The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier

Christoph Schell; Manuel Rogg; Martina Suhm; Martin Helmstädter; Dominik Sellung; Mako Yasuda-Yamahara; Oliver Kretz; Victoria Küttner; Hani Suleiman; Laxmikanth Kollipara; René P. Zahedi; Albert Sickmann; Stefan Eimer; Andrey S. Shaw; Albrecht Kramer-Zucker; Mariko Hirano-Kobayashi; Takaya Abe; Shinichi Aizawa; Florian Grahammer; Björn Hartleben; Jörn Dengjel; Tobias B. Huber

doi:10.1073/pnas.1617004114

The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier

Christoph Schell, Manuel Rogg, Martina Suhm, Martin Helmstädter, Dominik Sellung, Mako Yasuda-Yamahara, Oliver Kretz, Victoria Küttner, Hani Suleiman, Laxmikanth Kollipara, René P. Zahedi, Albert Sickmann, Stefan Eimer, Andrey S. Shaw, Albrecht Kramer-Zucker, Mariko Hirano-Kobayashi, Takaya Abe, Shinichi Aizawa, Florian Grahammer, Björn HartlebenJörn Dengjel, Tobias B. Huber^*

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

50 Citations (Scopus)

Abstract

Podocytes form the outer part of the glomerular filter, where they have to withstand enormous transcapillary filtration forces driving glomerular filtration. Detachment of podocytes from the glomerular basement membrane precedes most glomerular diseases. However, little is known about the regulation of podocyte adhesion in vivo. Thus, we systematically screened for podocyte-specific focal adhesome (FA) components, using genetic reporter models in combination with iTRAQ-based mass spectrometry. This approach led to the identification of FERM domain protein EPB41L5 as a highly enriched podocyte-specific FA component in vivo. Genetic deletion of Epb41l5 resulted in severe proteinuria, detachment of podocytes, and development of focal segmental glomerulosclerosis. Remarkably, by binding and recruiting the RhoGEF ARGHEF18 to the leading edge, EPB41L5 directly controls actomyosin contractility and subsequent maturation of focal adhesions, cell spreading, and migration. Furthermore, EPB41L5 controls matrixdependent outside-in signaling by regulating the focal adhesome composition. Thus, by linking extracellular matrix sensing and signaling, focal adhesion maturation, and actomyosin activation EPB41L5 ensures the mechanical stability required for podocytes at the kidney filtration barrier. Finally, a diminution of EPB41L5-dependent signaling programs appears to be a common theme of podocyte disease, and therefore offers unexpected interventional therapeutic strategies to prevent podocyte loss and kidney disease progression.

Original language	English
Pages (from-to)	E4621-E4630
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	23
Early online date	23 May 2017
DOIs	https://doi.org/10.1073/pnas.1617004114
Publication status	Published - 6 Jun 2017

Bibliographical note

Acknowledgments
We thank Charlotte Meyer, Christina Engel, Betina Kiefer, Barbara Joch, Helga Schachner, and Elisabeth Wiesner for expert technical assistance. In addition, we would like to express our gratitude to all members of our laboratories for helpful discussions and support, especially Ketan Patel for carefully reading the manuscript. We would also like to thank Ronald Roepman for generously providing antibodies and serum against EPB41L5. We thank Cristina Has for providing ITGalpha2 antibodies. This study was supported by the German Research Foundation: collaborative research centers (CRC) 1140 (to T.B.H. and F.G.) and CRC 992 (to T.B.H.), Heisenberg program (T.B.H.), HU 1016/5-1 and HU 1016/8-1 (to T.B.H.); by the European Research Council (T.B.H.), and by the H2020-IMI2 consortium Biomarker Enterprise to Attack Diabetic Kidney Disease (BEAt-DKD) (115974 to T.B.H.); by the Bundesministerium für Bildung und Forschung, STOP Fokale Segmentale Glomerulosklerose (BMBF-STOP-FSGS) 01GM1518C (T.B.H.); by the Excellence Initiative of the German Federal and State Governments (GSC-4, Spemann Graduate School, C.S. and T.B.H.; BIOSS, T.B.H.; and the Freiburg Institute for Advanced Studies, T.B.H. and J.D.); by the Else Kröner Fresenius Stiftung, Nierenfunktionsstörungen als Komplikation von Systemerkrankungen (NAKSYS) (C.S., M.R., and T.B.H.) and Molekulare und Translationale Forschung in Freiburg – Verantwortungsvolle Ausbildung Tatkräftige Ermutigung (MOTIVATE) (D.S.); by the German Society of Nephrology (C.S.); and we gratefully acknowledge the financial support from the Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen, the Senatsverwaltung für Wirtschaft, Technologie und Forschung des Landes Berlin, and the Bundesministerium für Bildung und Forschung (to L.K., R.P.Z., and A.S.).

