The hemochromatosis protein HFE inhibits iron export from macrophages
The hemochromatosis protein HFE inhibits iron export from macrophages
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DOI：
10.1073/pnas.242614699
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发表时间：
2002-11-26
影响因子：
11.1
通讯作者：
Townsend, ARM
中科院分区：
文献类型：
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作者：
Drakesmith, H;Sweetland, E;Townsend, ARM
遗传性血色素沉着症（HH）是由HFE基因常见突变引起的铁代谢紊乱。HFE蛋白与转铁蛋白竞争结合转铁蛋白受体-1（TfR 1），并在体外通过减少铁摄取来减少细胞铁。然而，在体内，HFE由肝巨噬细胞和肠隐窝细胞强烈表达，其表现好像它们在HH中相对缺铁。后者的观察结果表明，自相矛盾的是，野生型HFE的表达可能导致铁积累在这些专门的细胞类型。在这里，我们表明野生型HFE蛋白通过抑制单核细胞/巨噬细胞系THP-1的铁流出来提高细胞铁，并将这些结果扩展到来自健康个体和HH患者的巨噬细胞。此外，我们发现，HH相关的突变体H41 D已经失去了抑制铁释放的能力，尽管结合TfR 1以及野生型HFE。最后，我们表明，HFE阻止铁释放的能力不竞争性抑制转铁蛋白。我们的结论是，HFE有两个相互排斥的功能，结合TfR 1与Tf竞争，或抑制铁的释放。
Hereditary hemochromatosis (HH) is a disorder of iron metabolism caused by common mutations in the gene HFE. The HFE protein binds to transferrin receptor-1 (TfR1) in competition with transferrin, and in vitro, reduces cellular iron by reducing iron uptake. However, in vivo, HFE is strongly expressed by liver macrophages and intestinal crypt cells, which behave as though they are relatively iron-deficient in HH. These latter observations suggest, paradoxically, that expression of wild-type HFE may lead to iron accumulation in these specialized cell types. Here we show that wild-type HFE protein raises cellular iron by inhibiting iron efflux from the monocyte/macrophage cell line THP-1, and extend these results to macrophages derived from healthy individuals and HH patients. In addition, we find that the HH-associated mutant H41D has lost the ability to inhibit iron release despite binding to TfR1 as well as wild-type HFE. Finally, we show that the ability of HFE to block iron release is not competitively inhibited by transferrin. We conclude that HFE has two mutually exclusive functions, binding to TfR1 in competition with Tf, or inhibition of iron release.