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

Proc Natl Acad Sci U S A. 2017 Jun 6;114(23):E4621-E4630. doi: 10.1073/pnas.1617004114. Epub 2017 May 23.


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.

Keywords: FSGS; actomyosin; focal adhesion; podocyte.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actomyosin / metabolism*
  • Animals
  • Cytoskeletal Proteins / deficiency
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Female
  • Focal Adhesions / metabolism*
  • Focal Adhesions / pathology
  • Gene Knockout Techniques
  • Glomerulosclerosis, Focal Segmental / etiology
  • Glomerulosclerosis, Focal Segmental / metabolism
  • Glomerulosclerosis, Focal Segmental / pathology
  • Humans
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Nephrotic Syndrome / etiology
  • Nephrotic Syndrome / metabolism
  • Nephrotic Syndrome / pathology
  • Podocytes / metabolism*
  • Podocytes / pathology
  • Pregnancy
  • Proteomics
  • Rho Guanine Nucleotide Exchange Factors / metabolism
  • Signal Transduction


  • ARHGEF18 protein, human
  • Cytoskeletal Proteins
  • EPB41L5 protein, human
  • EPB41L5 protein, mouse
  • Membrane Proteins
  • Rho Guanine Nucleotide Exchange Factors
  • Actomyosin