Control of metazoan heme homeostasis by a conserved multidrug resistance protein.
Control of metazoan heme homeostasis by a conserved multidrug resistance protein.
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DOI：
10.1016/j.cmet.2014.03.030
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发表时间：
2014-06-03
期刊：
影响因子：
29
通讯作者：
Hamza I
中科院分区：
文献类型：
--
作者：
Korolnek T;Zhang J;Beardsley S;Scheffer GL;Hamza I
一些证据预测，特定的途径必须存在于后生动物的护送运动的血红素，一个必不可少的，但细胞毒性的含铁有机环，细胞和组织内和之间，但这些途径仍然模糊。在秀丽隐杆线虫中，胚胎发育不可避免地依赖于母体来源的血红素和环境获得的血红素。在这里，我们表明，多药耐药蛋白，MRP-5/ABCC 5，可能作为一个血红素出口商和有针对性的消耗mrp-5在肠道导致胚胎致死。斑马鱼中mrp 5的瞬时敲低导致形态缺陷和红细胞血红蛋白化失败。MRP 5位于质膜和内体区室上，并调节胞质血红素的输出。总之，我们在蠕虫、酵母、斑马鱼和哺乳动物细胞中的遗传研究确定了多药耐药蛋白在调节系统血红素稳态中的保守生理作用。我们设想其他MRP家族成员可能在动物发育中发挥类似的未预料到的生理作用。
Several lines of evidence predict that specific pathways must exist in metazoans for the escorted movement of heme, an essential but cytotoxic iron-containing organic ring, within and between cells and tissues, but these pathways remain obscure. In Caenorhabditis elegans, embryonic development is inextricably dependent on both maternally-derived heme and environmentally-acquired heme. Here, we show that the multidrug resistance protein, MRP-5/ABCC5, likely acts as a heme exporter and targeted depletion of mrp-5 in the intestine causes embryonic lethality. Transient knockdown of mrp5 in zebrafish leads to morphological defects and failure to hemoglobinize red blood cells. MRP5 resides on the plasma membrane and endosomal compartments and regulates export of cytosolic heme. Together, our genetic studies in worms, yeast, zebrafish, and mammalian cells identify a conserved, physiological role for a multidrug resistance protein in regulating systemic heme homeostasis. We envision other MRP family members may play similar unanticipated physiological roles in animal development.
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