Vaccinia virus strains use distinct forms of macropinocytosis for host-cell entry
Vaccinia virus strains use distinct forms of macropinocytosis for host-cell entry
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DOI：
10.1073/pnas.1004618107
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发表时间：
2010-05-18
影响因子：
11.1
通讯作者：
Helenius, Ari
中科院分区：
文献类型：
--
作者：
Mercer, Jason;Knebel, Stephan;Helenius, Ari
为了进入宿主细胞，牛痘病毒，一种原型痘病毒，可以诱导瞬时巨胞饮，随后内吞内化并通过膜融合穿透胞饮体的限制膜。虽然西方储备（WR）株的成熟病毒粒子（MV）通过激活瞬时质膜起泡在HeLa细胞中做到这一点，发现来自国际卫生部-J株的MV诱导丝状伪足的快速形成（和延长）。当这些反应背后的信号通路进行比较，观察到的差异在Rho GTP酶的水平。丝状伪足形成的关键是病毒诱导的Cdc 42激活，而起泡反应的关键是Rac 1激活。此外，与WR不同，国际卫生部J MV不依赖于染料木素敏感的酪氨酸激酶和PI（3）K活性。只有WR MV膜融合活性在低pH值。抑制剂分析表明，MV从两个菌株进入细胞的巨胞饮，这是由病毒体暴露的磷脂酰丝氨酸诱导。两种MV都依赖于表皮生长因子受体、丝氨酸/苏氨酸激酶、蛋白激酶C和p21激活激酶1的激活。结果表明，同一病毒的不同毒株在进入宿主细胞期间可引起显著不同的反应，并且通过活化配体的细微差异，在同一细胞系中可能存在不同的巨胞饮机制。
To enter host cells, vaccinia virus, a prototype poxvirus, can induce transient macropinocytosis followed by endocytic internalization and penetration through the limiting membrane of pinosomes by membrane fusion. Although mature virions (MVs) of the Western reserve (WR) strain do this in HeLa cells by activating transient plasma membrane blebbing, MVs from the International Health Department-J strain were found to induce rapid formation (and lengthening) of filopodia. When the signaling pathways underlying these responses were compared, differences were observed at the level of Rho GTPases. Key to the filopodial formation was the virus-induced activation of Cdc42, and for the blebbing response the activation of Rac1. In addition, unlike WR, International Health Department-J MVs did not rely on genistein-sensitive tyrosine kinase and PI(3) K activities. Only WR MVs had membrane fusion activity at low pH. Inhibitor profiling showed that MVs from both strains entered cells by macropinocytosis and that this was induced by virion-exposed phosphatidylserine. Both MVs relied on the activation of epidermal growth factor receptor, on serine/threonine kinases, protein kinase C, and p21-activated kinase 1. The results showed that different strains of the same virus can elicit dramatically different responses in host cells during entry, and that different macropinocytic mechanisms are possible in the same cell line through subtle differences in the activating ligand.