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Distinct roles of haptoglobin-related protein and apolipoprotein L-I in trypanolysis by human serum.

par Vanhollebeke, Benoît ;Nielsen, Marianne J;Watanabe, Yoshihisa;Truc, Philippe;Vanhamme, Luc ;Nakajima, Kazunori;Moestrup, Soren K;Pays, Etienne
Référence Proceedings of the National Academy of Sciences of the United States of America, 104, 10, page (4118-4123)
Publication Publié, 2007-03

Article révisé par les pairs

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Résumé :

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.