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

Research output: Contribution to journal › Article

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

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Uzureau, S., Lecordier, L., Uzureau, P., Hennig, D., Graversen, J. H., Homblé, F., ... 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

Uzureau, Sophie ; Lecordier, Laurence ; Uzureau, Pierrick ; Hennig, Dorle ; Graversen, Jonas H ; Homblé, Fabrice ; Mfutu, Pepe Ekulu ; Oliveira Arcolino, Fanny ; Ramos, Ana Raquel ; La Rovere, Rita M ; Luyten, Tomas ; Vermeersch, Marjorie ; Tebabi, Patricia ; Dieu, Marc ; Cuypers, Bart ; Deborggraeve, Stijn ; Rabant, Marion ; Legendre, Christophe ; Moestrup, Søren K ; Levtchenko, Elena ; Bultynck, Geert ; Erneux, Christophe ; Pérez-Morga, David ; Pays, Etienne. / APOL1 C-Terminal Variants May Trigger Kidney Disease through Interference with APOL3 Control of Actomyosin. In: Cell Reports. 2020 ; Vol. 30, No. 11. pp. 3821-3836.e13.

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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.",

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",

year = "2020",

month = "3",

day = "17",

doi = "10.1016/j.celrep.2020.02.064",

language = "English",

volume = "30",

pages = "3821--3836.e13",

journal = "Cell Reports",

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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

APOL1 C-Terminal Variants May Trigger Kidney Disease through Interference with APOL3 Control of Actomyosin. / Uzureau, Sophie; Lecordier, Laurence; Uzureau, Pierrick; Hennig, Dorle; Graversen, Jonas H; Homblé, Fabrice; Mfutu, Pepe Ekulu; Oliveira Arcolino, Fanny; Ramos, Ana Raquel; La Rovere, Rita M; Luyten, Tomas; Vermeersch, Marjorie; Tebabi, Patricia; Dieu, Marc; Cuypers, Bart; Deborggraeve, Stijn; Rabant, Marion; Legendre, Christophe; Moestrup, Søren K; Levtchenko, Elena; Bultynck, Geert; Erneux, Christophe; Pérez-Morga, David; Pays, Etienne.

In: Cell Reports, Vol. 30, No. 11, 17.03.2020, p. 3821-3836.e13.

Research output: Contribution to journal › Article

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

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.

U2 - 10.1016/j.celrep.2020.02.064

DO - 10.1016/j.celrep.2020.02.064

M3 - Article

C2 - 32187552

VL - 30

SP - 3821-3836.e13

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 11

ER -

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