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

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

doi:10.1016/j.celrep.2020.02.064

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

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

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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.

Original language	English
Pages (from-to)	3821-3836.e13
Journal	Cell Reports
Volume	30
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2020.02.064
Publication status	Published - 17 Mar 2020

Funding

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\u00E9 de Recherche FRS, and F.H. is Directeur de Recherche FRS. A.R.R. is supported by a T\u00E9l\u00E9vie 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. 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\u00E9 de Recherche FRS, and F.H. is Directeur de Recherche FRS. A.R.R. is supported by a T\u00E9l\u00E9vie 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).

Funders	Funder number
Waalse Gewest
KULeuven
CalcUA
University of Bristol, UK)
University of Leuven, Belgium and University of Cairo
Universiteit Antwerpen
European Regional Development Fund
University of Brussels	G0/G0
Horizon 2020 Framework Programme	669007
European Research Council	11O1614N
Fonds Wetenschappelijk Onderzoek	J.0078.18

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2020.02.064

2020_DieuM_articleFinal published version, 5.86 MBLicence: CC BY-NC-ND

Cite this

Uzureau, S., Lecordier, L., Uzureau, P., Hennig, D., Graversen, J. H., Homblé, F., Mfutu, P. E., Oliveira Arcolino, F., Ramos, A. R., La Rovere, R. M., Luyten, T., Vermeersch, M., Tebabi, P., Dieu, M., Cuypers, B., Deborggraeve, S., Rabant, M., Legendre, C., Moestrup, S. K., ... Pays, E. (2020). APOL1 C-Terminal Variants May Trigger Kidney Disease through Interference with APOL3 Control of Actomyosin. Cell Reports, 30(11), 3821-3836.e13. https://doi.org/10.1016/j.celrep.2020.02.064

@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",

}

Uzureau, S, Lecordier, L, Uzureau, P, Hennig, D, Graversen, JH, Homblé, F, Mfutu, PE, Oliveira Arcolino, F, Ramos, AR, La Rovere, RM, Luyten, T, Vermeersch, M, Tebabi, P, Dieu, M, Cuypers, B, Deborggraeve, S, Rabant, M, Legendre, C, Moestrup, SK, Levtchenko, E, Bultynck, G, Erneux, C, Pérez-Morga, D & Pays, E 2020, 'APOL1 C-Terminal Variants May Trigger Kidney Disease through Interference with APOL3 Control of Actomyosin', Cell Reports, vol. 30, no. 11, pp. 3821-3836.e13. https://doi.org/10.1016/j.celrep.2020.02.064

TY - JOUR

T1 - APOL1 C-Terminal Variants May Trigger Kidney Disease through Interference with APOL3 Control of Actomyosin

AU - Uzureau, Sophie

AU - Lecordier, Laurence

AU - Uzureau, Pierrick

AU - Hennig, Dorle

AU - Graversen, Jonas H

AU - Homblé, Fabrice

AU - Mfutu, Pepe Ekulu

AU - Oliveira Arcolino, Fanny

AU - Ramos, Ana Raquel

AU - La Rovere, Rita M

AU - Luyten, Tomas

AU - Vermeersch, Marjorie

AU - Tebabi, Patricia

AU - Dieu, Marc

AU - Cuypers, Bart

AU - Deborggraeve, Stijn

AU - Rabant, Marion

AU - Legendre, Christophe

AU - Moestrup, Søren K

AU - Levtchenko, Elena

AU - Bultynck, Geert

AU - Erneux, Christophe

AU - Pérez-Morga, David

AU - Pays, Etienne

N1 - 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 Chargé de Recherche FRS, and F.H. is Directeur de Recherche FRS. A.R.R. is supported by a Télévie 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 Chargé de Recherche FRS, and F.H. is Directeur de Recherche FRS. A.R.R. is supported by a Télévie 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: © 2020 The Author(s)

PY - 2020/3/17

Y1 - 2020/3/17

N2 - 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.

AB - 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.

KW - actomyosin cytoskeleton

KW - APOL1

KW - APOL3

KW - kidney disease

KW - MYH9

KW - NCS-1

KW - phosphoinositide control

KW - PI4KB

KW - sleeping sickness

UR - http://www.scopus.com/inward/record.url?scp=85081645033&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2020.02.064

DO - 10.1016/j.celrep.2020.02.064

M3 - Article

C2 - 32187552

SN - 2211-1247

VL - 30

SP - 3821-3836.e13

JO - Cell Reports

JF - Cell Reports

IS - 11

ER -

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

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Keywords

UN SDGs

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