Dengue Virus Uses a Non-Canonical Function of the Host GBF1-Arf-COPI System for Capsid Protein Accumulation on Lipid Droplets.
Dengue Virus Uses a Non-Canonical Function of the Host GBF1-Arf-COPI System for Capsid Protein Accumulation on Lipid Droplets.
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DOI：
10.1111/tra.12305
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发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
Gamarnik AV
中科院分区：
文献类型：
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作者：
Iglesias NG;Mondotte JA;Byk LA;De Maio FA;Samsa MM;Alvarez C;Gamarnik AV
登革热病毒是由蚊子传播的最重要的人类病毒性疾病。近年来，人们对登革病毒基因组复制的分子细节有了大量的了解;然而，对基因组复制和病毒衣壳蛋白的功能知之甚少。在感染过程中，登革病毒衣壳通过未知的机制在脂滴周围逐渐积累。在这里，我们研究了病毒衣壳从蛋白质合成的ER膜转运到脂滴的过程。使用不同的干预方法，我们发现GBF 1-Arf 1/Arf 4-COPI途径是衣壳转运到脂滴所必需的，而该过程独立于COPII组分和高尔基体完整性。该运输对布雷菲德菌素A敏感，而GBF 1的耐药形式足以恢复感染细胞中的衣壳亚细胞分布。脂滴获得或失去蛋白质的机制仍然是一个悬而未决的问题。我们的研究结果支持了一个模型，其中病毒使用非典型功能的COPI系统的衣壳积累的脂滴，提供了新的思路抗病毒策略。 抽象图形简介 登革病毒衣壳蛋白在感染过程中在称为脂滴（LD）的细胞器周围逐渐积累。使用不同的干预方法，我们确定了从病毒修饰的ER膜到LD的衣壳转运需要功能性GBF 1蛋白。该过程是COPI依赖的，而它是独立的COPII组件和高尔基体的完整性，支持GBF 1/ARF/COPI运输系统的非典型功能。
Dengue viruses cause the most important human viral disease transmitted by mosquitoes. In recent years, a great deal has been learned about molecular details of dengue virus genome replication; however, little is known about genome encapsidation and the functions of the viral capsid protein. During infection, dengue virus capsid progressively accumulates around lipid droplets by an unknown mechanism. Here, we examined the process by which the viral capsid is transported from the ER membrane, where the protein is synthesized, to lipid droplets. Using different methods of intervention, we found that the GBF1-Arf1/Arf4-COPI pathway is necessary for capsid transport to lipid droplets, while the process is independent of both COPII components and Golgi integrity. The transport was sensitive to brefeldin A, while a drug resistant form of GBF1 was sufficient to restore capsid subcellular distribution in infected cells. The mechanism by which lipid droplets gain or lose proteins is still an open question. Our results support a model in which the virus uses a non-canonical function of the COPI system for capsid accumulation on lipid droplets, providing new ideas for antiviral strategies. Brief synopsis of abstract figure The dengue virus capsid protein accumulates progressively around cellular organelles named lipid droplets (LDs) during infection. Using different methods of intervention, we defined that capsid transport from virally-modified ER membranes to LDs requires a functional GBF1 protein. The process was found to be COPI dependent, while it was independent of both COPII components and Golgi integrity, supporting a non-canonical function of GBF1/ARF/COPI transport system.