@article{ba88ca2f45334b008e8737e98b0b6744,
title = "APOL1 C-Terminal Variants May Trigger Kidney Disease through Interference with APOL3 Control of Actomyosin",
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 (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.",
keywords = "actomyosin cytoskeleton, APOL1, APOL3, kidney disease, MYH9, NCS-1, phosphoinositide control, PI4KB, sleeping sickness",
author = "Sophie Uzureau and Laurence Lecordier and Pierrick Uzureau and Dorle Hennig and Graversen, {Jonas H} and Fabrice Hombl{\'e} and Mfutu, {Pepe Ekulu} and {Oliveira Arcolino}, Fanny and Ramos, {Ana Raquel} and {La Rovere}, {Rita M} and Tomas Luyten and Marjorie Vermeersch and Patricia Tebabi and Marc Dieu and Bart Cuypers and Stijn Deborggraeve and Marion Rabant and Christophe Legendre and Moestrup, {S{\o}ren K} and Elena Levtchenko and Geert Bultynck and Christophe Erneux and David P{\'e}rez-Morga and Etienne Pays",
note = "Funding Information: We acknowledge M.A. Saleem (University of Bristol, UK), J.B. Kopp (NIH, USA), M. Deleu (University of Gembloux, Belgium), L. van den Heuvel (University of Leuven, Belgium), M.A. Elmonem (University of Leuven, Belgium and University of Cairo, Egypt), and V. Martens (University of Brussels, Belgium) for providing the original podocyte cell line, G0/G0 and G1/G2 urinary podocytes, PI(4)P-containing liposomes, and help in generating and cultivating podocyte lines. This work was supported by the European Research Council (ERC) grant 669007-APOLs (to E.P.), grant 11O1614N from the Research Foundation Flanders (to B.C.), and grants J.0078.18 and J.0091.17 from the Belgian Fonds de la Recherche Scientifique (FRS) (to C.E. and D.P.-M. respectively). S.U. is Charg{\'e} de Recherche FRS, and F.H. is Directeur de Recherche FRS. A.R.R. is supported by a T{\'e}l{\'e}vie fellowship. The CMMI is supported by the European Regional Development Fund and the Walloon Region. Computational resources were provided by the Flemish Supercomputer Center at the University of Antwerp (CalcUA). E.P. and S.U. conceived the work; S.U. L.L. P.U. D.H. J.H.G. F.H. P.E.M. F.O.A. A.R.R. R.M.L.R. T.L. M.V. P.T. M.D. and M.R. performed the experiments and/or the generation of cell lines or tissue samples; B.C. and S.D. analyzed the DNA of the different cell lines; S.U. C.L. S.K.M. E.L. G.B. C.E. D.P.-M. and E.P. supervised different aspects of the experimental plan; E.P. and S.U. wrote the paper. The authors declare no competing interests. Funding Information: We acknowledge M.A. Saleem (University of Bristol, UK), J.B. Kopp (NIH, USA), M. Deleu (University of Gembloux, Belgium), L. van den Heuvel (University of Leuven, Belgium), M.A. Elmonem (University of Leuven, Belgium and University of Cairo, Egypt), and V. Martens (University of Brussels, Belgium) for providing the original podocyte cell line, G0/G0 and G1/G2 urinary podocytes, PI(4)P-containing liposomes, and help in generating and cultivating podocyte lines. This work was supported by the European Research Council (ERC) grant 669007-APOLs (to E.P.), grant 11O1614N from the Research Foundation Flanders (to B.C.), and grants J.0078.18 and J.0091.17 from the Belgian Fonds de la Recherche Scientifique (FRS) (to C.E. and D.P.-M., respectively). S.U. is Charg{\'e} de Recherche FRS, and F.H. is Directeur de Recherche FRS. A.R.R. is supported by a T{\'e}l{\'e}vie fellowship . The CMMI is supported by the European Regional Development Fund and the Walloon Region . Computational resources were provided by the Flemish Supercomputer Center at the University of Antwerp (CalcUA). Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = mar,
day = "17",
doi = "10.1016/j.celrep.2020.02.064",
language = "English",
volume = "30",
pages = "3821--3836.e13",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",
}
