Apolipoprotein L-I Promotes Trypanosome Lysis by Forming Pores in Lysosomal Membranes

Abstract

Apolipoprotein L-I is the trypanolytic factor of human serum. Here we show that this protein contains a membrane pore-forming domain functionally similar to that of bacterial colicins, flanked by a membrane-addressing domain. In lipid bilayer membranes, apolipoprotein L-I formed anion channels. In Trypanosoma brucei, apolipoprotein L-I was targeted to the lysosomal membrane and triggered depolarization of this membrane, continuous influx of chloride, and subsequent osmotic swelling of the lysosome until the trypanosome lysed.

Sequence variation and structural conservation allows development of novel function and immune evasion in parasite surface protein families

“…TLFs are large lipoprotein complexes that contain the pore forming toxin, ApoLI 23. If taken up into the lysosome, ApoLI causes lysosomal swelling and cell death 24. Two trypanosome subspecies, T. b. rhodesiense and T. b. gambiense are able to infect humans by resisting the effects of TLFs.…”

L’histoire controversée du facteur trypanolytique humain

“…De plus, l'étude détaillée de l'apoL1 établit que cette protéine est le facteur trypanolytique tant recherché [7]. L'apoL1 tue le trypanosome par gonflement osmotique du lysosome résultant de l'activité formatrice de pores anioniques par cette protéine [8]. …”

In Vitro Generation of Human High-Density-Lipoprotein-Resistant Trypanosoma brucei brucei

“…It now appears that Hpr and apoL-I both have trypanosome-killing activity and that the assembly of these proteins into the same HDL particle is synergistic, resulting in a naturally occurring supercomplex with enhanced activity compared with that of HDLs lacking either Hpr or apoL-I (57). The biochemical mechanism of TLF killing of T. b. brucei also continues to be debated (4,36,37,45). However, there is good agreement that trypanosome killing by TLF follows a pathway beginning with high-affinity binding to a receptor in the flagellar pocket of the trypanosome, followed by endocytosis and localization to the lysosome.…”

“…Initially, Hpr was suggested to be the active component in TLF, based on the evolution of the Hpr gene during primate evolution, the correlation of the trypanolytic activity in primate sera, and the presence of the Hpr gene in T. b. brucei-resistant animals (33,56,59). More recently, highly purified, recombinant apoL-I has been shown to have trypanosome-killing activity (45,69). It now appears that Hpr and apoL-I both have trypanosome-killing activity and that the assembly of these proteins into the same HDL particle is synergistic, resulting in a naturally occurring supercomplex with enhanced activity compared with that of HDLs lacking either Hpr or apoL-I (57).…”

“…This innate protection is provided by trypanolytic activity found in normal human blood and also in the blood of most apes and Old World monkeys (24,31,46,56). The trypanosome lytic factor (TLF) is a minor subfraction of heterogeneous human high-density lipoprotein (HDL) particles containing apoliprotein A-I (apoA-I), apoliprotein A-II (apoA-II), apolipoprotein L-I (apoL-I), and haptoglobin-related protein (Hpr) (23,29,38,45,48,49,50,51,52,57,59,60,64,65,69). The mechanism of TLF killing of T. b. brucei has been controversial.…”