The role of transferrin receptor 2 in iron homeostasis

转铁蛋白受体2 （TfR2）是一种与经典转铁蛋白受体（TfR）序列相似的新发现蛋白。TfR2的功能未知。与TfR相反，TfR2几乎只存在于肝细胞和早期红细胞祖细胞中。TfR2的突变形式与遗传性血色素沉着症的一种形式有关，这种形式导致肝脏中的铁过载。肝脏是人体主要的铁加工器官，该器官的铁稳态紊乱会影响肠道对铁的吸收。基于对这一新发现的铁稳态参与者的有限信息，以下关于TfR2如何通过三种不同机制中的任何一种或全部参与铁稳态的假设将被验证。1) TfR2可通过促进铁负载转铁蛋白（Tf）的分泌调节铁从肝细胞外排。表达TfR的细胞系将以Tf合成、加工和铁负载的速率来表征。2) Tf与TfR2结合或通过TfR2摄取铁可以改变铁状态信号的分泌

Transferrin receptor 2 (TfR2) is a newly described protein with sequence similarity to the classical transferrin receptor (TfR). The function of TfR2 is unknown. In contrast to TfR, TfR2 is found almost exclusively in hepatocytes and early erythroid progenitor cells. Mutated forms of TfR2 are implicated in a form of hereditary hemochromatosis which results in iron overload in the liver. The liver is a major iron-processing organ in the body and disturbances in iron homeostasis in this organ could affect iron absorption by the intestines. On the basis of the limited information concerning this newly identified participant in iron homeostasis, the following hypotheses as to how TfR2 could plausibly participate in iron homeostasis by any or all of three different mechanisms will be tested. 1) TfR2 could regulate the efflux of iron out of the hepatocyte by facilitating the secretion of iron-loaded transferrin (Tf). Cell lines expressing TfR will be characterized for the rates of Tf synthesis, processing and iron-loading. 2) The binding of Tf to TfR2 or the uptake of iron via TfR2 could alter the secretion of iron-status signals from the hepatocytes. Alterations in the proteins secreted by hepatocytes will be examined by two-dimensional electrophoresis and mass spectrometry. Binding partners of TfR2 will be examined by immunoprecipitation and yeast two-hybrid studies to determine possible signaling mechanisms. 3) TfR2 could be located in the body in other locations that were not detected by northern analysis. Immunohistological staining of tissues with a monoclonal antibody generated against TfR2 will be used to examine specific cell types expressing TfR2. The long term goal of this research is to understand how the body regulates iron homeostasis and the mechanisms by which mutations in the key proteins result in disease.