Filamin-A regulates actin-dependent clustering of HIV receptors
Filamin-A regulates actin-dependent clustering of HIV receptors
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DOI：
10.1038/ncb1610
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发表时间：
2007-07-01
影响因子：
21.3
通讯作者：
Manes, Santos
中科院分区：
文献类型：
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作者：
Jimenez-Baranda, Sonia;Gomez-Mouton, Concepcion;Manes, Santos
人类免疫缺陷病毒（HIV）-1感染需要包膜（Env）糖蛋白gp 120诱导细胞表面CD 4和辅助受体（CCR 5或CXCR 4）聚集;这使得Env gp 41活化并形成复合物，介导含Env和靶细胞膜之间的融合（1）。动力学研究表明，病毒受体在依赖于质膜组成和肌动蛋白细胞骨架的过程中被主动转运到Env-受体界面（2-7）。HIV-1在靶细胞中诱导F-肌动蛋白重排的机制在很大程度上仍然未知。在这里，我们表明，CD 4和辅助受体与肌动蛋白结合蛋白细丝蛋白-A，其结合到HIV-1受体调节其在细胞表面上的集群相互作用。我们发现gp 120与细胞受体结合通过RhoA-ROCK依赖性机制诱导瞬时cofilin磷酸化失活。阻断细丝蛋白-A与CD 4和/或辅助受体的相互作用可抑制gp 120诱导的RhoA激活和cofilin失活。因此，我们的研究结果确定filamin-A作为衔接蛋白，连接HIV-1受体的肌动蛋白细胞骨架重塑机制，这可能有助于病毒感染。
Human immunodeficiency virus ( HIV)-1 infection requires envelope ( Env) glycoprotein gp120-induced clustering of CD4 and coreceptors (CCR5 or CXCR4) on the cell surface; this enables Env gp41 activation and formation of a complex that mediates fusion between Env-containing and target-cell membranes(1). Kinetic studies show that viral receptors are actively transported to the Env-receptor interface in a process that depends on plasma membrane composition and the actin cytoskeleton(2-7). The mechanisms by which HIV-1 induces F-actin rearrangement in the target cell remain largely unknown. Here, we show that CD4 and the coreceptors interact with the actin-binding protein filamin-A, whose binding to HIV-1 receptors regulates their clustering on the cell surface. We found that gp120 binding to cell receptors induces transient cofilin-phosphorylation inactivation through a RhoA-ROCK-dependent mechanism. Blockade of filamin-A interaction with CD4 and/or coreceptors inhibits gp120-induced RhoA activation and cofilin inactivation. Our results thus identify filamin-A as an adaptor protein that links HIV-1 receptors to the actin cytoskeleton remodelling machinery, which may facilitate virus infection.