Fast B, Kremp K, Boshart M, Steverding D
Max-Planck-Institut für Biochemie, Genzentrum, Martinsried, Germany and Institut für Molekularbiologie und Biochemie, Freie Universität Berlin, Germany.
Biochem J. 1999 Sep 15;342 Pt 3(Pt 3):691-6.
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 Deltaaco::NEO/Deltaaco::HYG null mutants generated by targeted disruption of the TbACO gene. Thus, the mechanism of post-transcriptional 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.
转铁蛋白是非洲锥虫必不可少的生长因子。在此我们表明，锥虫转铁蛋白受体的表达受铁供应的调节，该受体与哺乳动物转铁蛋白受体在结构上没有相似性。用铁螯合剂去铁胺使布氏锥虫血流形式的铁耗竭，导致转铁蛋白受体上调3倍，转铁蛋白摄取率增加3倍。编码锥虫转铁蛋白受体两个亚基之一的表达位点相关基因产物6（ESAG6）mRNA的丰度通过转录后机制受到5倍的调节。在哺乳动物细胞中，转铁蛋白受体mRNA的稳定性由与3'非翻译区（UTR）中的铁反应元件（IRE）结合的铁调节蛋白（IRP）控制。因此，研究了与哺乳动物IRP-1高度相关的布氏锥虫细胞质乌头酸酶（TbACO）的作用。发现在通过靶向破坏TbACO基因产生的Deltaaco::NEO/Deltaaco::HYG缺失突变体中，转铁蛋白受体的铁调节不受影响。因此，锥虫中转录后转铁蛋白受体调节的机制似乎与IRE/IRP模式不同。当锥虫从补充有胎牛血清的培养基转移到补充有其他脊椎动物血清的培养基时，转铁蛋白摄取率也会增加。由于锥虫转铁蛋白受体对不同物种转铁蛋白的结合亲和力不同，血清变化会导致铁饥饿。因此，转铁蛋白受体表达的调节可能是寄生虫传播到新宿主物种时的一种快速补偿机制。
