Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease
Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease
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DOI：
10.1172/jci32022
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发表时间：
2007-08-01
影响因子：
15.9
通讯作者：
Reiser, Jochen
中科院分区：
文献类型：
--
作者：
Sever, Sanja;Altintas, Mehmet M.;Reiser, Jochen
肾足细胞及其足突维持超滤屏障并防止尿蛋白丢失（蛋白尿）。在这里，我们证明 GTP 酶动力对于足细胞功能至关重要。在蛋白尿肾病期间，细胞质组织蛋白酶 L 的诱导导致动力蛋白在进化保守位点裂解，导致足细胞肌动蛋白细胞骨架重组和蛋白尿。缺乏组织蛋白酶 L 位点或通过动力自组装无法接近组织蛋白酶 L 位点的动力突变体对组织蛋白酶 L 裂解具有抵抗力。当将这些突变体递送至小鼠体内时，它们恢复了足细胞功能并解决了蛋白尿问题。我们的研究确定动力蛋白是肾脏通透选择性的关键调节剂，在病理条件下是蛋白水解的具体目标。
Kidney podocytes and their foot processes maintain the ultrafiltration barrier and prevent urinary protein loss (proteinuria). Here we show that the GTPase dynamin is essential for podocyte function. During proteinuric kidney disease, induction of cytoplasmic cathepsin L leads to cleavage of dynamin at an evolutionary conserved site, resulting in reorganization of the podocyte actin cytoskeleton and proteinuria. Dynamin mutants that lack the cathepsin L site, or render the cathepsin L site inaccessible through dynamin self-assembly, are resistant to cathepsin L cleavage. When delivered into mice, these mutants restored podocyte function and resolve proteinuria. Our study identifies dynamin as a critical regulator of renal permselectivity that is specifically targeted by proteolysis under pathological conditions.