Dengue virus ensures its fusion in late endosomes using compartment-specific lipids.
Dengue virus ensures its fusion in late endosomes using compartment-specific lipids.
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DOI：
10.1371/journal.ppat.1001131
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发表时间：
2010-10-07
期刊：
影响因子：
6.7
通讯作者：
Chernomordik LV
中科院分区：
文献类型：
--
作者：
Zaitseva E;Yang ST;Melikov K;Pourmal S;Chernomordik LV
许多包膜病毒通过内吞作用侵入细胞，并利用不同的环境因素触发病毒-核内体融合，将病毒基因组传递到细胞质中。有趣的是，登革热病毒（DEN）是最流行的蚊媒病毒，每年感染多达1亿人，仅在晚期核内体融合，而DEN蛋白融合原糖蛋白E的激活已经在早期核内体的pH值特征下被触发。是否有任何辅助因子将DEN融合时间定在病毒粒子进入晚期核内体的时间？在这里，我们发现DEN利用他（单酰基甘油）磷酸，一种晚期核内体特有的脂质，作为其核内体酸化依赖融合机制的辅助因子。病毒要与血浆膜和胞内膜以及无蛋白脂质体有效融合，需要靶膜含有阴离子脂质，如磷酸单酰基甘油和磷脂酰丝氨酸。阴离子脂质在低ph依赖性融合阶段的下游发挥作用，并促进从最早的半融合中间体到融合孔打开的进展。为了到达富含阴离子脂质的晚期核内体，DEN通过酸化的早期核内体，但我们发现，在无阴离子脂质的靶膜存在下，DEN低ph依赖性的促聚变特性损失相对较慢。我们提出，DEN融合机制的阴离子脂质依赖性保护其免受过早的不可逆重组和失活，并确保病毒在后期内体融合，在那里病毒在进入时第一次遇到阴离子脂质。目前还没有针对DEN的疫苗和有效的治疗方法，新发现的DEN-bis（单酰基甘油）磷酸盐相互作用在病毒基因组从内体逃逸中的重要作用为药物设计提供了新的靶点。登革热病毒感染是一个日益严重的公共卫生问题，每年有多达1亿例病例，而且既没有疫苗，也没有有效的治疗方法。为了寻找预防和治疗登革热感染的方法，我们需要更好地了解其分子机制。与许多其他病毒一样，登革病毒通过病毒膜和细胞内囊泡（内体）膜的融合进入细胞。在这项工作中，我们探索了登革热病毒在不同实验系统中的融合阶段，从病毒融合到人工脂膜再到细胞内融合。虽然早期关于登革热病毒进入的工作主要集中在介导融合的病毒蛋白上，但我们发现该蛋白的有效作用需要病毒融合的膜的特定脂质组成。实际上，这种脂质依赖性使病毒能够控制融合事件的细胞内位置，从而通过利用病毒所经过的不同细胞器的脂质组成之间的细胞控制差异来控制RNA释放的位置。登革病毒及其脂质辅助因子在病毒进入过程中相互作用的重要作用表明，这些相互作用可能是药物设计的目标。
Many enveloped viruses invade cells via endocytosis and use different environmental factors as triggers for virus-endosome fusion that delivers viral genome into cytosol. Intriguingly, dengue virus (DEN), the most prevalent mosquito-borne virus that infects up to 100 million people each year, fuses only in late endosomes, while activation of DEN protein fusogen glycoprotein E is triggered already at pH characteristic for early endosomes. Are there any cofactors that time DEN fusion to virion entry into late endosomes? Here we show that DEN utilizes bis(monoacylglycero)phosphate, a lipid specific to late endosomes, as a co-factor for its endosomal acidification-dependent fusion machinery. Effective virus fusion to plasma- and intracellular- membranes, as well as to protein-free liposomes, requires the target membrane to contain anionic lipids such as bis(monoacylglycero)phosphate and phosphatidylserine. Anionic lipids act downstream of low-pH-dependent fusion stages and promote the advance from the earliest hemifusion intermediates to the fusion pore opening. To reach anionic lipid-enriched late endosomes, DEN travels through acidified early endosomes, but we found that low pH-dependent loss of fusogenic properties of DEN is relatively slow in the presence of anionic lipid-free target membranes. We propose that anionic lipid-dependence of DEN fusion machinery protects it against premature irreversible restructuring and inactivation and ensures viral fusion in late endosomes, where the virus encounters anionic lipids for the first time during entry. Currently there are neither vaccines nor effective therapies for DEN, and the essential role of the newly identified DEN-bis(monoacylglycero)phosphate interactions in viral genome escape from the endosome suggests a novel target for drug design. Dengue virus infection is a growing public health problem with up to 100 million cases annually, and neither vaccines nor effective therapies are available. To search for the ways of preventing and treating dengue infections we need to better understand their molecular mechanisms. As with many other viruses, dengue virus enters cells by fusion between the viral membrane and the membrane of intracellular vesicles (endosomes). In this work we explored the fusion stage of dengue virus entry in different experimental systems ranging from virus fusion to artificial lipid membranes to fusion inside the cells. While earlier work on dengue virus entry has focused on viral protein that mediates fusion, we found that effective action of this protein requires specific lipid composition of the membrane the virus fuses to. In effect, this lipid dependence allows virus to control intracellular location of the fusion event and, thus, the place of its RNA release by exploiting cell-controlled differences between lipid compositions of different organelles the virus travels through. The essential role of the interactions between dengue virus and its lipid cofactors during viral entry suggests that these interactions may be targeted in drug design.
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10.4269/ajtmh.1982.31.548
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