Distinct roles of haptoglobin-related protein and apolipoprotein L-1 in trypanolysis by human serum
Distinct roles of haptoglobin-related protein and apolipoprotein L-1 in trypanolysis by human serum
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DOI：
10.1073/pnas.0609902104
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发表时间：
2007-03-06
影响因子：
11.1
通讯作者：
Pays, Etienne
中科院分区：
文献类型：
--
作者：
Vanhollebeke, Benoit;Nielsen, Marianne J.;Pays, Etienne
载脂蛋白L-I （apoli）是一种人类高密度脂蛋白（HDL）成分，能够通过在寄生虫的溶酶体膜上形成阴离子选择性孔来杀死布氏锥虫。另一种HDL成分，触珠蛋白相关蛋白（Hpr），已被认为是正常人血清充分发挥锥虫酶活性所需的额外毒素。我们最近报道了由于两个apoli等位基因的移码突变而导致人类缺乏apoli - 1 （apoli -/- hs）的病例。在这里，我们显示这种血清，缺乏任何锥虫酶活性，显示正常浓度的hdl结合Hpr。相反，具有正常hdl结合的pol - 1，但由于基因缺失而缺乏Hpr和触珠蛋白[Hp(r)-/- hs]的个体（无触珠蛋白血症）的血清表现出表型正常但延迟的锥虫水解活性。Hp(r)-/- hs对锥虫的降解作用可通过重组pol - 1进行模拟，而重组Hpr对锥虫没有影响。用Hp(r)-/- hs或重组pol - 1观察到的裂解延迟可以完全归因于裂解组分摄取的缺陷。因此，pol - 1负责正常人类血清的锥虫分解活性，而Hpr允许载体HDL颗粒的快速摄取，可能是通过它们与寄生虫的Hp/Hpr表面受体的结合。
Apolipoprotein L-I (apoL-I) is a human high-density lipoprotein (HDL) component able to kill Trypanosoma brucei brucei by forming anion-selective pores in the lysosomal membrane of the parasite. Another HDL component, haptoglobin-related protein (Hpr), has been suggested as an additional toxin required for full trypanolytic activity of normal human serum. We recently reported the case of a human lacking apoL-I (apoL-I-/-HS) as the result of frameshift mutations in both apoL-I alleles. Here, we show that this serum, devoid of any trypanolytic activity, exhibits normal concentrations of HDL-bound Hpr. Conversely, the serum of individuals with normal HDL-bound apoL-I but who lack Hpr and haptoglobin [Hp(r)-/-HS] as the result of gene deletion (anhaptoglobinemia) exhibited phenotypically normal but delayed trypanolytic activity. The trypanolytic properties of Hp(r)-/-HS were mimicked by free recombinant apoL-I, whereas recombinant Hpr did not affect trypanosomes. The lysis delay observed with either Hp(r)-/-HS or recombinant apoL-I could entirely be attributed to a defect in the uptake of the lytic components. Thus, apoL-I is responsible for the trypanolytic activity of normal human serum, whereas Hpr allows fast uptake of the carrier HDL particles, presumably through their binding to an Hp/Hpr surface receptor of the parasite.