The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, CA, USA.
Blood Cells Mol Dis. 2012 Mar 15;48(3):173-8. doi: 10.1016/j.bcmd.2011.12.005. Epub 2012 Jan 14.
Cell surface proteins Hfe, Tfr2, hemojuvelin and Tmprss6 play key roles in iron homeostasis. Hfe and Tfr2 induce transcription of hepcidin, a small peptide that promotes the degradation of the iron transporter ferroportin. Hemojuvelin, a co-receptor for bone morphogenic proteins, induces hepcidin transcription through a Smad signaling pathway. Tmprss6 (also known as matriptase-2), a membrane serine protease that has been found to bind and degrade hemojuvelin in vitro, is a potent suppressor of hepcidin expression. In order to examine if Hfe and Tfr2 are substrates for Tmprss6, we generated mice lacking functional Hfe or Tfr2 and Tmprss6. We found that double mutant mice lacking functional Hfe or Tfr2 and Tmprss6 exhibited a severe iron deficiency microcytic anemia phenotype mimicking the phenotype of single mutant mice lacking functional Tmprss6 (Tmprss6msk/msk mutant) demonstrating that Hfe and Tfr2 are not substrates for Tmprss6. Nevertheless, the phenotype of the mice lacking Hfe or Tfr2 and Tmprss6 differed from Tmprss6 deficient mice alone, in that the double mutant mice exhibited much greater erythropoiesis. Hfe and Tfr2 have been shown to play important roles in the erythron, independent of their role in regulating liver hepcidin transcription. We demonstrate that lack of functional Tfr2 and Hfe allows for increased erythropoiesis even in the presence of high hepcidin expression, but the high levels of hepcidin levels significantly limit the availability of iron to the erythron, resulting in ineffective erythropoiesis. Furthermore, repression of hepcidin expression by hypoxia was unaffected by the loss of functional Hfe, Tfr2 and Tmprss6.
细胞表面蛋白 Hfe、Tfr2、hemojuvelin 和 Tmprss6 在铁稳态中发挥关键作用。Hfe 和 Tfr2 诱导小肽 hepcidin 的转录，hepcidin 促进铁转运蛋白 ferroportin 的降解。骨形态发生蛋白的共同受体 hemojuvelin 通过 Smad 信号通路诱导 hepcidin 的转录。Tmprss6（也称为 matriptase-2），一种已被发现体外结合和降解 hemojuvelin 的膜丝氨酸蛋白酶，是 hepcidin 表达的有效抑制剂。为了研究 Hfe 和 Tfr2 是否是 Tmprss6 的底物，我们生成了缺乏功能性 Hfe 或 Tfr2 和 Tmprss6 的小鼠。我们发现，缺乏功能性 Hfe 或 Tfr2 和 Tmprss6 的双突变小鼠表现出严重的缺铁性小细胞贫血表型，类似于缺乏功能性 Tmprss6 的单突变小鼠（Tmprss6msk/msk 突变体）的表型，表明 Hfe 和 Tfr2 不是 Tmprss6 的底物。然而，缺乏 Hfe 或 Tfr2 和 Tmprss6 的小鼠表型与 Tmprss6 缺乏的小鼠不同，双突变小鼠表现出更强的红细胞生成。Hfe 和 Tfr2 已被证明在红细胞中发挥重要作用，独立于其在调节肝脏 hepcidin 转录中的作用。我们证明，缺乏功能性 Tfr2 和 Hfe 即使在高水平 hepcidin 表达的情况下也能促进红细胞生成，但高水平的 hepcidin 显著限制了铁向红细胞的供应，导致红细胞生成无效。此外，缺氧对 hepcidin 表达的抑制作用不受功能性 Hfe、Tfr2 和 Tmprss6 缺失的影响。
