CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival
CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival
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DOI：
10.1172/jci58552
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发表时间：
2011-10-01
影响因子：
15.9
通讯作者：
Reiser, Jochen
中科院分区：
文献类型：
--
作者：
Yaddanapudi, Suma;Altintas, Mehmet M.;Reiser, Jochen
肾足细胞是高度分化的上皮细胞，其形成具有调节肾超滤的桥接狭缝隔膜（SD）的交错足突。足细胞损伤导致蛋白尿性肾病，SD相关的CD 2相关蛋白（CD 2AP）的基因缺失导致小鼠和人类进行性肾衰竭。在这里，我们已经表明，CD 2AP调节TGF-β 1依赖的树突状蛋白从SD到细胞核的易位。核树突素作为一种转录因子促进胞浆组织蛋白酶L（CatL）的表达。CatL蛋白水解调节GT3发动蛋白和肌动蛋白相关的适配器synaptopodin，导致足细胞微丝系统的重组和随后的蛋白尿。CD 2AP本身被CatL蛋白水解，促进足细胞损伤期间蛋白酶的持续表达，进而增加足细胞对TGF-β 1的凋亡易感性。我们的研究确定了CD 2AP作为足细胞TGF-β反应的看门人，通过其调节CatL表达，并定义了蛋白尿肾病的分子机制。
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-beta 1-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-beta 1. Our study identifies CD2AP as the gatekeeper of the podocyte TGF-beta response through its regulation of CatL expression and defines a molecular mechanism underlying proteinuric kidney disease.