Vanhollebeke Benoit, Nielsen Marianne J, Watanabe Yoshihisa, Truc Philippe, Vanhamme Luc, Nakajima Kazunori, Moestrup Soren K, Pays Etienne
Laboratory of Molecular Parasitology, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, 12 Rue des Profs Jeener et Brachet, B6041 Gosselies, Belgium.
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4118-23. doi: 10.1073/pnas.0609902104. Epub 2007 Feb 26.
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.
载脂蛋白L-I（apoL-I）是一种人类高密度脂蛋白（HDL）成分，能够通过在布氏锥虫溶酶体膜上形成阴离子选择性孔道来杀死布氏锥虫。另一种HDL成分，触珠蛋白相关蛋白（Hpr），被认为是正常人血清完全发挥锥虫溶解活性所需的另一种毒素。我们最近报道了一名由于apoL-I两个等位基因发生移码突变而缺乏apoL-I的人（apoL-I(-/-)HS）的病例。在此，我们表明这种缺乏任何锥虫溶解活性的血清中，HDL结合的Hpr浓度正常。相反，由于基因缺失（无触珠蛋白血症）而缺乏Hpr和触珠蛋白[Hp(r)(-/-)HS]但HDL结合的apoL-I正常的个体血清，其锥虫溶解活性在表型上正常但延迟。游离重组apoL-I模拟了Hp(r)(-/-)HS的锥虫溶解特性，而重组Hpr对锥虫没有影响。用Hp(r)(-/-)HS或重组apoL-I观察到的裂解延迟完全可归因于裂解成分摄取的缺陷。因此，apoL-I负责正常人血清的锥虫溶解活性，而Hpr可能通过其与寄生虫的Hp/Hpr表面受体结合，使载体HDL颗粒快速摄取。
