Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis
Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis
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DOI：
10.1073/pnas.94.24.13198
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发表时间：
1997-11-25
影响因子：
11.1
通讯作者：
Sly, WS
中科院分区：
文献类型：
--
作者：
Parkkila, S;Waheed, A;Sly, WS
遗传性血色素沉着症是一种常见的常染色体隐性遗传病，与饮食铁吸收调节丧失和身体主要器官铁沉积过多有关。最近，HH（也称为HFE）的候选基因被鉴定为编码一种新的MHC I类蛋白。大多数HH患者在HFE基因中的相同突变是纯合的，导致HFE蛋白中的C282 Y改变。在培养细胞中的研究表明，C282 Y突变消除了重组HFE蛋白与β 2-微球蛋白（β 2 M）的结合，并破坏了其向细胞表面的转运。HFE蛋白通过免疫组织化学显示在整个人类消化道的某些上皮细胞中表达，并且在小肠的隐窝细胞中具有独特的定位，其中从身体接收调节铁吸收的信号。在这里提出的研究中，我们证明了免疫组化HFE蛋白在人类胎盘中的合体滋养层细胞，其中转铁蛋白结合的铁通常通过受体介导的内吞作用运输到胎儿的顶端质膜中表达。蛋白质印迹分析表明，HFE蛋白与胎盘膜中的β（2）M相关。出乎意料的是，转铁蛋白受体也被发现与HFE蛋白/β（2）M复合物相关。这些研究将正常HFE蛋白置于与母体循环接触的部位，在该部位，其与转铁蛋白受体的结合提高了HFE蛋白在决定母体/胎儿铁稳态中起一定作用的可能性。这些发现还提出了一个问题，即HFE基因突变是否会破坏这种关联，从而导致某些形式的新生儿铁过载。
Hereditary hemochromatosis (HH) is a common autosomal recessive disease associated with loss of regulation of dietary iron absorption and excessive iron deposition in major organs of the body. Recently, a candidate gene for HH (also called HFE) was identified that encodes a novel MHC class I-like protein. Most patients with HH are homozygous for the same mutation in the HFE gene, resulting in a C282Y change in the HFE protein. Studies in cultured cells show that the C282Y mutation abrogates the binding of the recombinant HFE protein to beta(2)-microglobulin (beta(2)M) and disrupts its transport to the cell surface. The HFE protein was shown by immunohistochemistry to be expressed in certain epithelial cells throughout the human alimentary tract and to have a unique localization in the cryptal cells of small intestine, where signals to regulate iron absorption are received from the body. In the studies presented here, we demonstrate by immunohistochemistry that the HFE protein is expressed in human placenta in the apical plasma membrane of the syncytiotrophoblasts, where the transferrin-bound iron is normally transported to the fetus via receptor-mediated endocytosis. Western blot analyses show that the HFE protein is associated with beta(2)M in placental membranes. Unexpectedly, the transferrin receptor was also found to be associated with the HFE protein/beta(2)M complex. These studies place the normal HFE protein at the site of contact with the maternal circulation where its association with transferrin receptor raises the possibility that the HFE protein plays some role in determining maternal/fetal iron homeostasis. These findings also raise the question of whether mutations in the HFE gene can disrupt this association and thereby contribute to some forms of neonatal iron overload.