title: Secreted dengue virus nonstructural protein NS1 is an atypical barrel-shaped high-density lipoprotein.
abstract: 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.
authors.affiliation: Laboratoire de Virologie Moléculaire et Structurale, Centre National de la Recherche Scientifique, Unité Propre de Recherche 3296, F-91198 Gif-sur-Yvette, France.
authors.forename: Irina
authors.initials: I
authors.lastname: Gutsche
authors.forename: Fasséli
authors.initials: F
authors.lastname: Coulibaly
authors.forename: James E
authors.initials: JE
authors.lastname: Voss
authors.forename: Jérôme
authors.initials: J
authors.lastname: Salmon
authors.forename: Jacques
authors.initials: J
authors.lastname: d'Alayer
authors.forename: Myriam
authors.initials: M
authors.lastname: Ermonval
authors.forename: Eric
authors.initials: E
authors.lastname: Larquet
authors.forename: Pierre
authors.initials: P
authors.lastname: Charneau
authors.forename: Thomas
authors.initials: T
authors.lastname: Krey
authors.forename: Françoise
authors.initials: F
authors.lastname: Mégret
authors.forename: Eric
authors.initials: E
authors.lastname: Guittet
authors.forename: Félix A
authors.initials: FA
authors.lastname: Rey
authors.forename: Marie
authors.initials: M
authors.lastname: Flamand
mesh_terms: D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D020285:Cryoelectron Microscopy; D003716:Dengue Virus / Q000737:chemistry* / Q000648:ultrastructure; D004330:Drosophila; D057809:HEK293 Cells; D006801:Humans; D021621:Imaging, Three-Dimensional; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000648:ultrastructure; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D021122:Protein Subunits; D011994:Recombinant Proteins / Q000737:chemistry / Q000648:ultrastructure; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000648:ultrastructure
chemical_list: D008075:Lipoproteins, HDL; C079340:NS1 protein, Dengue virus type 2; C082515:NS1 protein, dengue-1 virus; D021122:Protein Subunits; D011994:Recombinant Proteins; D017361:Viral Nonstructural Proteins