Release of the soluble transferrin receptor is directly regulated by binding of its ligand ferritransferrin
Release of the soluble transferrin receptor is directly regulated by binding of its ligand ferritransferrin
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DOI：
10.1074/jbc.m511341200
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发表时间：
2006-02-10
影响因子：
4.8
通讯作者：
Fuchs, H
中科院分区：
文献类型：
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作者：
Dassler, K;Zydek, M;Fuchs, H
人转铁蛋白受体（TfR）由整合的金属蛋白酶脱落，释放可溶形式（sTfR）到血清中。sTfR反映了身体的铁需求，并被假定为通过与遗传性血色病蛋白HFE结合来调节铁稳态。为了研究转铁蛋白在这一过程中的作用，我们研究了转铁蛋白受体脱落在HL 60细胞和转铁蛋白受体缺陷的中国仓鼠卵巢细胞转染人转铁蛋白受体。TfR表达的独立性，sTfR释放随铁转铁蛋白浓度的增加而降低，而脱辅基转铁蛋白没有表现出抑制作用。为了研究潜在的机制，我们产生了几个转铁蛋白的转铁蛋白受体突变体具有不同的结合亲和力。转染细胞中TfR突变体的脱落与它们的结合亲和力完全相关，这意味着铁转铁蛋白对TfR脱落的影响是由直接的分子相互作用介导的。对纯化微粒体膜中sTfR释放的分析表明，这种调节独立于细胞内运输或细胞信号事件。我们的研究结果清楚地表明，sTfR不仅反映了细胞的铁需求，而且还反映了血液中的铁的可用性，反映了转铁蛋白的铁饱和度，证实了sTfR作为铁稳态调节剂的重要潜在功能。
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.