title: Regulation of cell surface transferrin receptor-2 by iron-dependent cleavage and release of a soluble form.
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.
authors: Vita Salute San Raffaele University, Milan, Italy Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors: Alessia
authors: A
authors: Pagani
authors: Institut Cochin, INSERM, U1016, Université Paris Descartes, CNRS (UMR8104), Paris, France Ligue National contre le Cancer, Paris, France.
authors: Maud
authors: M
authors: Vieillevoye
authors: Vita Salute San Raffaele University, Milan, Italy Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors: Antonella
authors: A
authors: Nai
authors: Vita Salute San Raffaele University, Milan, Italy Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors: Marco
authors: M
authors: Rausa
authors: Institut Cochin, INSERM, U1016, Université Paris Descartes, CNRS (UMR8104), Paris, France Ligue National contre le Cancer, Paris, France.
authors: Meriem
authors: M
authors: Ladli
authors: Institut Cochin, INSERM, U1016, Université Paris Descartes, CNRS (UMR8104), Paris, France Ligue National contre le Cancer, Paris, France.
authors: Catherine
authors: C
authors: Lacombe
authors: Institut Cochin, INSERM, U1016, Université Paris Descartes, CNRS (UMR8104), Paris, France Ligue National contre le Cancer, Paris, France.
authors: Patrick
authors: P
authors: Mayeux
authors: Ligue National contre le Cancer, Paris, France.
authors: Frédérique
authors: F
authors: Verdier
authors: Vita Salute San Raffaele University, Milan, Italy Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors: Clara
authors: C
authors: Camaschella
authors: Vita Salute San Raffaele University, Milan, Italy Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy silvestri.laura@hsr.it.
authors: Laura
authors: L
authors: Silvestri
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D041905:Erythroid Cells / Q000378:metabolism; D004921:Erythropoietin / Q000378:metabolism; D015870:Gene Expression; D064451:Hepcidins / Q000235:genetics; D006801:Humans; D007501:Iron / Q000378:metabolism*; D009154:Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021381:Protein Transport; D059748:Proteolysis; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D011990:Receptors, Transferrin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014168:Transferrin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C068126:CD71 antigen; D064451:Hepcidins; D017467:Receptors, Erythropoietin; D011990:Receptors, Transferrin; C503640:TFR2 protein, human; D014168:Transferrin; C110714:holotransferrin; D004921:Erythropoietin; D007501:Iron
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