Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival
Suma Yaddanapudi, … , Sanja Sever, Jochen Reiser
Suma Yaddanapudi, … , Sanja Sever, Jochen Reiser
Published September 12, 2011
Citation Information: J Clin Invest. 2011;121(10):3965-3980. https://doi.org/10.1172/JCI58552.
View: Text | PDF | Corrigendum
Research Article Nephrology Article has an altmetric score of 1

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

  • Text
  • PDF
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

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

×

Figure 7

Cytosolic CatL proteolytically processes CD2AP in podocytes.

Options: View larger image (or click on image) Download as PowerPoint
Cytosolic CatL proteolytically processes CD2AP in podocytes.
(A) Immunob...
(A) Immunoblot of cleaved CD2AP fragments tagged with N-terminal GFP. At pH 7.0, CD2AP cleaved into a stable 55-kDa fragment (squares), as detected with anti-GFP antibody. We detect the same fragment with the N-CD2AP antiserum. This antiserum also detected a weak band corresponding to a 44-kDa fragment (triangle). (B) Match of cleavage fragments with predicted CatL cleavage site QPLGS. (C) Deletion of the CatL cleavage site LSAAE protected CD2AP from limited proteolysis into p32 (circle). (D) Match of p32 with predicted CatL cleavage site LSAAE. (E) CatL cleaved CD2AP-FLAG, yielding p32 (circle), detected by anti–C-CD2AP. (F) WT Ctsl cleaved CD2AP in HEK 293 cells. Cytosolic CatL (CatL M1) was sufficient to cleave CD2AP, yielding p32 (circle). These cleavage reactions were prevented by incubation of the cells with E64. (G) Coimmunoprecipitation of nephrin, synaptopodin, and dendrin from HEK 293 cells transfected with full-length CD2AP, N-terminal CD2AP, and p32. (H) Structural domains of CD2AP, together with major CatL cleavage sites, predicted sizes of resulting fragments from CatL digestion, and recognition sites of the antibodies used. SH3, src homology domain 3; PR, proline-rich motif; CC, coiled-coil domain. (I) Immunofluorescent staining of kidney biopsies from patients with MCD and FSGS. N-terminal CD2AP was reduced only in progressive disease (i.e., FSGS). Scale bar: 30 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 1 X users
80 readers on Mendeley
1 readers on CiteULike
See more details