CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival
Yaddanapudi S, Altintas MM, Kistler AD, Fernandez I, Moeller CC, Wei C, Peev V, Flesche JB, Forst AL, Li J, Patrakka J, Xiao Z, Grahammer F, Schiffer M, Lohmueller T, Reinheckel T, Gu C, Huber TB, Ju W, Bitzer M, Rastaldi MP, Ruiz P, Tryggvason K, Shaw AS, Faul C, Sever S, Reiser J (2011)
Publication Type: Journal article
Publication year: 2011
Journal
Book Volume: 121
Pages Range: 3965-3980
Journal Issue: 10
DOI: 10.1172/JCI58552
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.
Authors with CRIS profile
Involved external institutions
University of Miami
United States (USA) (US)
Medizinische Hochschule Hannover (MHH) / Hannover Medical School
Germany (DE)
Harvard University
United States (USA) (US)
Washington University
United States (USA) (US)
Albert-Ludwigs-Universität Freiburg
Germany (DE)
Karolinska University Hospital / Karolinska Universitetssjukhuset
Sweden (SE)
Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
Italy (IT)
University of Michigan
United States (USA) (US)
Universitätsklinikum Freiburg
Germany (DE)
Karolinska Institute
Sweden (SE)
United States (USA) (US)
Medizinische Hochschule Hannover (MHH) / Hannover Medical School
Germany (DE)
Harvard University
United States (USA) (US)
Washington University
United States (USA) (US)
Albert-Ludwigs-Universität Freiburg
Germany (DE)
Karolinska University Hospital / Karolinska Universitetssjukhuset
Sweden (SE)
Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
Italy (IT)
University of Michigan
United States (USA) (US)
Universitätsklinikum Freiburg
Germany (DE)
Karolinska Institute
Sweden (SE)
How to cite
APA:
Yaddanapudi, S., Altintas, M.M., Kistler, A.D., Fernandez, I., Moeller, C.C., Wei, C.,... 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
MLA:
Yaddanapudi, Suma, et al. "CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival." Journal of Clinical Investigation 121.10 (2011): 3965-3980.
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