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

Patricia Tebabi, Etienne Pays, David Pérez-Morga, Christophe Erneux, Geert Bultynck, Elena Levtchenko, Søren K Moestrup, Christophe Legendre, Marion Rabant, Stijn Deborggraeve, Bart Cuypers, Marc Dieu, Sophie Uzureau, Marjorie Vermeersch, Tomas Luyten, Rita M La Rovere, Ana Raquel Ramos, Fanny Oliveira Arcolino, Pepe Ekulu Mfutu, Fabrice Homblé, Jonas H Graversen, Dorle Hennig, Pierrick Uzureau, Laurence Lecordier

Journal: Cell reports 2021;30(11):3821-3836.e13

PMID: 32187552

Free Full Text on Elsevier Science View on PubMed

Abstract

["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 (APOL1\u0394) 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 Ca-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 APOL1\u0394 or APOL3KO-like phenotype, APOL1 C-terminal variants may induce kidney disease by preventing APOL3 from activating PI4KB, with consecutive actomyosin reorganization of podocytes.",{"copyright":"Copyright \u00a9 2020 The Author(s). Published by Elsevier Inc. All rights reserved."}]

Address: Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles, 6041 Gosselies, Belgium.; Laboratory of Experimental Medicine (ULB222), CHU Charleroi, Université Libre de Bruxelles, Montigny le Tilleul, Belgium.; Department of Molecular Medicine, Cancer and Inflammation Research, University of Southern Denmark, 5000 Odense C, Denmark.; Laboratory of Structure and Function of Biological Membranes, Université Libre de Bruxelles, 1050 Brussels, Belgium.; Pediatric Nephrology, University Hospital Leuven, 3000 Leuven, Belgium.; Institute of Interdisciplinary Research in Human and Molecular Biology, Campus Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium.; Laboratory of Molecular and Cellular Signalling, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.; Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles, 6041 Gosselies, Belgium.; URBC-Narilis, University of Namur, 5000 Namur, Belgium.; Biomedical Sciences Department, Institute of Tropical Medicine, 2000 Antwerpen, Belgium; Adrem Data Lab, Department of Mathematics and Computer Science, University of Antwerp, 2000 Antwerpen, Belgium.; Biomedical Sciences Department, Institute of Tropical Medicine, 2000 Antwerpen, Belgium.; Adult Nephrology-Transplantation Department, Paris Hospitals and Paris Descartes University, 75006 Paris, France.; Pathology Department, Paris Hospitals and Paris Descartes University, 75006 Paris, France.; Department of Molecular Medicine, Cancer and Inflammation Research, University of Southern Denmark, 5000 Odense C, Denmark; Department of Biomedicine, University of Aarhus, 8000 Aarhus, Denmark.; Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles, 6041 Gosselies, Belgium; Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles, 6041 Gosselies, Belgium.; Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles, 6041 Gosselies, Belgium. Electronic address: [email protected].

DOI: 10.1016/j.celrep.2020.02.064