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

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.

Pubmed ID: 21911934 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | Animals | Cathepsin L | Cell Survival | Cells, Cultured | Cytoskeletal Proteins | Cytoskeleton | HEK293 Cells | Humans | Mice | Mice, Knockout | Mice, Transgenic | Nerve Tissue Proteins | Peptide Hydrolases | Podocytes | Proteinuria | RNA, Messenger | Signal Transduction | Transforming Growth Factor beta1

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Associated grants

  • Agency: NIDDK NIH HHS, Id: DK073495
  • Agency: NIDDK NIH HHS, Id: DK087985
  • Agency: NIDDK NIH HHS, Id: DK089394
  • Agency: NIDDK NIH HHS, Id: R01 DK087985
  • Agency: NIDDK NIH HHS, Id: T32DK007540

Mouse Genome Informatics (Data, Gene Annotation)

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