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

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.focal adhesion | actomyosin | podocyte | FSGS

The Evolving Complexity of the Podocyte Cytoskeleton

“…By combining in vivo quantitative MS analysis with complementary in vitro adhesomics, major progress has recently been made. 105 This approach allowed for the identification of a highly selectively expressed FA component of podocytes, the FERMdomain protein EPB41L5. Mechanistically, EPB41L5 recruits the small GTPase ARHGEF18 thereby titrating the activity of the actomyosin cytoskeleton and efficient podocyte adhesion (see Figure 2).…”

Morphogenesis of neurons and glia within an epithelium

“…Each of these proteins has been shown to interact with the Crumbs apical polarity complex to regulate epithelial morphogenesis (Hsu et al, 2006;Laprise et al, 2006;Gosens et al, 2007;Laprise et al, 2009;Salis et al, 2017). Disruption of EPB41L5, moe, and Yrt has been shown in each of these systems to cause disorganized tight junctions and loss of epithelial integrity (Jensen and Westerfield, 2004;Salis et al, 2017;Schell et al, 2017). Interestingly, in Drosophila trachea, the relationship between Yrt and apical ECM has been examined, and these pathways were found to act independently and in parallel to shape epithelial tubes, an observation that would be consistent with the loss of FRM-2 enhancing dyf-7 defects (Laprise et al, 2010).…”

Potential Crosstalk between Liver and Extra-liver Organs in Mouse Models of Acute Liver Injury

“…Loss of podocytes adhesion is a hallmark of glomerular disease progression. Rap1 was reported as an important mediator for integrin activation and rap1 reduction in podocytes led to severe renal disease [35][36][37]. At the early stages of cholestasis and ALF model, changes in podocyte behavior might be crucial.…”