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 Bitzer; Maria P Rastaldi; Phillip Ruiz; Karl Tryggvason; Andrey S Shaw; Christian Faul; Sanja Sever; Jochen Reiser

doi:10.1172/JCI58552

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

Journal article

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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, …

The Journal of clinical investigation, Vol.121(10), pp.3965-3980

2011-10-03

DOI: https://doi.org/10.1172/JCI58552

PMCID: PMC3266811

PMID: 21911934

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.55 Urology & Nephrology - General; 1.55.820 IgA Nephropathy
Web Of Science research areas: Medicine, Research & Experimental
ESI research areas: Clinical Medicine

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Title: CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival
Creators: Suma Yaddanapudi - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Mehmet M Altintas - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Andreas D Kistler - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Isabel Fernandez - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Clemens C Möller - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Changli Wei - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Vasil Peev - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Jan B Flesche - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Anna-Lena Forst - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Jing Li - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Jaakko Patrakka - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Zhijie Xiao - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Florian Grahammer - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Mario Schiffer - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Tobias Lohmüller - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Thomas Reinheckel - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Changkyu Gu - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Tobias B Huber - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Wenjun Ju - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Markus Bitzer - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Maria P Rastaldi - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Phillip Ruiz - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Karl Tryggvason - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Andrey S Shaw - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Christian Faul - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Sanja Sever - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Jochen Reiser - Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
Publication Details: The Journal of clinical investigation, Vol.121(10), pp.3965-3980
Publisher: American Society for Clinical Investigation
Academic Unit: Miller School of Medicine; UMMG Department of Surgery; UMMG Dept of Surgery - Div of General Surgery
Language: English
Resource Type: Journal article
PMID: 21911934
PMCID: PMC3266811
Record Identifier: 991031577269302976