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

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

doi:10.1073/pnas.1617004114

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Journal article

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

Schell, Christoph Institute of Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Rogg, Manuel Department of Medicine IV, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Suhm, Martina Department of Medicine IV, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Helmstädter, Martin Department of Medicine IV, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Sellung, Dominik Department of Medicine IV, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Yasuda-Yamahara, Mako Department of Medicine IV, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Kretz, Oliver Department of Medicine IV, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Küttner, Victoria Department of Dermatology, Faculty of Medicine, Medical Center, University of Freiburg, Germany
Suleiman, Hani Department of Pathology, Washington University in St. Louis, USA
Kollipara, Laxmikanth Leibniz-Institut für Analytische Wissenschaften – ISAS – e.V., Dortmund, Germany
Zahedi, René P. Leibniz-Institut für Analytische Wissenschaften – ISAS – e.V., Dortmund, Germany
Sickmann, Albert Leibniz-Institut für Analytische Wissenschaften – ISAS – e.V., Dortmund, Germany - Department of Chemistry, College of Physical Sciences, University of Aberdeen, Scotland, United Kingdom - Medizinische Proteom-Center, Ruhr-Universität Bochum, Bochum, Germany
Eimer, Stefan BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, 79106 Freiburg, Germany
Shaw, Andrey S. Department of Pathology, Washington University in St. Louis, USA
Kramer-Zucker, Albrecht Department of Medicine IV, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Hirano-Kobayashi, Mariko Laboratory for Vertebrate Body Plan, Center for Developmental Biology, RIKEN Kobe, Japan
Abe, Takaya Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, Japan
Aizawa, Shinichi Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, Japan
Grahammer, Florian Department of Medicine IV, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Hartleben, Björn Department of Medicine IV, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Dengjel, Jörn BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, 79106 Freiburg, Germany
Huber, Tobias B. Department of Medicine IV, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany

06.06.2017

Published in:

Proceedings of the National Academy of Sciences. - 2017, vol. 114, no. 23, p. E4621–E4630

English 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 matrix-dependent 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.

Faculty

Faculté des sciences et de médecine

Department

Département de Biologie

Language