Transferrin receptor 2 is a component of the erythropoietin receptor complex and is required for efficient erythropoiesis.
Erythropoietin (Epo) is required for erythroid progenitor differentiation. Although Epo crosslinking experiments have revealed the presence of Epo receptor (EpoR)-associated proteins that could never be identified, EpoR is considered to be a paradigm for homodimeric cytokine receptors. We purified EpoR-binding partners and identified the type 2 transferrin receptor (TfR2) as a component of the EpoR complex corresponding to proteins previously detected in cross-linking experiments. TfR2 is involved in iron metabolism by regulating hepcidin production in liver cells. We show that TfR2 and EpoR are synchronously coexpressed during the differentiation of erythroid progenitors. TfR2 associates with EpoR in the endoplasmic reticulum and is required for the efficient transport of this receptor to the cell surface. Erythroid progenitors from TfR2(-/-)mice show a decreased sensitivity to Epo and increased circulating Epo levels. In human erythroid progenitors, TfR2 knockdown delays the terminal differentiation. Erythroid cells produce growth differentiation factor-15, a cytokine that suppresses hepatic hepcidin production in certain erythroid diseases such as thalassemia. We show that the production of growth differentiation factor-15 by erythroid cells is dependent on both Epo and TfR2. Taken together, our results show that TfR2 exhibits a non hepatic function as a component of the EpoR complex and is required for efficient erythropoiesis.
Forejtnikovà
Hana
H
Institut Cochin, Université Paris Descartes, Centre National de la recherche Scientifique (Unité Mixte de Recherche 8104), Paris, France.
Vieillevoye
Maud
M
Zermati
Yael
Y
Lambert
Mireille
M
Pellegrino
Rosa Maria
RM
Guihard
Soizic
S
Gaudry
Muriel
M
Camaschella
Clara
C
Lacombe
Catherine
C
Roetto
Antonella
A
Mayeux
Patrick
P
Verdier
Frédérique
F
D000818:Animals; D002454:Cell Differentiation; D004920:Erythropoiesis; D005786:Gene Expression Regulation; D055436:Growth Differentiation Factor 15 / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000737:chemistry; D021381:Protein Transport; D017467:Receptors, Erythropoietin / Q000737:chemistry*; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; D046912:Multiprotein Complexes; D017467:Receptors, Erythropoietin; D011990:Receptors, Transferrin; C503641:TFR2 protein, mouse