The late endosome-resident lipid bis(monoacylglycero)phosphate is a cofactor for Lassa virus fusion
| Autor: | Ruben M. Markosyan, You Zhang, Mariana Marin, Fredric S. Cohen, Gregory B. Melikyan |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
viruses
Cell Membranes medicine.disease_cause Membrane Fusion Biochemistry Cell Fusion Viral Envelope Proteins Chlorocebus aethiops Biology (General) Late endosome Cell fusion biology Chemistry Eukaryota Entry into host Lipids Cell biology Cholesterol COS Cells Vertebrates Monoglycerides Cellular Structures and Organelles Research Article Cell Physiology Viral Entry QH301-705.5 Endosome Immunology Endosomes Transfection Research and Analysis Methods Microbiology Birds Lassa Fever Viral entry Virology Genetics medicine Animals Humans Vesicles Lassa virus Molecular Biology Techniques Molecular Biology Arenavirus Organisms Biology and Life Sciences Lipid bilayer fusion Cell Biology Virus Internalization RC581-607 biology.organism_classification HEK293 Cells Junin virus Amniotes Parasitology Lysophospholipids Immunologic diseases. Allergy Zoology Viral Transmission and Infection |
| Zdroj: | PLoS Pathogens, Vol 17, Iss 9, p e1009488 (2021) PLoS Pathogens |
| DOI: | 10.1101/2021.03.22.436413 |
| Popis: | Arenavirus entry into host cells occurs through a low pH-dependent fusion with late endosomes that is mediated by the viral glycoprotein complex (GPC). The mechanisms of GPC-mediated membrane fusion and of virus targeting to late endosomes are not well understood. To gain insights into arenavirus fusion, we examined cell-cell fusion induced by the Old World Lassa virus (LASV) GPC complex. LASV GPC-mediated cell fusion is more efficient and occurs at higher pH with target cells expressing human LAMP1 compared to cells lacking this cognate receptor. However, human LAMP1 is not absolutely required for cell-cell fusion or LASV entry. We found that GPC-induced fusion progresses through the same lipid intermediates as fusion mediated by other viral glycoproteins–a lipid curvature-sensitive intermediate upstream of hemifusion and a hemifusion intermediate downstream of acid-dependent steps that can be arrested in the cold. Importantly, GPC-mediated fusion and LASV pseudovirus entry are specifically augmented by an anionic lipid, bis(monoacylglycero)phosphate (BMP), which is highly enriched in late endosomes. This lipid also specifically promotes cell fusion mediated by Junin virus GPC, an unrelated New World arenavirus. We show that BMP promotes late steps of LASV fusion downstream of hemifusion–the formation and enlargement of fusion pores. The BMP-dependence of post-hemifusion stages of arenavirus fusion suggests that these viruses evolved to use this lipid as a cofactor to selectively fuse with late endosomes. Author summary Pathogenic arenaviruses pose a serious health threat. The viral envelope glycoprotein GPC mediates attachment to host cells and drives virus entry via endocytosis and low pH-dependent fusion within late endosomes. Understanding the host factors and processes that are essential for arenavirus fusion may identify novel therapeutic targets. To delineate the mechanism of arenavirus entry, we examined cell-cell fusion induced by the Old World Lassa virus GPC proteins at low pH. Lassa GPC-mediated fusion was augmented by the human LAMP1 receptor and progressed through lipid curvature-sensitive intermediates, such as hemifusion (merger of contacting leaflets of viral and cell membrane without the formation of a fusion pore). We found that most GPC-mediated fusion events were off-path hemifusion structures and that the transition from hemifusion to full fusion and fusion pore enlargement were specifically promoted by an anionic lipid, bis(monoacylglycero)phosphate, which is highly enriched in late endosomes. This lipid also specifically promotes fusion of unrelated New World Junin arenavirus. Our results imply that arenaviruses evolved to use bis(monoacylglycero)phosphate to enter cells from late endosomes. |
| Databáze: | OpenAIRE |
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