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

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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 languageEnglish
Pages (from-to)E4621-E4630
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number23
DOIs
StatePublished - Jun 6 2017

Keywords

  • Actomyosin
  • FSGS
  • Focal adhesion
  • Podocyte

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