Functional consequences of ferroportin 1 mutations
Functional consequences of ferroportin 1 mutations
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DOI：
10.1016/j.bcmd.2005.04.005
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发表时间：
2005-07-01
影响因子：
2.3
通讯作者：
Haile, DJ
中科院分区：
文献类型：
--
作者：
Liu, XB;Yang, FM;Haile, DJ
细胞铁输出蛋白ferroportin I在十二指肠和单核吞噬细胞系统的细胞中表达。膜铁转运蛋白I在细胞表面的表达受膜铁转运蛋白I与铁调素的相互作用调节。铁调素处理细胞导致细胞表面膜铁转运蛋白1的内化和溶酶体降解。最近，已经鉴定了导致血色素沉着症（HFE 4）的膜铁转运蛋白I突变。HFE 4与经典血色素沉着症的不同之处在于，巨噬细胞铁封存量更大。本文提供的数据表明，HFE 4突变对蛋白质功能的影响是异质的。一些突变导致ER中部分蛋白螯合的功能丧失。其他的与天然的膜铁转运蛋白I没有区别，并且具有类似的耗尽转染细胞铁的能力，如通过铁应答蛋白的激活和细胞铁蛋白耗尽所证明的。值得注意的是，所有突变体似乎对铁调素无反应，并且在暴露于铁调素时没有表现出预期的内化。在患者中观察到的临床表型可能继发于铁调素介导的膜铁转运蛋白I表达抑制中的细胞类型特异性缺陷。爱思唯尔公司出版
The cellular iron exporter ferroportin I is expressed in both the duodenum and in cells of the mononuclear phagocyte system. Expression of ferroportin I protein on the cell surface is regulated by the interaction of ferroportin I with hepcidin. Hepcidin treatment of cells results in internalization and lysosomal degradation of cell surface ferroportin 1. Recently, ferroportin I mutations leading to hemochromatosis (HFE4) have been identified. HFE4 differs from classical hemochromatosis in that there is a greater amount of macrophage iron sequestration. The data presented here demonstrate that HFE4 mutations are heterogeneous in their effects on protein function. Some mutations result in loss of function with partial protein sequestration in the ER. Others are indistinguishable from native ferroportin I and have a similar ability to deplete transfected cells of iron as evidenced by activation of the iron-response proteins and cellular ferritin depletion. Significantly, all mutants appear to be unresponsive to hepcidin and do not demonstrate the expected internalization on exposure to hepcidin. The clinical phenotypes observed in patients may be secondary to cell-type-specific defects in hepcidin-mediated inhibition of ferroportin I expression. Published by Elsevier Inc.