Roy C N, Penny D M, Feder J N, Enns C A
Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland, Oregon 97201-3098, USA.
J Biol Chem. 1999 Mar 26;274(13):9022-8. doi: 10.1074/jbc.274.13.9022.
HFE is the protein product of the gene mutated in the autosomal recessive disease hereditary hemochromatosis (Feder, J. N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy, D. A., Basava, A., Dormishian, F., Domingo, R. J., Ellis, M. C., Fullan, A., Hinton, L. M., Jones, N. L., Kimmel, B. E., Kronmal, G. S., Lauer, P., Lee, V. K., Loeb, D. B., Mapa, F. A., McClelland, E., Meyer, N. C., Mintier, G. A., Moeller, N., Moore, T., Morikang, E., Prasss, C. E., Quintana, L., Starnes, S. M., Schatzman, R. C., Brunke, K. J., Drayna, D. T., Risch, N. J., Bacon, B. R., and Wolff, R. R. (1996) Nat. Genet. 13, 399-408). At the cell surface, HFE complexes with transferrin receptor (TfR), increasing the dissociation constant of transferrin (Tf) for its receptor 10-fold (Gross, C. N., Irrinki, A., Feder, J. N., and Enns, C. A. (1998) J. Biol. Chem. 273, 22068-22074; Feder, J. N., Penny, D. M., Irrinki, A., Lee, V. K., Lebron, J. A., Watson, N. , Tsuchihashi, Z., Sigal, E., Bjorkman, P. J., and Schatzman, R. C. (1998) Proc. Natl. Acad. Sci. U S A 95, 1472-1477). HFE does not remain at the cell surface, but traffics with TfR to Tf-positive internal compartments (Gross et al., 1998). Using a HeLa cell line in which the expression of HFE is controlled by tetracycline, we show that the expression of HFE reduces 55Fe uptake from Tf by 33% but does not affect the endocytic or exocytic rates of TfR cycling. Therefore, HFE appears to reduce cellular acquisition of iron from Tf within endocytic compartments. HFE specifically reduces iron uptake from Tf, as non-Tf-mediated iron uptake from Fe-nitrilotriacetic acid is not altered. These results explain the decreased ferritin levels seen in our HeLa cell system and demonstrate the specific control of HFE over the Tf-mediated pathway of iron uptake. These results also have implications for the understanding of cellular iron homeostasis in organs such as the liver, pancreas, heart, and spleen that are iron loaded in hereditary hemochromatotic individuals lacking functional HFE.
HFE是常染色体隐性疾病遗传性血色素沉着症中发生突变的基因的蛋白质产物（费德，J.N.，格尼克，A.，托马斯，W.，土桥，Z.，鲁迪，D.A.，巴萨瓦，A.，多尔米西安，F.，多明戈，R.J.，埃利斯，M.C.，富兰，A.，欣顿，L.M.，琼斯，N.L.，金梅尔，B.E.，克龙马尔，G.S.，劳尔,P.，李，V.K.，勒布，D.B.，马帕，F.A.，麦克莱兰，E.，迈耶，N.C.，明蒂尔，G.A.，莫勒，N.，摩尔，T.，莫里康,E.，普拉斯，C.E.，金塔纳，L.，斯塔恩斯，S.M.，沙茨曼，R.C.，布伦克，K.J.，德雷纳，D.T.，里施，N.J.，培根，B.R.，沃尔夫，R.R.（1996年）《自然遗传学》第13卷，第399 - 408页）。在细胞表面，HFE与转铁蛋白受体（TfR）形成复合物，使转铁蛋白（Tf）与其受体的解离常数增加10倍（格罗斯，C.N.，伊林基，A.，费德，J.N.，恩斯，C.A.（1998年）《生物化学杂志》第273卷，第22068 - 22074页；费德，J.N.，彭尼，D.M.，伊林基，A.，李，V.K.，勒布朗，J.A.，沃森，N.，土桥，Z.，西加尔，E.，比约克曼，P.J.，沙茨曼，R.C.（1998年）《美国国家科学院院刊》第95卷，第1472 - 1477页）。HFE不会停留在细胞表面，而是与TfR一起转运至富含Tf的内部区室（格罗斯等人，1998年）。利用一种通过四环素控制HFE表达的HeLa细胞系，我们发现HFE的表达使从Tf摄取的55Fe减少了33%，但不影响TfR循环的内吞或外排速率。因此，HFE似乎在细胞内吞区室中减少了细胞从Tf获取铁的过程。HFE特异性地减少从Tf摄取的铁，因为从次氮基三乙酸铁摄取的非Tf介导的铁没有改变。这些结果解释了在我们的HeLa细胞系统中观察到的铁蛋白水平降低的现象，并证明了HFE对Tf介导的铁摄取途径的特异性控制。这些结果对于理解遗传性血色素沉着症患者中缺乏功能性HFE时肝脏、胰腺、心脏和脾脏等器官中的细胞铁稳态也具有重要意义。
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