SUMOylation determines turnover and localization of nephrin at the plasma membrane.
SUMOylation determines turnover and localization of nephrin at the plasma membrane.
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DOI：
10.1038/ki.2014.198
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发表时间：
2014-12
影响因子：
19.6
通讯作者：
Irini Tossidou;Erik Himmelseher;Beina Teng;H. Haller;M. Schiffer
中科院分区：
文献类型：
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作者：
Irini Tossidou;Erik Himmelseher;Beina Teng;H. Haller;M. Schiffer
足细胞消失，足突和裂隙隔膜的重建可以在几分钟内诱导实验。因此，它似乎可能是狭缝隔膜蛋白质的基础精心策划的回收机制下的翻译后修饰剂的控制。SUMO（small ubiquitin-like modifier）是一种泛素样蛋白，与泛素有20%的同源性。SUMO对蛋白质赖氨酸残基的修饰可以阻断同一位点的泛素化，从而导致靶蛋白的稳定。我们在体外和体内发现nephrin是SUMO蛋白修饰的底物，从而增加其稳态水平和质膜表达。在鼠nephrin的细胞内尾的位置1114和1224处赖氨酸转化为赖氨酸导致nephrin的稳定性降低、质膜表达降低和PI 3 K/AKT信号传导降低。此外，用SUMO化抑制剂银杏酸处理足细胞导致nephrin的膜表达减少。类似地，在人nephrin的位置1100处赖氨酸转化为精氨酸导致质膜上的稳定性和表达降低。由于SUMO化是一个可逆的过程，我们的研究结果表明，SUMO化参与了在狭缝隔膜的nephrin周转的紧密协调。
Podocyte effacement and the reformation of foot processes and slit diaphragms can be induced within minutes experimentally. Therefore, it seems likely that the slit diaphragm proteins underlie orchestrated recycling mechanisms under the control of posttranslational modifiers. One of these modifiers, SUMO (small ubiquitin-like modifier), is an ubiquitin-like protein with a 20% corresponding identity to ubiquitin. Modification by SUMOs to proteins on lysine residues can block the ubiquitination of the same site leading to the stabilization of the target protein. Here we foundin vitroandin vivothat nephrin is a substrate modified by SUMO proteins thereby increasing its steady-state level and expression at the plasma membrane. A conversion of lysines to arginines at positions 1114 and 1224 of the intracellular tail of murine nephrin led to decreased stability of nephrin, decreased expression at the plasma membrane, and decreased PI3K/AKT signaling. Furthermore, treatment of podocytes with the SUMOylation inhibitor ginkgolic acid led to reduced membrane expression of nephrin. Similarly, the conversion of lysine to arginine at position 1100 of human nephrin caused decreased stability and expression at the plasma membrane. As SUMOylation is a reversible process, our results suggest that SUMOylation participates in the tight orchestration of nephrin turnover at the slit diaphragm.