Søren Kragh Moestrup

APOL1 C-Terminal Variants May Trigger Kidney Disease through Interference with APOL3 Control of Actomyosin

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Sophie Uzureau, Université Libre de Bruxelles
  • ,
  • Laurence Lecordier, Université Libre de Bruxelles
  • ,
  • Pierrick Uzureau, Université Libre de Bruxelles
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  • Dorle Hennig, University of Southern Denmark
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  • Jonas H. Graversen, University of Southern Denmark
  • ,
  • Fabrice Homblé, Université Libre de Bruxelles
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  • Pepe Ekulu Mfutu, Dentistry, University Hospitals, KU Leuven
  • ,
  • Fanny Oliveira Arcolino, Dentistry, University Hospitals, KU Leuven
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  • Ana Raquel Ramos, Université Libre de Bruxelles
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  • Rita M. La Rovere, Katholieke Universiteit Leuven
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  • Tomas Luyten, Katholieke Universiteit Leuven
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  • Marjorie Vermeersch, Université Libre de Bruxelles
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  • Patricia Tebabi, Université Libre de Bruxelles
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  • Marc Dieu, Fac. Notre-Dame de la Paix
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  • Bart Cuypers, Institute of Tropical Medicine Antwerp, University of Antwerp
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  • Stijn Deborggraeve, Institute of Tropical Medicine Antwerp
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  • Marion Rabant, Paris Descartes University
  • ,
  • Christophe Legendre, Paris Descartes University
  • ,
  • Søren K. Moestrup
  • Elena Levtchenko, Dentistry, University Hospitals, KU Leuven
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  • Geert Bultynck, Katholieke Universiteit Leuven
  • ,
  • Christophe Erneux, Université Libre de Bruxelles
  • ,
  • David Pérez-Morga, Université Libre de Bruxelles
  • ,
  • Etienne Pays, Université Libre de Bruxelles

The C-terminal variants G1 and G2 of apolipoprotein L1 (APOL1) confer human resistance to the sleeping sickness parasite Trypanosoma rhodesiense, but they also increase the risk of kidney disease. APOL1 and APOL3 are death-promoting proteins that are partially associated with the endoplasmic reticulum and Golgi membranes. We report that in podocytes, either APOL1 C-terminal helix truncation (APOL1Δ) or APOL3 deletion (APOL3KO) induces similar actomyosin reorganization linked to the inhibition of phosphatidylinositol-4-phosphate [PI(4)P] synthesis by the Golgi PI(4)-kinase IIIB (PI4KB). Both APOL1 and APOL3 can form K+ channels, but only APOL3 exhibits Ca2+-dependent binding of high affinity to neuronal calcium sensor-1 (NCS-1), promoting NCS-1-PI4KB interaction and stimulating PI4KB activity. Alteration of the APOL1 C-terminal helix triggers APOL1 unfolding and increased binding to APOL3, affecting APOL3-NCS-1 interaction. Since the podocytes of G1 and G2 patients exhibit an APOL1Δ or APOL3KO-like phenotype, APOL1 C-terminal variants may induce kidney disease by preventing APOL3 from activating PI4KB, with consecutive actomyosin reorganization of podocytes.

Original languageEnglish
JournalCell Reports
Volume30
Issue11
Pages (from-to)3821-3836.e13
Number of pages16
ISSN2211-1247
DOIs
Publication statusPublished - 17 Mar 2020

    Research areas

  • actomyosin cytoskeleton, APOL1, APOL3, kidney disease, MYH9, NCS-1, phosphoinositide control, PI4KB, sleeping sickness

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