Endocytosis of a cytotoxic human high density lipoprotein results in disruption of acidic intracellular vesicles and subsequent killing of African trypanosomes.
The host range of Trypanosoma brucei brucei is restricted by the cytolytic effects of human serum high-density lipoprotein (HDL). The lytic activity is caused by a minor subclass of human serum HDL called trypanosome lytic factor (TLF). TLF binds in the flagellar pocket to specific TLF-binding sites. Internalization and localization of TLF to a population of endocytic vesicles, and ultimately large lysosome-like vesicles, precedes lysis of T. b. brucei. The membranes of these large vesicles are disrupted by the accumulation of TLF particles. Inhibitor studies with lysosomotropic amines have shown these large vesicles to be acidic in nature and that prevention of their rupture spares the cells from TLF-mediated lysis. Furthermore, leupeptin inhibition suggests that a thioprotease may be involved in the mechanism of TLF-mediated lysis of T. b. brucei. Based on these results, we propose a lytic mechanism involving cell surface binding, endocytosis and lysosomal targeting. This is followed by lysosomal disruption and subsequent autodigestion of the cell.
Hager
K M
KM
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, School of Medicine 35294.
Pierce
M A
MA
Moore
D R
DR
Tytler
E M
EM
Esko
J D
JD
Hajduk
S L
SL
D000143:Acids / Q000494:pharmacology; D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D002738:Chloroquine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D005407:Flagella / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D007425:Intracellular Membranes / Q000187:drug effects*; D007976:Leupeptins / Q000494:pharmacology; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016253:Microscopy, Immunoelectron; D008954:Models, Biological; D008985:Monensin / Q000494:pharmacology; D015388:Organelles / Q000187:drug effects*; D011485:Protein Binding; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure
D000143:Acids; D007976:Leupeptins; D008075:Lipoproteins, HDL; D000643:Ammonium Chloride; D002738:Chloroquine; D008985:Monensin; C032854:leupeptin