HIV-1 Nef Interferes with Host Cell Motility by Deregulation of Cofilin
HIV-1 Nef Interferes with Host Cell Motility by Deregulation of Cofilin
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DOI：
10.1016/j.chom.2009.06.004
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发表时间：
2009-08-20
影响因子：
30.3
通讯作者：
Fackler, Oliver T.
中科院分区：
文献类型：
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作者：
Stolp, Bettina;Reichman-Fried, Michal;Fackler, Oliver T.
HIV-1 Nef是艾滋病发病机制的关键因素。在这里，我们报道 Nef 有效抑制成纤维细胞的运动和 HIV-1 感染的原代人 T 淋巴细胞对趋化因子 SDF-1 α、CCL-19 和 CCL-21 的体外趋化性。此外，Nef 抑制斑马鱼原始生殖细胞向内源性 SDF-1a 的引导运动。体内。这些迁移缺陷是由 Nef 介导的对通常由迁移刺激触发的肌动蛋白重塑的抑制造成的。 Nef 强烈诱导丝切蛋白的磷酸化，使这种进化上保守的肌动蛋白解聚因子失活，该因子在未磷酸化时可促进细胞运动。 Nef 依赖性肌动蛋白丝切蛋白失调需要 Nef 与细胞激酶 Pak2 结合。 Nef-Pak2 关联的破坏可恢复丝动蛋白磷酸化水平和肌动蛋白重塑，从而促进细胞运动。我们得出的结论是，HIV-1 Nef 改变了 Pak2 功能，直接或间接使 cofilin 失活，从而限制受感染 T 淋巴细胞的迁移，作为优化免疫逃避和 HIV-1 复制策略的一部分。
HIV-1 Nef is a key factor in AIDS pathogenesis. Here, we report that Nef potently inhibits motility of fibroblasts and chemotaxis of HIV-1-infected primary human T lymphocytes toward the chemokines SDF-1 alpha, CCL-19, and CCL-21 ex vivo. Furthermore, Nef inhibits guided motility of zebrafish primordial germ cells toward endogenous SDF-1a. in vivo. These migration defects result from Nef-mediated inhibition of the actin remodeling normally triggered by migratory stimuli. Nef strongly induces phosphorylation of cofilin, inactivating this evolutionarily conserved actin-depolymerizing factor that promotes cell motility when unphosphorylated. Nef-dependent cofilin deregulation requires association of Nef with the cellular kinase Pak2. Disruption of Nef-Pak2 association restores the cofilin phosphorylation levels and actin remodeling that facilitate cell motility. We conclude that HIV-1 Nef alters Pak2 function, which directly or indirectly inactivates cofilin, thereby restricting migration of infected T lymphocytes as part of a strategy to optimize immune evasion and HIV-1 replication.