Secreted dengue virus nonstructural protein NS1 is an atypical barrel-shaped high-density lipoprotein

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 19; pp. 8003 - 8008
• Main Authors: Gutsche, Irina, Coulibaly, Fasséli, Voss, James E, Salmon, Jérôme, d'Alayer, Jacques, Ermonval, Myriam, Larquet, Eric, Charneau, Pierre, Krey, Thomas, Mégret, Françoise, Guittet, Eric, Rey, Félix A, Flamand, Marie
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 10.05.2011; National Acad Sciences
• Subjects: Animals; biochemical pathways; Biological Sciences; blood flow; Cell Line; cell membranes; Cells; Cercopithecus aethiops; cholesteryl esters; complement; Computer Simulation; cryo-electron microscopy; Cryoelectron Microscopy; Dengue; Dengue fever; Dengue virus; Dengue Virus - chemistry; Dengue Virus - ultrastructure; Detergents; Drosophila; endothelium; Fatty acids; Glycoproteins; HDL lipoproteins; HEK293 Cells; Hemorrhage; high density lipoprotein; Homeostasis; Humans; Imaging, Three-Dimensional; Life Sciences; Lipids; Lipoproteins; Lipoproteins, HDL - chemistry; Lipoproteins, HDL - ultrastructure; Microbiology and Parasitology; Models, Molecular; Molecules; NMR; Nuclear magnetic resonance; nuclear magnetic resonance spectroscopy; Nuclear Magnetic Resonance, Biomolecular; patients; phospholipids; Protein Multimerization; Protein Structure, Quaternary; Protein Subunits; Recombinant Proteins - chemistry; Recombinant Proteins - ultrastructure; Secretion; triacylglycerols; Triglycerides; tropics; Vero Cells; viral nonstructural proteins; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - ultrastructure
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1017338108

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.