Transferrin receptor 2: Evidence for ligand-induced stabilization and redirection to a recycling pathway
Transferrin receptor 2: Evidence for ligand-induced stabilization and redirection to a recycling pathway
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DOI：
10.1091/mbc.e06-09-0798
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发表时间：
2007-03-01
影响因子：
3.3
通讯作者：
Enns, Caroline A.
中科院分区：
文献类型：
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作者：
Johnson, Martha B.;Chen, Juxing;Enns, Caroline A.
转铁蛋白受体2(TfR2)是转铁蛋白受体1(TfR1)的同系物，TfR1是一种通过受体介导的二铁转铁蛋白(Fe2Tf)内吞将铁输送到细胞内的蛋白质。TfR2也与Fe2Tf结合，但它似乎主要在调节全身铁稳态方面发挥作用。与TfR1不同的是，TfR2在细胞内的转运尚未得到广泛的表征。此前，我们发现Fe2Tf增加了TfR2的稳定性，表明TfR2的运输可能通过与其配体的相互作用来调节。因此，在本研究中，我们试图确定TfR2的降解模式，以表征TfR2的贩运，并确定Fe2Tf如何稳定TfR2。巴菲罗星稳定TfR2意味着TfR2转运到溶酶体进行降解。共聚焦显微镜显示，用Fe2Tf处理细胞后，TfR2定位于循环内小体的比例增加，而TfR2定位于晚期内小体的比例减少。TfR2的突变分析表明，阻断TfR2与Fe2Tf结合的突变G679A增加了受体的周转率，阻止了Fe2Tf的稳定，表明Fe2Tf在TfR2稳定中起直接作用。Y23A突变位于TfR2胞浆区，抑制其内化和降解，提示YQRV为内吞基序。
Transferrin receptor 2 (TfR2) is a homologue of transferrin receptor 1 (TfR1), the protein that delivers iron to cells through receptor-mediated endocytosis of diferric transferrin (Fe2Tf). TfR2 also binds Fe2Tf, but it seems to function primarily in the regulation of systemic iron homeostasis. In contrast to TfR1, the trafficking of TfR2 within the cell has not been extensively characterized. Previously, we showed that Fe2Tf increases TfR2 stability, suggesting that trafficking of TfR2 may be regulated by interaction with its ligand. In the present study, therefore, we sought to identify the mode of TfR2 degradation, to characterize TfR2 trafficking, and to determine how Fe2Tf stabilizes TfR2. Stabilization of TfR2 by bafilomycin implies that TfR2 traffics to the lysosome for degradation. Confocal microscopy reveals that treatment of cells with Fe2Tf increases the fraction of TfR2 localizing to recycling endosomes and decreases the fraction of TfR2 localizing to late endosomes. Mutational analysis of TfR2 shows that the mutation G679A, which blocks TfR2 binding to Fe2Tf, increases the rate of receptor turnover and prevents stabilization by Fe2Tf, indicating a direct role of Fe2Tf in TfR2 stabilization. The mutation Y23A in the cytoplasmic domain of TfR2 inhibits its internalization and degradation, implicating YQRV as an endocytic motif.