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

Irina Gutsche, Fasseli Coulibaly, James Voss, Jerome Salmon, Jacques D'Alayer, Myriam Ermonval, Eric Larquet, Pierre Charneau, Thomas Krey, Francoise Megret, Eric Guittet, Felix Rey, Marie Flamand

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)8003 - 8008
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume108
Issue number19
DOIs
Publication statusPublished - 2011

Cite this

Gutsche, Irina ; Coulibaly, Fasseli ; Voss, James ; Salmon, Jerome ; D'Alayer, Jacques ; Ermonval, Myriam ; Larquet, Eric ; Charneau, Pierre ; Krey, Thomas ; Megret, Francoise ; Guittet, Eric ; Rey, Felix ; Flamand, Marie. / Secreted dengue virus nonstructural protein NS1 is an atypical barrel-shaped high-density lipoprotein. In: Proceedings of the National Academy of Sciences. 2011 ; Vol. 108, No. 19. pp. 8003 - 8008.
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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.",
author = "Irina Gutsche and Fasseli Coulibaly and James Voss and Jerome Salmon and Jacques D'Alayer and Myriam Ermonval and Eric Larquet and Pierre Charneau and Thomas Krey and Francoise Megret and Eric Guittet and Felix Rey and Marie Flamand",
year = "2011",
doi = "10.1073/pnas.1017338108",
language = "English",
volume = "108",
pages = "8003 -- 8008",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
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Gutsche, I, Coulibaly, F, Voss, J, Salmon, J, D'Alayer, J, Ermonval, M, Larquet, E, Charneau, P, Krey, T, Megret, F, Guittet, E, Rey, F & Flamand, M 2011, 'Secreted dengue virus nonstructural protein NS1 is an atypical barrel-shaped high-density lipoprotein' Proceedings of the National Academy of Sciences, vol. 108, no. 19, pp. 8003 - 8008. https://doi.org/10.1073/pnas.1017338108

Secreted dengue virus nonstructural protein NS1 is an atypical barrel-shaped high-density lipoprotein. / Gutsche, Irina; Coulibaly, Fasseli; Voss, James; Salmon, Jerome; D'Alayer, Jacques; Ermonval, Myriam; Larquet, Eric; Charneau, Pierre; Krey, Thomas; Megret, Francoise; Guittet, Eric; Rey, Felix; Flamand, Marie.

In: Proceedings of the National Academy of Sciences, Vol. 108, No. 19, 2011, p. 8003 - 8008.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Secreted dengue virus nonstructural protein NS1 is an atypical barrel-shaped high-density lipoprotein

AU - Gutsche, Irina

AU - Coulibaly, Fasseli

AU - Voss, James

AU - Salmon, Jerome

AU - D'Alayer, Jacques

AU - Ermonval, Myriam

AU - Larquet, Eric

AU - Charneau, Pierre

AU - Krey, Thomas

AU - Megret, Francoise

AU - Guittet, Eric

AU - Rey, Felix

AU - Flamand, Marie

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N2 - 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.

AB - 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.

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SP - 8003

EP - 8008

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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