Regulated intramembrane proteolysis of transferrin receptor 1 and the role of the released intracellular domain in singaling of iron metabolism

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The understanding of the pathogenesis of hemochromatosis and other diseases of iron metabolism requires knowledge of the molecular regulation mechanism to retain systemic iron homeostasis. Transferrin receptor 1 (TfR1) regulates iron uptake into the cell. Ist ectodomain is released into the serum. As far as is known no function has been assigned to this soluble form of TfR1 to date emphasizing the role of the intracellular located TfR1-N-terminal fragment. As shown in our peliminary work, the intracellular fragment is further cleaved by an intramembrane cleaving protease (I-CLiP). Intramembrane proteolysis promotes the release of intracellular signal molecules and transcription factors. Aim of the project is thus to characterize the role of TfR1 intramembrane proteolysis and of the released intracellular domain (ICD) for the molecular regulation of systemic iron homeostasis. This will be achieved by identification of the I-CLiP-protease, investigations on the regulation of proteolysis as well as by studies on ICD trafficking and ist final localization. Furthermore, identification of interaction partners within the involved compartments is of great importance. Therefore, the ICD will be accumulated by proteasome inhibition and recombinant expression.