期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：9
页码：2894-2899
DOI：10.1073/pnas.1421953112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceAfrican trypanosomes are parasites that can cause African sleeping sickness in humans. Host defense against some of these is provided by the human serum factor apolipoprotein L-1 (APOL1), which causes swelling and lysis of susceptible trypanosomes. Lysis follows uptake of APOL1 into acidic parasite endosomes and is thought to involve ion influx across the plasma membrane. In this paper we show that, after interaction of APOL1 with lipid bilayers at acidic pH, subsequent pH neutralization triggers the opening of pH-gated channels that selectively conduct cations across the bilayer. Based on these results, we propose a mechanism of trypanosome lysis that involves endocytic recycling of APOL1 and the opening of APOL1-induced cation-selective channels, at neutral pH, in the parasite plasma membrane. Apolipoprotein L-1 (APOL1), the trypanolytic factor of human serum, can lyse several African trypanosome species including Trypanosoma brucei brucei, but not the human-infective pathogens T. brucei rhodesiense and T. brucei gambiense, which are resistant to lysis by human serum. Lysis follows the uptake of APOL1 into acidic endosomes and is apparently caused by colloid-osmotic swelling due to an increased ion permeability of the plasma membrane. Here we demonstrate that nanogram quantities of full-length recombinant APOL1 induce ideally cation-selective macroscopic conductances in planar lipid bilayers. The conductances were highly sensitive to pH: their induction required acidic pH (pH 5.3), but their magnitude could be increased 3,000-fold upon alkalinization of the milieu (pKa = 7.1). We show that this phenomenon can be attributed to the association of APOL1 with the bilayer at acidic pH, followed by the opening of APOL1-induced cation-selective channels upon pH neutralization. Furthermore, the conductance increase at neutral pH (but not membrane association at acidic pH) was prevented by the interaction of APOL1 with the serum resistance-associated protein, which is produced by T. brucei rhodesiense and prevents trypanosome lysis by APOL1. These data are consistent with a model of lysis that involves endocytic recycling of APOL1 and the formation of cation-selective channels, at neutral pH, in the parasite plasma membrane.