Keywords

Actomyosin
Focal adhesion
FSGS
Podocyte

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10.1073/pnas.1617004114

Cite this

Schell, C., Rogg, M., Suhm, M., Helmstädter, M., Sellung, D., Yasuda-Yamahara, M., Kretz, O., Küttner, V., Suleiman, H., Kollipara, L., Zahedi, R. P., Sickmann, A., Eimer, S., Shaw, A. S., Kramer-Zucker, A., Hirano-Kobayashi, M., Abe, T., Aizawa, S., Grahammer, F., ... Huber, T. B. (2017). The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier. Proceedings of the National Academy of Sciences of the United States of America, 114(23), E4621-E4630. https://doi.org/10.1073/pnas.1617004114

The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier. / Schell, Christoph; Rogg, Manuel; Suhm, Martina et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 23, 06.06.2017, p. E4621-E4630.

Research output: Contribution to journal › Article › peer-review

Schell, C, Rogg, M, Suhm, M, Helmstädter, M, Sellung, D, Yasuda-Yamahara, M, Kretz, O, Küttner, V, Suleiman, H, Kollipara, L, Zahedi, RP, Sickmann, A, Eimer, S, Shaw, AS, Kramer-Zucker, A, Hirano-Kobayashi, M, Abe, T, Aizawa, S, Grahammer, F, Hartleben, B, Dengjel, J & Huber, TB 2017, 'The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 23, pp. E4621-E4630. https://doi.org/10.1073/pnas.1617004114

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abstract = "Podocytes form the outer part of the glomerular filter, where they have to withstand enormous transcapillary filtration forces driving glomerular filtration. Detachment of podocytes from the glomerular basement membrane precedes most glomerular diseases. However, little is known about the regulation of podocyte adhesion in vivo. Thus, we systematically screened for podocyte-specific focal adhesome (FA) components, using genetic reporter models in combination with iTRAQ-based mass spectrometry. This approach led to the identification of FERM domain protein EPB41L5 as a highly enriched podocyte-specific FA component in vivo. Genetic deletion of Epb41l5 resulted in severe proteinuria, detachment of podocytes, and development of focal segmental glomerulosclerosis. Remarkably, by binding and recruiting the RhoGEF ARGHEF18 to the leading edge, EPB41L5 directly controls actomyosin contractility and subsequent maturation of focal adhesions, cell spreading, and migration. Furthermore, EPB41L5 controls matrixdependent outside-in signaling by regulating the focal adhesome composition. Thus, by linking extracellular matrix sensing and signaling, focal adhesion maturation, and actomyosin activation EPB41L5 ensures the mechanical stability required for podocytes at the kidney filtration barrier. Finally, a diminution of EPB41L5-dependent signaling programs appears to be a common theme of podocyte disease, and therefore offers unexpected interventional therapeutic strategies to prevent podocyte loss and kidney disease progression.",

