Human gelsolin prevents apoptosis by inhibiting apoptotic mitochondrial changes via closing VDAC
Human gelsolin prevents apoptosis by inhibiting apoptotic mitochondrial changes via closing VDAC
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DOI：
10.1038/sj.onc.1203868
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发表时间：
2000-10-05
期刊：
影响因子：
8
通讯作者：
Tsujimoto, Y
中科院分区：
文献类型：
--
作者：
Kusano, H;Shimizu, S;Tsujimoto, Y
明胶蛋白是一种钙离子依赖的肌动蛋白调节蛋白，它调节肌动蛋白的组装和分解，并被认为通过调节肌动蛋白网络来调节细胞的运动。明胶蛋白最近也被认为参与了细胞凋亡的调节：人的明胶蛋白(HGsn)具有抗凋亡活性，而小鼠的明胶蛋白(MGsn)则根据不同的细胞类型而发挥促凋亡或抗凋亡的活性。在这里，我们研究了hGsn的抗凋亡活性基础，我们发现内源性和过表达的hGsn都具有抗凋亡活性，这依赖于其C末端的一半。我们还发现，hGsn及其C末端的一半，而不是mGsn，可以阻止线粒体的凋亡改变，如Delta psi丢失和细胞色素c的释放，其程度与Bclx(L)相似，表明hGsn通过其C末端的一半靶向线粒体来防止细胞凋亡。与我们最近发现的通过结合和关闭电压依赖阴离子通道(VDAC)来防止线粒体凋亡的抗细胞凋亡的Bcl-xL一样，hGsn及其C端的一半通过钙依赖的直接结合方式抑制脂质体上VDAC的活性。这些结果提示hGsn通过阻断线粒体VDAC活性而抑制细胞凋亡。
Gelsolin is a Ca2+-dependent actin-regulatory protein that modulates actin assembly and disassembly, and is believed to regulate cell motility through modulation of the actin network. Gelsolin was also recently suggested to be involved in the regulation of apoptosis: human gelsolin (hGsn) has anti-apoptotic activity, whereas mouse gelsolin (mGsn) exerts either proapoptotic or anti-apoptotic activity depending on different cell types. Here, we studied the basis of anti-apoptotic activity of hGsn, We showed that both endogenous and overexpressed hGsn has anti-apoptotic activity, that depends on its C-terminal half. We also found that hGsn and its C-terminal half but not mGsn could prevent apoptotic mitochondrial changes such as Delta psi loss and cytochrome c release in isolated mitochondria to a similar extent as Bcl-x(L), indicating that hGsn targets the mitochondria to prevent apoptosis via its C-terminal half. In the same way as anti-apoptotic Bcl-xL, which we recently found to prevent apoptotic mitochondrial changes by binding and closing the voltage-dependent anion channel (VDAC), hGsn and its C-terminal half inhibited the activity of VDAC on liposomes through direct binding in a Ca2+-dependent manner. These results suggest that hGsn inhibits apoptosis by blocking mitochondrial VDAC activity.