Characterization of the iron transporter DMT1 (NRAMP2/DCT1) in red blood cells of normal and anemic mk/mk mice
Characterization of the iron transporter DMT1 (NRAMP2/DCT1) in red blood cells of normal and anemic mk/mk mice
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DOI：
10.1182/blood.v98.13.3823
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发表时间：
2001-12-15
期刊：
影响因子：
20.3
通讯作者：
Gros, P
中科院分区：
文献类型：
--
作者：
Canonne-Hergaux, F;Zhang, AS;Gros, P
二价金属转运蛋白1（DMT 1）是肠细胞顶端主要的非转铁蛋白依赖性铁摄取系统，但它也可以转运铁穿过外周组织中酸化的内体膜。在消耗大量铁用于血红蛋白生物合成的红系细胞中研究了铁转运和DMT 1的2种亚型的表达。在表达DMT 1的功能丧失突变变体的BALB/c小鼠中，网织红细胞具有降低的细胞铁摄取和铁掺入血红素。有趣的是，在mk/mk网织红细胞中，内体内部转铁蛋白的铁释放是正常的，这表明随后Fe++跨内体膜转运存在缺陷。使用来自正常小鼠的外周血或脾脏的膜组分的免疫印迹研究表明，DMT 1与转铁蛋白受体（TfR）在红系细胞中共表达，其中网织红细胞增多症由红细胞生成素（EPO）或苯肼（PHZ）处理诱导。免疫荧光和共聚焦显微镜检测网织红细胞中DMT 1和TfR的共表达。同种型特异性抗DMT 1抗血清的实验强烈表明，它是非铁反应元件，主要由红系细胞表达的DMT 1的同种型II。与野生型网织红细胞相反，尽管TfR的强表达，但A1/A2网织红细胞表达很少（如果有的话）DMT 1，这表明突变对这些细胞中DMT 1亚型II的稳定性和靶向的可能影响。总之，这些结果提供了进一步的证据，证明DMT 1在红系细胞中通过转铁蛋白循环获得铁中起着核心作用。(C)2001年，美国血液学会。
Divalent metal transporter 1 (DMT1) is the major transferrin-independent iron uptake system at the apical pole of intestinal cells, but it may also transport iron across the membrane of acidified endosomes in peripheral tissues. Iron transport and expression of the 2 isoforms of DMT1 was studied in erythroid cells that consume large quantities of iron for biosynthesis of hemoglobin. In mk/mk mice that express a loss-of-function mutant variant of DMT1, reticulocytes have a decreased cellular iron uptake and iron incorporation into heme. Interestingly, iron release from transferrin inside the endosome is normal in mk/mk reticulocytes, suggesting a subsequent defect in Fe++ transport across the endosomal membrane. Studies by immunoblotting using membrane fractions from peripheral blood or spleen from normal mice where reticulocytosis was induced by erythropoletin (EPO) or phenylhydrazine (PHZ) treatment suggest that DMT1 is coexpressed with transferrin receptor (TfR) in erythroid cells. Coexpression of DMT1 and TfR in reticulocytes was also detected by double immunofluorescence and confocal microscopy. Experiments with isoform-specific anti-DMT1 antiserum strongly suggest that it is the non-iron-response element containing isoform II of DMT1 that is predominantly expressed by the erythroid cells. As opposed to wild-type reticulocytes, mk/mk reticulocytes express little if any DMT1, despite robust expression of TfR, suggesting a possible effect of the mutation on stability and targeting of DMT1 isoform II in these cells. Together, these results provide further evidence that DMT1 plays a central role in iron acquisition via the transferrin cycle in erythroid cells. (C) 2001 by The American Society of Hematology.