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author = "Christoph Schell and Manuel Rogg and Martina Suhm and Martin Helmst{\"a}dter and Dominik Sellung and Mako Yasuda-Yamahara and Oliver Kretz and Victoria K{\"u}ttner and Hani Suleiman and Laxmikanth Kollipara and Zahedi, {Ren{\'e} P.} and Albert Sickmann and Stefan Eimer and Shaw, {Andrey S.} and Albrecht Kramer-Zucker and Mariko Hirano-Kobayashi and Takaya Abe and Shinichi Aizawa and Florian Grahammer and Bj{\"o}rn Hartleben and J{\"o}rn Dengjel and Huber, {Tobias B.}",

note = "Acknowledgments We thank Charlotte Meyer, Christina Engel, Betina Kiefer, Barbara Joch, Helga Schachner, and Elisabeth Wiesner for expert technical assistance. In addition, we would like to express our gratitude to all members of our laboratories for helpful discussions and support, especially Ketan Patel for carefully reading the manuscript. We would also like to thank Ronald Roepman for generously providing antibodies and serum against EPB41L5. We thank Cristina Has for providing ITGalpha2 antibodies. This study was supported by the German Research Foundation: collaborative research centers (CRC) 1140 (to T.B.H. and F.G.) and CRC 992 (to T.B.H.), Heisenberg program (T.B.H.), HU 1016/5-1 and HU 1016/8-1 (to T.B.H.); by the European Research Council (T.B.H.), and by the H2020-IMI2 consortium Biomarker Enterprise to Attack Diabetic Kidney Disease (BEAt-DKD) (115974 to T.B.H.); by the Bundesministerium f{\"u}r Bildung und Forschung, STOP Fokale Segmentale Glomerulosklerose (BMBF-STOP-FSGS) 01GM1518C (T.B.H.); by the Excellence Initiative of the German Federal and State Governments (GSC-4, Spemann Graduate School, C.S. and T.B.H.; BIOSS, T.B.H.; and the Freiburg Institute for Advanced Studies, T.B.H. and J.D.); by the Else Kr{\"o}ner Fresenius Stiftung, Nierenfunktionsst{\"o}rungen als Komplikation von Systemerkrankungen (NAKSYS) (C.S., M.R., and T.B.H.) and Molekulare und Translationale Forschung in Freiburg – Verantwortungsvolle Ausbildung Tatkr{\"a}ftige Ermutigung (MOTIVATE) (D.S.); by the German Society of Nephrology (C.S.); and we gratefully acknowledge the financial support from the Ministerium f{\"u}r Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen, the Senatsverwaltung f{\"u}r Wirtschaft, Technologie und Forschung des Landes Berlin, and the Bundesministerium f{\"u}r Bildung und Forschung (to L.K., R.P.Z., and A.S.).",

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doi = "10.1073/pnas.1617004114",

language = "English",

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journal = "Proceedings of the National Academy of Sciences of the United States of America",

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TY - JOUR

T1 - The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier

AU - Schell, Christoph

AU - Rogg, Manuel

AU - Suhm, Martina

AU - Helmstädter, Martin

AU - Sellung, Dominik

AU - Yasuda-Yamahara, Mako

AU - Kretz, Oliver

AU - Küttner, Victoria

AU - Suleiman, Hani

AU - Kollipara, Laxmikanth

AU - Zahedi, René P.

AU - Sickmann, Albert

AU - Eimer, Stefan

AU - Shaw, Andrey S.

AU - Kramer-Zucker, Albrecht

AU - Hirano-Kobayashi, Mariko

AU - Abe, Takaya

AU - Aizawa, Shinichi

AU - Grahammer, Florian

AU - Hartleben, Björn

AU - Dengjel, Jörn

AU - Huber, Tobias B.

