β-Arrestin2 mediates nephrin endocytosis and impairs slit diaphragm integrity

*Department of Nephrology, Marienhospital Herne, Hospital of the University of Bochum, D-44625 Herne, Germany;
^†Renal Division, Department of Medicine, University Hospital Freiburg, D-79104 Freiburg, Germany; and
^‡Department of Molecular and Medical Virology, University of Bochum, D-44801 Bochum, Germany

Edited by Robert J. Lefkowitz, Duke University Medical Center, Durham, NC, and approved August 1, 2006 (received for review March 30, 2006)

Abstract

β-Arrestins mediate internalization of plasma membrane receptors. Nephrin, a structural component of the glomerular slit diaphragm, is a single transmembrane spanning receptor and belongs to the family of adhesion molecules. Its mutation causes a hereditary nephrotic syndrome. We report the previously undescribed interaction of β-arrestin2 with the nephrin C terminus. The phosphorylation status of nephrin Y1193 regulates inversely the binding of β-arrestin2 and podocin. The Src-family member Yes, known to enhance podocin–nephrin interaction by nephrin phosphorylation, diminishes β-arrestin2–nephrin interaction. β-Arrestin2 induces nephrin endocytosis and attenuates nephrin signaling. This finding suggests that nephrin Y1193 serves as a molecular switch that determines the integrity of the slit diaphragm by functional competition between β-arrestin2 and podocin. This concept offers a molecular pathomechanism of slit diaphragm distortion and opens therapeutic avenues for glomerular diseases.

Footnotes

^§To whom correspondence should be addressed. E-mail: lorenz.sellin{at}ruhr-uni-bochum.de
Author contributions: I.Q. and L.C.R. contributed equally to this work; L.S. designed research; I.Q., P.G., I.W., T.V., T.G., and L.S. performed research; P.G. contributed new reagents/analytic tools; I.Q., O.V., and T.G. analyzed data; and L.C.R. and L.S. wrote the paper.
The authors declare no conflict of interest.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviation:

AP-1,

activator protein 1
Freely available online through the PNAS open access option.