title: Host Cell Plasma Membrane Phosphatidylserine Regulates the Assembly and Budding of Ebola Virus.
abstract: Lipid-enveloped viruses replicate and bud from the host cell where they acquire their lipid coat. Ebola virus, which buds from the plasma membrane of the host cell, causes viral hemorrhagic fever and has a high fatality rate. To date, little has been known about how budding and egress of Ebola virus are mediated at the plasma membrane. We have found that the lipid phosphatidylserine (PS) regulates the assembly of Ebola virus matrix protein VP40. VP40 binds PS-containing membranes with nanomolar affinity, and binding of PS regulates VP40 localization and oligomerization on the plasma membrane inner leaflet. Further, alteration of PS levels in mammalian cells inhibits assembly and egress of VP40. Notably, interactions of VP40 with the plasma membrane induced exposure of PS on the outer leaflet of the plasma membrane at sites of egress, whereas PS is typically found only on the inner leaflet. Taking the data together, we present a model accounting for the role of plasma membrane PS in assembly of Ebola virus-like particles.
  
  
  OBJECTIVE
  The lipid-enveloped Ebola virus causes severe infection with a high mortality rate and currently lacks FDA-approved therapeutics or vaccines. Ebola virus harbors just seven genes in its genome, and there is a critical requirement for acquisition of its lipid envelope from the plasma membrane of the human cell that it infects during the replication process. There is, however, a dearth of information available on the required contents of this envelope for egress and subsequent attachment and entry. Here we demonstrate that plasma membrane phosphatidylserine is critical for Ebola virus budding from the host cell plasma membrane. This report, to our knowledge, is the first to highlight the role of lipids in human cell membranes in the Ebola virus replication cycle and draws a clear link between selective binding and transport of a lipid across the membrane of the human cell and use of that lipid for subsequent viral entry.
authors.affiliation: Department of Chemistry and Biochemistry, the Eck Institute for Global Health, and the Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Adu-Gyamfi
authors.affiliation: Department of Chemistry and Biochemistry, the Eck Institute for Global Health, and the Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Johnson
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine-South Bend, South Bend, Indiana, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fraser
authors.affiliation: Department of Chemistry and Biochemistry, the Eck Institute for Global Health, and the Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Jordan L
authors.initials: JL
authors.lastname: Scott
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine-South Bend, South Bend, Indiana, USA.
authors.forename: Smita P
authors.initials: SP
authors.lastname: Soni
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine-South Bend, South Bend, Indiana, USA.
authors.forename: Keaton R
authors.initials: KR
authors.lastname: Jones
authors.affiliation: Department of Biomedical Engineering, University of California, Irvine, Irvine, California, USA Centre for Bioactive Discovery in Health and Ageing, School of Science and Technology, University of New England, Armidale, Australia.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Digman
authors.affiliation: Department of Biomedical Engineering, University of California, Irvine, Irvine, California, USA.
authors.forename: Enrico
authors.initials: E
authors.lastname: Gratton
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine-South Bend, South Bend, Indiana, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Tessier
authors.affiliation: Department of Chemistry and Biochemistry, the Eck Institute for Global Health, and the Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, Indiana, USA Department of Biochemistry and Molecular Biology, Indiana University School of Medicine-South Bend, South Bend, Indiana, USA rstaheli@iu.edu.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Stahelin
mesh_terms: D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D002522:Chlorocebus aethiops; D003412:Cricetulus; D029043:