title: Coupling of lysosomal and mitochondrial membrane permeabilization in trypanolysis by APOL1.
abstract: Humans resist infection by the African parasite Trypanosoma brucei owing to the trypanolytic activity of the serum apolipoprotein L1 (APOL1). Following uptake by endocytosis in the parasite, APOL1 forms pores in endolysosomal membranes and triggers lysosome swelling. Here we show that APOL1 induces both lysosomal and mitochondrial membrane permeabilization (LMP and MMP). Trypanolysis coincides with MMP and consecutive release of the mitochondrial TbEndoG endonuclease to the nucleus. APOL1 is associated with the kinesin TbKIFC1, of which both the motor and vesicular trafficking VHS domains are required for MMP, but not for LMP. The presence of APOL1 in the mitochondrion is accompanied by mitochondrial membrane fenestration, which can be mimicked by knockdown of a mitochondrial mitofusin-like protein (TbMFNL). The BH3-like peptide of APOL1 is required for LMP, MMP and trypanolysis. Thus, trypanolysis by APOL1 is linked to apoptosis-like MMP occurring together with TbKIFC1-mediated transport of APOL1 from endolysosomal membranes to the mitochondrion.
authors: Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles (ULB), 12 rue des Prof Jeener et Brachet, B-6041 Gosselies, Belgium.
authors: Gilles
authors: G
authors: Vanwalleghem
authors: Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles (ULB), 12 rue des Prof Jeener et Brachet, B-6041 Gosselies, Belgium.
authors: Frédéric
authors: F
authors: Fontaine
authors: Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles (ULB), 12 rue des Prof Jeener et Brachet, B-6041 Gosselies, Belgium.
authors: Laurence
authors: L
authors: Lecordier
authors: Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles (ULB), 12 rue des Prof Jeener et Brachet, B-6041 Gosselies, Belgium.
authors: Patricia
authors: P
authors: Tebabi
authors: Institute of Biochemistry and Pathobiochemistry, Ruhr-Universität Bochum, Universitätsstrasse 150, 44780 Bochum, Germany.
authors: Kristoffer
authors: K
authors: Klewe
authors: Molecular Parasitology Group, School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland.
authors: Derek P
authors: DP
authors: Nolan
authors: Apicolipid Group, CNRS, Laboratoire Adaptation et Pathogénie des Microorganismes UMR5163/ Institut Albert Bonniot CRI Inserm/UJF U823, CNRS, Institut Jean Roget, 38700 La Tronche, France.
authors: Yoshiki
authors: Y
authors: Yamaryo-Botté
authors: Apicolipid Group, CNRS, Laboratoire Adaptation et Pathogénie des Microorganismes UMR5163/ Institut Albert Bonniot CRI Inserm/UJF U823, CNRS, Institut Jean Roget, 38700 La Tronche, France.
authors: Cyrille
authors: C
authors: Botté
authors: IRC/VIB Bio Imaging Core, Gent, Technologiepark 927, B-9052 Gent, Belgium.
authors: Anneke
authors: A
authors: Kremer
authors: Institute of Cell Biology, University of Bern, Baltzerstrasse 4, CH-3012 Bern, Switzerland.
authors: Gabriela Schumann
authors: GS
authors: Burkard
authors: Institute of Biochemistry and Pathobiochemistry, Ruhr-Universität Bochum, Universitätsstrasse 150, 44780 Bochum, Germany.
authors: Joachim
authors: J
authors: Rassow
authors: Institute of Cell Biology, University of Bern, Baltzerstrasse 4, CH-3012 Bern, Switzerland.
authors: Isabel
authors: I
authors: Roditi
authors: Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles (ULB), 12 rue des Prof Jeener et Brachet, B-6041 Gosselies, Belgium.|Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles (ULB), 8 rue Adrienne Bolland, B-6041 Gosselies, Belgium.
authors: David
authors: D
authors: Pérez-Morga
authors: Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles (ULB), 12 rue des Prof Jeener et Brachet, B-6041 Gosselies, Belgium.|Walloon Excellence in Life sciences and Biotechnology (WELBIO), Wavre, Belgium.
authors: Etienne
authors: E
authors: Pays
mesh_terms: D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000378:metabolism*; D017209:Apoptosis; D001692:Biological Transport; D004705:Endocytosis; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D016547:Kinesins / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D010539:Permeability; D015800:Protozoan Proteins / Q000378:metabolism*; D014346:Trypanosoma brucei brucei / Q000378:metabolism / Q000472:pathogenicity; D014347:Trypanosoma brucei gambiense / Q000378:metabolism / Q000472:pathogenicity; D016833:Trypanosoma brucei rhodesiense / Q000378:metabolism / Q000472:pathogenicity
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; C445315:KIFC1 protein, Trypanosoma brucei; D008075:Lipoproteins, HDL; D015800:Protozoan Proteins; D016547:Kinesins