Secreted dengue virus nonstructural protein NS1 is an atypical barrel-shaped high-density lipoprotein
Secreted dengue virus nonstructural protein NS1 is an atypical barrel-shaped high-density lipoprotein
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DOI：
10.1073/pnas.1017338108
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发表时间：
2011-05-10
影响因子：
11.1
通讯作者：
Flamand, Marie
中科院分区：
文献类型：
--
作者：
Gutsche, Irina;Coulibaly, Fasseli;Flamand, Marie
登革病毒（DENV）引起热带地区的主要虫媒病毒疾病，其严重形式的特征在于出血和血浆渗漏的迹象。登革病毒编码一种非结构性糖蛋白NS1，它与细胞内膜和细胞表面结合。NS1最终作为可溶性六聚体从DENV感染的细胞中分泌出来，并在感染患者的血液中循环。细胞外NS1已显示出调节补体系统并增强DENV感染，但其结构和功能基本上仍不清楚。通过结合冷冻电子显微镜分析与表征的NS1两亲性，我们表明，分泌的NS1六聚体形成一个脂蛋白颗粒与一个开放的桶蛋白壳和一个突出的中央通道富含脂质。NS1脂质货物的生化和NMR分析揭示了甘油三酯的存在，以等摩尔比结合到NS1原聚体，以及胆固醇酯和磷脂，一种组合物，唤起参与血管稳态的血浆脂蛋白。这项研究表明，DENV NS1通过模仿或劫持脂质代谢途径，导致内皮功能障碍，这是严重登革热疾病的一个关键特征。
Dengue virus (DENV) causes the major arboviral disease of the tropics, characterized in its severe forms by signs of hemorrhage and plasma leakage. DENV encodes a nonstructural glycoprotein, NS1, that associates with intracellular membranes and the cell surface. NS1 is eventually secreted as a soluble hexamer from DENV-infected cells and circulates in the bloodstream of infected patients. Extracellular NS1 has been shown to modulate the complement system and to enhance DENV infection, yet its structure and function remain essentially unknown. By combining cryoelectron microscopy analysis with a characterization of NS1 amphipathic properties, we show that the secreted NS1 hexamer forms a lipoprotein particle with an open-barrel protein shell and a prominent central channel rich in lipids. Biochemical and NMR analyses of the NS1 lipid cargo reveal the presence of triglycerides, bound at an equimolar ratio to the NS1 protomer, as well as cholesteryl esters and phospholipids, a composition evocative of the plasma lipoproteins involved in vascular homeostasis. This study suggests that DENV NS1, by mimicking or hijacking lipid metabolic pathways, contributes to endothelium dysfunction, a key feature of severe dengue disease.