Regulation of cell surface transferrin receptor-2 by iron-dependent cleavage and release of a soluble form

Alessia Pagani, Maud Vieillevoye, Antonella Nai, Marco Rausa, Meriem Ladli, Catherine Lacombe, Patrick Mayeux, Frédérique Verdier, Clara Camaschella, Laura Silvestri

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Transferrin receptor-2 is a transmembrane protein whose expression is restricted to hepatocytes and erythroid cells. Transferrin receptor-2 has a regulatory function in iron homeostasis, since its inactivation causes systemic iron overload. Hepatic transferrin receptor-2 participates in iron sensing and is involved in hepcidin activation, although the mechanism remains unclear. Erythroid transferrin receptor-2 associates with and stabilizes erythropoietin receptors on the erythroblast surface and is essential to control erythrocyte production in iron deficiency. We identified a soluble form of transferrin receptor-2 in the media of transfected cells and showed that cultured human erythroid cells release an endogenous soluble form. Soluble transferrin receptor-2 originates from a cleavage of the cell surface protein, which is inhibited by diferric transferrin in a dose-dependent manner. Accordingly, the shedding of the transferrin receptor-2 variant G679A, mutated in the Arginine-Glycine-Aspartic acid motif and unable to bind diferric transferrin, is not modulated by the ligand. This observation links the process of transferrin receptor-2 removal from the plasma membrane to iron homeostasis. Soluble transferrin receptor-2 does not affect the binding of erythropoietin to erythropoietin receptor or the consequent signaling and partially inhibits hepcidin promoter activation only in vitro. Whether it is a component of the signals released by erythropoiesis in iron deficiency remains to be investigated. Our results indicate that membrane transferrin receptor-2, a sensor of circulating iron, is released from the cell membrane in iron deficiency.

Original languageEnglish
Pages (from-to)458-465
Number of pages8
JournalHaematologica
Volume100
Issue number4
DOIs
Publication statusPublished - 2015

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Transferrin Receptors
Cell Surface Receptors
Iron
Hepcidins
Erythropoietin Receptors
Erythroid Cells
Homeostasis
Cell Membrane
Erythroblasts
Iron Overload
Erythropoiesis
Erythropoietin
Aspartic Acid
Glycine
Arginine
Hepatocytes
Cultured Cells
Membrane Proteins
Erythrocytes
Ligands

ASJC Scopus subject areas

  • Hematology

Cite this

Pagani, A., Vieillevoye, M., Nai, A., Rausa, M., Ladli, M., Lacombe, C., ... Silvestri, L. (2015). Regulation of cell surface transferrin receptor-2 by iron-dependent cleavage and release of a soluble form. Haematologica, 100(4), 458-465. https://doi.org/10.3324/haematol.2014.118521

Regulation of cell surface transferrin receptor-2 by iron-dependent cleavage and release of a soluble form. / Pagani, Alessia; Vieillevoye, Maud; Nai, Antonella; Rausa, Marco; Ladli, Meriem; Lacombe, Catherine; Mayeux, Patrick; Verdier, Frédérique; Camaschella, Clara; Silvestri, Laura.

In: Haematologica, Vol. 100, No. 4, 2015, p. 458-465.

Research output: Contribution to journalArticle

Pagani, A, Vieillevoye, M, Nai, A, Rausa, M, Ladli, M, Lacombe, C, Mayeux, P, Verdier, F, Camaschella, C & Silvestri, L 2015, 'Regulation of cell surface transferrin receptor-2 by iron-dependent cleavage and release of a soluble form', Haematologica, vol. 100, no. 4, pp. 458-465. https://doi.org/10.3324/haematol.2014.118521
Pagani, Alessia ; Vieillevoye, Maud ; Nai, Antonella ; Rausa, Marco ; Ladli, Meriem ; Lacombe, Catherine ; Mayeux, Patrick ; Verdier, Frédérique ; Camaschella, Clara ; Silvestri, Laura. / Regulation of cell surface transferrin receptor-2 by iron-dependent cleavage and release of a soluble form. In: Haematologica. 2015 ; Vol. 100, No. 4. pp. 458-465.
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