title: Release of the soluble transferrin receptor is directly regulated by binding of its ligand ferritransferrin.
abstract: The human transferrin receptor (TfR) is shed by an integral metalloprotease releasing a soluble form (sTfR) into serum. The sTfR reflects the iron demand of the body and is postulated as a regulator of iron homeostasis via binding to the hereditary hemochromatosis protein HFE. To study the role of transferrin in this process, we investigated TfR shedding in HL60 cells and TfR-deficient Chinese hamster ovary cells transfected with human TfR. Independent of TfR expression, sTfR release decreases with increasing ferritransferrin concentrations, whereas apo-transferrin exhibits no inhibitory effect. To investigate the underlying mechanism, we generated several TfR mutants with different binding affinities for transferrin. Shedding of TfR mutants in transfected cells correlates exactly with their binding affinity, implying that the effect of ferritransferrin on TfR shedding is mediated by a direct molecular interaction. Analysis of sTfR release from purified microsomal membranes revealed that the regulation is independent from intracellular trafficking or cellular signaling events. Our results clearly demonstrated that sTfR does not only reflect the iron demand of the cells but also the iron availability in the bloodstream, mirrored by iron saturation of transferrin, corroborating the important potential function of sTfR as a regulator of iron homeostasis.
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin 12200, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Dassler
authors.forename: Martin
authors.initials: M
authors.lastname: Zydek
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Wandzik
authors.forename: Matthias
authors.initials: M
authors.lastname: Kaup
authors.forename: Hendrik
authors.initials: H
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003470:Culture Media / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D018922:HL-60 Cells; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008954:Models, Biological; D009154:Mutation; D016366:Open Reading Frames; D011485:Protein Binding; D011990:Receptors, Transferrin / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction; D013696:Temperature; D013997:Time Factors; D014162:Transfection; D014168:Transferrin / Q000737:chemistry*
chemical_list: D003470:Culture Media; D008024:Ligands; D011990:Receptors, Transferrin; D014168:Transferrin; D007501:Iron