Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin
Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin
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DOI：
10.1182/blood-2010-04-277954
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发表时间：
2010-12-16
期刊：
影响因子：
20.3
通讯作者：
Fleming, Mark D.
中科院分区：
文献类型：
--
作者：
Schmidt, Paul J.;Andrews, Nancy C.;Fleming, Mark D.
HFE 突变会导致最常见的遗传性血色素沉着病 (HH)。我们之前表明，小鼠 Hfe 的肝脏特异性转基因过度表达会刺激铁调节激素铁调素的产生。在这里，我们开发了几种额外的转基因小鼠品系，以进一步探讨 HFE 在 HH 病理生理学中功能的结构基础。我们假设 HFE 的小细胞质结构域可能是 HFE 介导的铁调素诱导所必需的。我们证明，与全长蛋白一样，缺乏胞质结构域的 Hfe 蛋白的过度表达会导致铁调素诱导、铁缺乏和低色素性小细胞性贫血。然而，携带与常见 HFE C282Y 人类致病突变（小鼠 C294Y）小鼠等效的肝脏特异性 Hfe 转基因的高水平表达并不会导致缺铁。此外，在缺乏血幼素（Hjv）的情况下，编码WT Hfe和缺乏胞质结构域的Hfe的转基因对铁调素的诱导作用大大减弱。我们的观察表明，Hfe 的胞外和跨膜结构域对于 Hfe 介导的铁调素表达诱导来说是足够的，并且 Hjv 是必需的。 （血。2010；116（25）：5679-5687）
Mutations in HFE cause the most common form of hereditary hemochromatosis (HH). We previously showed that liver-specific, transgenic overexpression of murine Hfe stimulates production of the iron regulatory hormone hepcidin. Here, we developed several additional transgenic mouse strains to further interrogate the structural basis of HFE function in the pathophysiology of HH. We hypothesized that the small, cytoplasmic domain of HFE might be necessary for HFE-mediated induction of hepcidin. We demonstrate that, like the full-length protein, overexpression of Hfe proteins lacking the cytoplasmic domain leads to hepcidin induction, iron deficiency and a hypochromic, microcytic anemia. However, high-level expression of a liver-specific Hfe transgene carrying the mouse equivalent of the common HFE C282Y human disease-causing mutation (murine C294Y) did not cause iron deficiency. Furthermore, hepcidin induction by transgenes encoding both WT Hfe and Hfe lacking its cytoplasmic domain is greatly attenuated in the absence of hemojuvelin (Hjv). Our observations indicate that the extracellular and transmembrane domains of Hfe are sufficient, and Hjv is essential, for Hfe-mediated induction of hepcidin expression. (Blood. 2010;116(25):5679-5687)