N1 - Acknowledgments We thank Charlotte Meyer, Christina Engel, Betina Kiefer, Barbara Joch, Helga Schachner, and Elisabeth Wiesner for expert technical assistance. In addition, we would like to express our gratitude to all members of our laboratories for helpful discussions and support, especially Ketan Patel for carefully reading the manuscript. We would also like to thank Ronald Roepman for generously providing antibodies and serum against EPB41L5. We thank Cristina Has for providing ITGalpha2 antibodies. This study was supported by the German Research Foundation: collaborative research centers (CRC) 1140 (to T.B.H. and F.G.) and CRC 992 (to T.B.H.), Heisenberg program (T.B.H.), HU 1016/5-1 and HU 1016/8-1 (to T.B.H.); by the European Research Council (T.B.H.), and by the H2020-IMI2 consortium Biomarker Enterprise to Attack Diabetic Kidney Disease (BEAt-DKD) (115974 to T.B.H.); by the Bundesministerium für Bildung und Forschung, STOP Fokale Segmentale Glomerulosklerose (BMBF-STOP-FSGS) 01GM1518C (T.B.H.); by the Excellence Initiative of the German Federal and State Governments (GSC-4, Spemann Graduate School, C.S. and T.B.H.; BIOSS, T.B.H.; and the Freiburg Institute for Advanced Studies, T.B.H. and J.D.); by the Else Kröner Fresenius Stiftung, Nierenfunktionsstörungen als Komplikation von Systemerkrankungen (NAKSYS) (C.S., M.R., and T.B.H.) and Molekulare und Translationale Forschung in Freiburg – Verantwortungsvolle Ausbildung Tatkräftige Ermutigung (MOTIVATE) (D.S.); by the German Society of Nephrology (C.S.); and we gratefully acknowledge the financial support from the Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen, the Senatsverwaltung für Wirtschaft, Technologie und Forschung des Landes Berlin, and the Bundesministerium für Bildung und Forschung (to L.K., R.P.Z., and A.S.).

PY - 2017/6/6

Y1 - 2017/6/6

N2 - Podocytes form the outer part of the glomerular filter, where they have to withstand enormous transcapillary filtration forces driving glomerular filtration. Detachment of podocytes from the glomerular basement membrane precedes most glomerular diseases. However, little is known about the regulation of podocyte adhesion in vivo. Thus, we systematically screened for podocyte-specific focal adhesome (FA) components, using genetic reporter models in combination with iTRAQ-based mass spectrometry. This approach led to the identification of FERM domain protein EPB41L5 as a highly enriched podocyte-specific FA component in vivo. Genetic deletion of Epb41l5 resulted in severe proteinuria, detachment of podocytes, and development of focal segmental glomerulosclerosis. Remarkably, by binding and recruiting the RhoGEF ARGHEF18 to the leading edge, EPB41L5 directly controls actomyosin contractility and subsequent maturation of focal adhesions, cell spreading, and migration. Furthermore, EPB41L5 controls matrixdependent outside-in signaling by regulating the focal adhesome composition. Thus, by linking extracellular matrix sensing and signaling, focal adhesion maturation, and actomyosin activation EPB41L5 ensures the mechanical stability required for podocytes at the kidney filtration barrier. Finally, a diminution of EPB41L5-dependent signaling programs appears to be a common theme of podocyte disease, and therefore offers unexpected interventional therapeutic strategies to prevent podocyte loss and kidney disease progression.

AB - Podocytes form the outer part of the glomerular filter, where they have to withstand enormous transcapillary filtration forces driving glomerular filtration. Detachment of podocytes from the glomerular basement membrane precedes most glomerular diseases. However, little is known about the regulation of podocyte adhesion in vivo. Thus, we systematically screened for podocyte-specific focal adhesome (FA) components, using genetic reporter models in combination with iTRAQ-based mass spectrometry. This approach led to the identification of FERM domain protein EPB41L5 as a highly enriched podocyte-specific FA component in vivo. Genetic deletion of Epb41l5 resulted in severe proteinuria, detachment of podocytes, and development of focal segmental glomerulosclerosis. Remarkably, by binding and recruiting the RhoGEF ARGHEF18 to the leading edge, EPB41L5 directly controls actomyosin contractility and subsequent maturation of focal adhesions, cell spreading, and migration. Furthermore, EPB41L5 controls matrixdependent outside-in signaling by regulating the focal adhesome composition. Thus, by linking extracellular matrix sensing and signaling, focal adhesion maturation, and actomyosin activation EPB41L5 ensures the mechanical stability required for podocytes at the kidney filtration barrier. Finally, a diminution of EPB41L5-dependent signaling programs appears to be a common theme of podocyte disease, and therefore offers unexpected interventional therapeutic strategies to prevent podocyte loss and kidney disease progression.

KW - Actomyosin

KW - Focal adhesion

KW - FSGS

KW - Podocyte

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ER -

The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier

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Keywords

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