Laboratoire de Virologie Moléculaire et Structurale, Centre National de la Recherche Scientifique, Unité Propre de Recherche 3296, F-91198 Gif-sur-Yvette, France.
Proc Natl Acad Sci U S A. 2011 May 10;108(19):8003-8. doi: 10.1073/pnas.1017338108. Epub 2011 Apr 25.
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.
登革热病毒（DENV）引起热带地区的主要虫媒病毒病，其严重形式的特征是出血和血浆渗漏的迹象。DENV 编码一种非结构糖蛋白，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感染 DENV 的细胞中分泌，并在感染患者的血液中循环。已经证明细胞外 NS1 可以调节补体系统并增强 DENV 感染，但它的结构和功能仍然基本未知。通过将冷冻电子显微镜分析与 NS1 两亲性特性的表征相结合，我们表明分泌的 NS1 六聚体形成具有开放桶状蛋白壳和富含脂质的突出中央通道的脂蛋白颗粒。对 NS1 脂质货物的生化和 NMR 分析揭示了存在甘油三酯，与 NS1 原聚体以等摩尔比结合，以及胆固醇酯和磷脂，这种组成类似于参与血管稳态的血浆脂蛋白。这项研究表明，DENV NS1 通过模拟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。
