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Coupling of lysosomal and mitochondrial membrane permeabilization in trypanolysis by APOL1

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DOI

  • Gilles Vanwalleghem
  • Frédéric Fontaine, Université Libre de Bruxelles
  • ,
  • Laurence Lecordier, Université Libre de Bruxelles
  • ,
  • Patricia Tebabi, Université Libre de Bruxelles
  • ,
  • Kristoffer Klewe, Ruhr University Bochum
  • ,
  • Derek P. Nolan, Trinity College Dublin
  • ,
  • Yoshiki Yamaryo-Botté, Institut Albert Bonniot CRI Inserm/UJF U823
  • ,
  • Cyrille Botté, Institut Albert Bonniot CRI Inserm/UJF U823
  • ,
  • Anneke Kremer, Gent
  • ,
  • Gabriela Schumann Burkard, University of Bern
  • ,
  • Joachim Rassow, Ruhr University Bochum
  • ,
  • Isabel Roditi, University of Bern
  • ,
  • David Pérez-Morga, Université Libre de Bruxelles
  • ,
  • Etienne Pays, Université Libre de Bruxelles, Walloon Excellence in Life Sciences and Biotechnology (WELBIO)

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.

Original languageEnglish
Article number8078
JournalNature Communications
Volume6
ISSN2041-1723
DOIs
Publication statusPublished - 26 Aug 2015
Externally publishedYes

Bibliographical note

Funding Information:
We thank T. Baltz (Bordeaux), S. Gannavaram (Bethesda), A. Schneider (Bern), M. Parsons (Seattle) and J. Lukes (Ceské Budejovice) for the gift of plasmids and/or antibodies, A. Van Acker and M. Stefkova (Gosselies) for production of the H3 monoclonal, E. Maréchal (Grenoble) for providing a data set and Chris Guerin (IRC/VIB Gent) for FIB–SEM assistance. This work was supported by the Belgian Fund for Scientific Research (FRSM), the Walloon WELBIO excellence programme and the Interuniversity Attraction Poles Programme—Belgian Science Policy. The CMMI is supported by the European Regional Development Fund and Wallonia. The Auriga FIB–SEM at the VIB was obtained through a special grant from the government of Flanders. I.R. and G.S.B. were supported by grants from the Velux Foundation and HHMI. Y.Y.-B. and C.B. are supported by Agence Nationale de la Recherche, Atip-Avenir-Finovi CNRS Inserm (Apicolipid project).

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