Dengue virus ensures its fusion in late endosomes using compartment-specific lipids

• Published in: PLoS pathogens Vol. 6; no. 10; p. e1001131
• Main Authors: Zaitseva, Elena, Yang, Sung-Tae, Melikov, Kamran, Pourmal, Sergei, Chernomordik, Leonid V
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.10.2010; Public Library of Science (PLoS)
• Subjects: Animals; Cell Compartmentation - physiology; Cell Membrane - metabolism; Cell Membrane - physiology; Cells, Cultured; Cercopithecus aethiops; CHO Cells; Cricetinae; Cricetulus; Dengue - metabolism; Dengue - virology; Dengue fever; Dengue virus; Dengue Virus - physiology; Dengue viruses; Endocytosis - physiology; Endosomes - chemistry; Endosomes - metabolism; Endosomes - virology; Experiments; Genomes; Humans; Infections; Lipids; Membrane Lipids - metabolism; Membrane Lipids - physiology; Mice; Models, Biological; NIH 3T3 Cells; Phospholipids; Physiological aspects; Proteins; Substrate Specificity; Vero Cells; Virology/Host Invasion and Cell Entry; Virus Internalization; United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1001131

Many enveloped viruses invade cells via endocytosis and use different environmental factors as triggers for virus-endosome fusion that delivers viral genome into cytosol. Intriguingly, dengue virus (DEN), the most prevalent mosquito-borne virus that infects up to 100 million people each year, fuses only in late endosomes, while activation of DEN protein fusogen glycoprotein E is triggered already at pH characteristic for early endosomes. Are there any cofactors that time DEN fusion to virion entry into late endosomes? Here we show that DEN utilizes bis(monoacylglycero)phosphate, a lipid specific to late endosomes, as a co-factor for its endosomal acidification-dependent fusion machinery. Effective virus fusion to plasma- and intracellular- membranes, as well as to protein-free liposomes, requires the target membrane to contain anionic lipids such as bis(monoacylglycero)phosphate and phosphatidylserine. Anionic lipids act downstream of low-pH-dependent fusion stages and promote the advance from the earliest hemifusion intermediates to the fusion pore opening. To reach anionic lipid-enriched late endosomes, DEN travels through acidified early endosomes, but we found that low pH-dependent loss of fusogenic properties of DEN is relatively slow in the presence of anionic lipid-free target membranes. We propose that anionic lipid-dependence of DEN fusion machinery protects it against premature irreversible restructuring and inactivation and ensures viral fusion in late endosomes, where the virus encounters anionic lipids for the first time during entry. Currently there are neither vaccines nor effective therapies for DEN, and the essential role of the newly identified DEN-bis(monoacylglycero)phosphate interactions in viral genome escape from the endosome suggests a novel target for drug design.