FERMT2 links cortical actin structures, plasma membrane tension and focal adhesion function to stabilize podocyte morphology

Simplification and retraction of podocyte protrusions, generally termed as foot process effacement, is a uniform pathological pattern observed in the majority of glomerular disease, including focal segmental glomerulosclerosis. However, it is still incompletely understood how the interaction of cort...

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Bibliographic Details
Published in:Matrix biology 2018-08, Vol.68-69, p.263-279
Main Authors: Yasuda-Yamahara, M., Rogg, M., Frimmel, J., Trachte, P., Helmstaedter, M., Schroder, P., Schiffer, M., Schell, C., Huber, T.B.
Format: Article
Language:English
Subjects:
Actin
Actins - metabolism
Actomyosin
Actomyosin - metabolism
Animals
Cell Adhesion
Cell adhesion & migration
Cell Membrane - physiology
Cell Movement
Contractility
Cortex
CRISPR
Disease Models, Animal
Drosophila
Extracellular matrix
Extracellular Matrix - metabolism
Feet
Focal Adhesions - metabolism
Gene Knockout Techniques
Homeostasis
Humans
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Morphology
Neoplasm Proteins - genetics
Neoplasm Proteins - metabolism
Phenotypes
Podocytes - cytology
Podocytes - metabolism
Podocytes - physiology
Proteomics
RhoA protein
Zebrafish
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Summary:Simplification and retraction of podocyte protrusions, generally termed as foot process effacement, is a uniform pathological pattern observed in the majority of glomerular disease, including focal segmental glomerulosclerosis. However, it is still incompletely understood how the interaction of cortical actin structures, actomyosin contractility and focal adhesions, is being orchestrated to control foot process morphology in health and disease. By uncovering the functional role of fermitin family member 2 (FERMT2 or kindlin-2) in podocytes, we provide now evidence, how cell-extracellular matrix (ECM) interactions modulate membrane tension and actomyosin contractility. A genetic modeling approach was applied by deleting FERMT2 in a set of in vivo systems as well as in CRISPR/Cas9 modified human podocytes. Loss of FERMT2 results in altered cortical actin composition, cell cortex destabilization associated with plasma membrane blebbing and a remodeling of focal adhesions. We further show that FERMT2 knockout podocytes have high levels of RhoA activation and concomitantly increased actomyosin contractility. Inhibition of actomyosin tension reverses the membrane blebbing phenotype. Thus, our findings establish a direct link between cell-matrix adhesions, cortical actin structures and plasma membrane tension allowing to better explain cell morphological changes in foot process effacement. •Adhesion plays a central role in podocyte disease - how cell-matrix interactions control cell morphology is not understood•Genome editing in podocytes as well as in vivo modeling unravels the importance of FERMT2 for podocyte function.•FERMT2 thereby functionally links cortical actin structures, plasma membrane tension and cell-matrix interactions.•This inherent link allows for prediction of morphological alterations responsible for foot process effacement.
ISSN:0945-053X
1569-1802
DOI:10.1016/j.matbio.2018.01.003