Iron-dependent regulation of transferrin receptor expression in Trypanosoma brucei
Iron-dependent regulation of transferrin receptor expression in Trypanosoma brucei
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DOI：
10.1042/0264-6021:3420691
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发表时间：
1999-09-15
影响因子：
4.1
通讯作者：
Steverding, D
中科院分区：
文献类型：
--
作者：
Fast, B;Kremp, K;Steverding, D
转铁蛋白是非洲锥虫的重要生长因子。在这里，我们表明锥体转铁蛋白受体的表达，它与哺乳动物转铁蛋白受体在结构上没有相似之处，受铁供应的调节。用铁络合剂去铁胺耗尽布鲁氏锥虫血液中的铁，转铁蛋白受体上调3倍，转铁蛋白摄取率增加3倍。表达位点相关基因产物6(ESAG6)的丰度编码锥虫转铁蛋白受体的两个亚基之一，受转录后机制的5倍调节。在哺乳动物细胞中，转铁蛋白受体mRNA的稳定性是由铁调节蛋白(IRPS)与3‘-非翻译区的铁反应元件(IRES)结合控制的。因此，研究了与哺乳动物IRP-1高度相关的布氏毛滴虫胞质乌头酸酶(TbACO)的作用。铁对转铁蛋白受体的调节在Delta ACO：：NEO/Delta ACO：：HYG空突变体中被发现不受影响，这些突变是由TbACO基因的靶向破坏产生的。因此，锥虫体内转录后转铁蛋白受体调节的机制似乎不同于IRE/IRP范式。当锥虫从添加胎牛血清的培养液转移到添加其他脊椎动物血清的培养液中时，转铁蛋白的摄取率也增加。由于锥体转铁蛋白受体与不同物种的转铁蛋白的结合亲和力不同，血清变化可能导致铁饥饿。因此，对转铁蛋白受体表达的调节可能是寄生虫传播到新寄主物种时的一种快速代偿机制。
Transferrin is an essential growth factor for African trypanosomes. Here we show that expression of the trypanosomal transferrin receptor, which bears no structural similarity with mammalian transferrin receptors, is regulated by iron availability. Iron depletion of bloodstream forms of Trypanosoma brucei with the iron chelator deferoxamine resulted in a 3-fold up-regulation of the transferrin receptor and a 3-fold increase of the transferrin uptake rate. The abundance of expression site associated gene product 6 (ESAG6) mRNA, which encodes one of the two subunits of the trypanosome transferrin receptor, is regulated 5-fold by a post-transcriptional mechanism. In mammalian cells the stability of transferrin receptor mRNA is controlled by iron regulatory proteins (IRPs) binding to iron-responsive elements (IREs) in the 3'-untranslated region (UTR). Therefore, the role of a T. brucei cytoplasmic aconitase (TbACO) that is highly related to mammalian IRP-1 was investigated. Iron regulation of the transferrin receptor was found to be unaffected in Delta aco::NEO/Delta aco::HYG null mutants generated by targeted disruption of the TbACO gene. Thus, the mechanism of posttranscriptional transferrin receptor regulation in trypanosomes appears to be distinct from the IRE/IRP paradigm. The transferrin uptake rate was also increased when trypanosomes were transferred from medium supplemented with foetal bovine serum to medium supplemented with sera from other vertebrates. Due to varying binding affinities of the trypanosomal transferrin receptor for transferrins of different species, serum change can result in iron starvation. Thus, regulation of transferrin receptor expression may be a fast compensatory mechanism upon transmission of the parasite to a new host species.