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

转铁蛋白受体 1 的膜内蛋白水解调节以及释放的胞内结构域在铁代谢信号传导中的作用

• 批准号: 73952010
• 负责人: Professor Dr. Hendrik Fuchs
• 金额: --
• 依托单位: Institut für Laboratoriumsmedizin, Klinische Chemie und Pathobiochemie (CVK)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/73952010?language=en
• 关键词: Regulated; intramembrane; proteolysis; transferrin; receptor

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.

了解血色素沉着症等铁代谢疾病的发病机制，需要了解维持全身铁稳态的分子调控机制。转铁蛋白受体1 （TfR1）调节铁进入细胞的摄取。第一个外结构域被释放到血清中。据我们所知，迄今为止，这种可溶性形式的TfR1没有功能，强调了细胞内定位的TfR1- n端片段的作用。正如我们的初步工作所示，细胞内片段被膜内切割蛋白酶（I-CLiP）进一步切割。膜内蛋白水解促进细胞内信号分子和转录因子的释放。因此，该项目的目的是表征TfR1膜内蛋白水解和释放的胞内结构域（ICD）在全身铁稳态的分子调节中的作用。这将通过i - clip蛋白酶的鉴定、蛋白质水解调控的研究以及ICD转运和最终定位的研究来实现。此外，在相关隔间内识别交互伙伴是非常重要的。因此，ICD将通过蛋白酶体抑制和重组表达来积累。