Adenovirus triggers macropinocytosis and endosomal leakage together with its clathrin-mediated uptake.
Adenovirus triggers macropinocytosis and endosomal leakage together with its clathrin-mediated uptake.
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DOI：
10.1083/jcb.200112067
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发表时间：
2002-09-16
期刊：
影响因子：
--
通讯作者：
Greber UF
中科院分区：
文献类型：
--
作者：
Meier O;Boucke K;Hammer SV;Keller S;Stidwill RP;Hemmi S;Greber UF
2型腺病毒（Ad 2）与科萨基B病毒Ad受体结合，并在αv整联蛋白辅助受体活化后被内吞。在这里，我们表明，显性负网格蛋白枢纽，eps 15，或K44 A-动力蛋白（动力蛋白）的表达抑制Ad 2摄取到上皮细胞，表明网格蛋白依赖的病毒内吞作用。令人惊讶的是，广告强烈刺激内吞摄取的液相示踪剂，符合病毒的内化，但不影响受体介导的转铁蛋白摄取。大量的刺激内吞活性是巨胞饮。巨胞饮依赖于αv整合素、PKC、F-肌动蛋白和阿米洛利敏感的Na+/H+交换蛋白，这些都是Ad从内体逃逸和感染所必需的。巨胞饮刺激不是病毒逃逸的结果，因为它发生在K44 A-dyn表达细胞中。令人惊讶的是，30-50%的内体内容物被释放到对照细胞和K44 A-dyn表达细胞的胞质溶胶中，并且液相阳性内体的数量下降到低于未感染细胞的水平，表明大胞饮体溶解。大胞饮体内容物的释放是Ad剂量依赖性的，但大胞饮体膜上Ad颗粒的存在不足以释放内容物。我们的结论是，从细胞表面的广告信号控制的诱导巨胞饮体的形成和泄漏，这与病毒退出到胞质溶胶和感染。
Adenovirus type 2 (Ad2) binds the coxsackie B virus Ad receptor and is endocytosed upon activation of the αv integrin coreceptors. Here, we demonstrate that expression of dominant negative clathrin hub, eps15, or K44A-dynamin (dyn) inhibited Ad2 uptake into epithelial cells, indicating clathrin-dependent viral endocytosis. Surprisingly, Ad strongly stimulated the endocytic uptake of fluid phase tracers, coincident with virus internalization but without affecting receptor-mediated transferrin uptake. A large amount of the stimulated endocytic activity was macropinocytosis. Macropinocytosis depended on αv integrins, PKC, F-actin, and the amiloride-sensitive Na+/H+ exchanger, which are all required for Ad escape from endosomes and infection. Macropinocytosis stimulation was not a consequence of viral escape, since it occurred in K44A-dyn–expressing cells. Surprisingly, 30–50% of the endosomal contents were released into the cytosol of control and also K44A-dyn–expressing cells, and the number of fluid phase–positive endosomes dropped below the levels of noninfected cells, indicating macropinosomal lysis. The release of macropinosomal contents was Ad dose dependent, but the presence of Ad particles on macropinosomal membranes was not sufficient for contents release. We conclude that Ad signaling from the cell surface controls the induction of macropinosome formation and leakage, and this correlates with viral exit to the cytosol and infection.
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