title: CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival.
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.affiliation: Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors.forename: Suma
authors.initials: S
authors.lastname: Yaddanapudi
authors.forename: Mehmet M
authors.initials: MM
authors.lastname: Altintas
authors.forename: Andreas D
authors.initials: AD
authors.lastname: Kistler
authors.forename: Isabel
authors.initials: I
authors.lastname: Fernandez
authors.forename: Clemens C
authors.initials: CC
authors.lastname: Möller
authors.forename: Changli
authors.initials: C
authors.lastname: Wei
authors.forename: Vasil
authors.initials: V
authors.lastname: Peev
authors.forename: Jan B
authors.initials: JB
authors.lastname: Flesche
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Forst
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Jaakko
authors.initials: J
authors.lastname: Patrakka
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Xiao
authors.forename: Florian
authors.initials: F
authors.lastname: Grahammer
authors.forename: Mario
authors.initials: M
authors.lastname: Schiffer
authors.forename: Tobias
authors.initials: T
authors.lastname: Lohmüller
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinheckel
authors.forename: Changkyu
authors.initials: C
authors.lastname: Gu
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ju
authors.forename: Markus
authors.initials: M
authors.lastname: Bitzer
authors.forename: Maria P
authors.initials: MP
authors.lastname: Rastaldi
authors.forename: Phillip
authors.initials: P
authors.lastname: Ruiz
authors.forename: Karl
authors.initials: K
authors.lastname: Tryggvason
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Shaw
authors.forename: Christian
authors.initials: C
authors.lastname: Faul
authors.forename: Sanja
authors.initials: S
authors.lastname: Sever
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D056668:Cathepsin L / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D050199:Podocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D011507:Proteinuria / Q000209:etiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; C104328:dendrin; D010447:Peptide Hydrolases; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse