The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression.
Hemochromatosis is caused by mutations in HFE, a protein that competes with transferrin (TF) for binding to transferrin receptor 1 (TFR1). We developed mutant mouse strains to gain insight into the role of the Hfe/Tfr1 complex in regulating iron homeostasis. We introduced mutations into a ubiquitously expressed Tfr1 transgene or the endogenous Tfr1 locus to promote or prevent the Hfe/Tfr1 interaction. Under conditions favoring a constitutive Hfe/Tfr1 interaction, mice developed iron overload attributable to inappropriately low expression of the hormone hepcidin. In contrast, mice carrying a mutation that interferes with the Hfe/Tfr1 interaction developed iron deficiency associated with inappropriately high hepcidin expression. High-level expression of a liver-specific Hfe transgene in Hfe-/- mice was also associated with increased hepcidin production and iron deficiency. Together, these models suggest that Hfe induces hepcidin expression when it is not in complex with Tfr1.
Schmidt
Paul J
PJ
Division of Hematology/Oncology, Children's Hospital Boston, Boston, MA 02115, USA.
Toran
Paul T
PT
Giannetti
Anthony M
AM
Bjorkman
Pamela J
PJ
Andrews
Nancy C
NC
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D004920:Erythropoiesis; D005786:Gene Expression Regulation; D005838:Genotype; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D007501:Iron / Q000378:metabolism*; D000090463:Iron Deficiencies; D019190:Iron Overload / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020125:Mutation, Missense; D010641:Phenotype; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014168:Transferrin / Q000378:metabolism
D023181:Antimicrobial Cationic Peptides; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D012333:RNA, Messenger; D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; D014168:Transferrin; D007501:Iron