title: Distinct roles of apolipoprotein components within the trypanosome lytic factor complex revealed in a novel transgenic mouse model.
abstract: Humans express a unique subset of high-density lipoproteins (HDLs) called trypanosome lytic factors (TLFs) that kill many Trypanosoma parasite species. The proteins apolipoprotein (apo) A-I, apoL-I, and haptoglobin-related protein, which are involved in TLF structure and function, were expressed through the introduction of transgenes in mice to explore their physiological roles in vivo. Transgenic expression of human apolipoprotein L-I alone conferred trypanolytic activity in vivo. Coexpression of human apolipoprotein A-I and haptoglobin-related protein (Hpr) had an effect on the integration of apolipoprotein L-I into HDL, and both proteins were required to increase the specific activity of TLF, which was measurable in vitro. Unexpectedly, truncated apolipoprotein L-I devoid of the serum resistance gene interacting domain, which was previously shown to kill human infective trypanosomes, was not trypanolytic in transgenic mice despite being coexpressed with human apolipoprotein A-I and Hpr and incorporated into HDLs. We conclude that all three human apolipoproteins act cooperatively to achieve maximal killing capacity and that truncated apolipoprotein L-I does not function in transgenic animals.
authors.affiliation: Department of Medical Parasitology, New York University Langone Medical Center/School of Medicine, New York, NY 10010, USA.
authors.forename: Maria Pilar
authors.initials: MP
authors.lastname: Molina-Portela
authors.forename: Marie
authors.initials: M
authors.lastname: Samanovic
authors.forename: Jayne
authors.initials: J
authors.lastname: Raper
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics / Q000378:metabolism*; D001054:Apolipoproteins A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006242:Haptoglobins / Q000235:genetics / Q000378:metabolism; D006790:Host-Parasite Interactions / Q000502:physiology; D006801:Humans; D008075:Lipoproteins, HDL / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014345:Trypanosoma / Q000472:pathogenicity*; D014346:Trypanosoma brucei brucei / Q000472:pathogenicity; D014348:Trypanosoma congolense / Q000472:pathogenicity; D014352:Trypanosomiasis / Q000517:prevention & control
chemical_list: C108666:APOL1 protein, human; D000951:Antigens, Neoplasm; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D001054:Apolipoproteins A; C058632:HPR protein, human; D006242:Haptoglobins; D008075:Lipoproteins, HDL; D011994:Recombinant Proteins