beta-Arrestin2 mediates nephrin endocytosis and impairs slit diaphragm integrity.
beta-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 beta-arrestin2 with the nephrin C terminus. The phosphorylation status of nephrin Y1193 regulates inversely the binding of beta-arrestin2 and podocin. The Src-family member Yes, known to enhance podocin-nephrin interaction by nephrin phosphorylation, diminishes beta-arrestin2-nephrin interaction. beta-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 beta-arrestin2 and podocin. This concept offers a molecular pathomechanism of slit diaphragm distortion and opens therapeutic avenues for glomerular diseases.
Quack
Ivo
I
Department of Nephrology, Marienhospital Herne, Hospital of the University of Bochum, D-44625 Herne, Germany.
Rump
L Christian
LC
Gerke
Peter
P
Walther
Inga
I
Vinke
Tobias
T
Vonend
Oliver
O
Grunwald
Thomas
T
Sellin
Lorenz
L
D000595:Amino Acid Sequence; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004705:Endocytosis / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism / Q000648:ultrastructure*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D050199:Podocytes / Q000166:cytology / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000071557:beta-Arrestins
D019390:Arrestins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D011993:Recombinant Fusion Proteins; D000071557:beta-Arrestins; C113267:nephrin