CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival

Suma Yaddanapudi, Mehmet M. Altintas, Andreas D. Kistler, Isabel Fernandez, Clemens C. Möller, Changli Wei, Vasil Peev, Jan B. Flesche, Anna Lena Forst, Jing Li, Jaakko Patrakka, Zhijie Xiao, Florian Grahammer, Mario Schiffer, Tobias Lohmüller, Thomas Reinheckel, Changkyu Gu, Tobias B. Huber, Wenjun Ju, Markus BitzerMaria P. Rastaldi, Phillip Ruiz, Karl Tryggvason, Andrey S. Shaw, Christian Faul, Sanja Sever, Jochen Reiser

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98 Scopus citations

Abstract

Kidney podocytes are highly differentiated epithelial cells that form interdigitating foot processes with bridging slit diaphragms (SDs) that regulate renal ultrafiltration. Podocyte injury results in proteinuric kidney disease, and genetic deletion of SD-associated CD2-associated protein (CD2AP) leads to progressive renal failure in mice and humans. Here, we have shown that CD2AP regulates the TGF-β1-dependent translocation of dendrin from the SD to the nucleus. Nuclear dendrin acted as a transcription factor to promote expression of cytosolic cathepsin L (CatL). CatL proteolyzed the regulatory GTPase dynamin and the actin-associated adapter synaptopodin, leading to a reorganization of the podocyte microfilament system and consequent proteinuria. CD2AP itself was proteolyzed by CatL, promoting sustained expression of the protease during podocyte injury, and in turn increasing the apoptotic susceptibility of podocytes to TGF-β1. Our study identifies CD2AP as the gatekeeper of the podocyte TGF-β response through its regulation of CatL expression and defines a molecular mechanism underlying proteinuric kidney disease.

Original languageEnglish (US)
Pages (from-to)3965-3980
Number of pages16
JournalJournal of Clinical Investigation
Volume121
Issue number10
DOIs
StatePublished - Oct 3 2011

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Yaddanapudi, S., Altintas, M. M., Kistler, A. D., Fernandez, I., Möller, C. C., Wei, C., Peev, V., Flesche, J. B., Forst, A. L., Li, J., Patrakka, J., Xiao, Z., Grahammer, F., Schiffer, M., Lohmüller, T., Reinheckel, T., Gu, C., Huber, T. B., Ju, W., ... Reiser, J. (2011). CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival. Journal of Clinical Investigation, 121(10), 3965-3980. https://doi.org/10.1172/JCI58552