sufficient to ameliorate the anemia. Observations in heterozygous mice further support a role for relative N vs C lobe iron occupancy in transferrin-mediated regulation of iron homeostasis and erythropoiesis. •Iron occupancy of the N compared with C lobe of transferrin confers functionally distinct properties.•The monoferric forms of transferrin influence hepcidin expression and erythropoietin responsiveness. 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In contrast, the TfC-bl/C-bl mice had elevated RBC counts and an exaggerated response to exogenous erythropoietin sufficient to ameliorate the anemia. Observations in heterozygous mice further support a role for relative N vs C lobe iron occupancy in transferrin-mediated regulation of iron homeostasis and erythropoiesis. •Iron occupancy of the N compared with C lobe of transferrin confers functionally distinct properties.•The monoferric forms of transferrin influence hepcidin expression and erythropoietin responsiveness. 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Transferrin binds and releases iron via either or both of 2 homologous lobes (N and C). To test the hypothesis that the specificity of iron occupancy in the N vs C lobe influences transferrin function, we generated mice with mutations to abrogate iron binding in either lobe (TfN-bl or TfC-bl). Mice homozygous for either mutation had hepatocellular iron loading and decreased liver hepcidin expression (relative to iron concentration), although to different magnitudes. Both mouse models demonstrated some aspects of iron-restricted erythropoiesis, including increased zinc protoporphyrin levels, decreased hemoglobin levels, and microcytosis. Moreover, the TfN-bl/N-bl mice demonstrated the anticipated effect of iron restriction on red cell production (ie, no increase in red blood cell [RBC] count despite elevated erythropoietin levels), along with a poor response to exogenous erythropoietin. 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subjects Animals
Binding Sites
Erythrocyte Count
Erythropoiesis
Erythropoietin - metabolism
Female
Homeostasis
Iron - metabolism
Male
Mice
Mice, Transgenic
Mutagenesis, Site-Directed
Plenary Paper
Proto-Oncogene Proteins c-akt - metabolism
Transferrin - chemistry
Transferrin - genetics
Transferrin - metabolism
title Lobe specificity of iron binding to transferrin modulates murine erythropoiesis and iron homeostasis
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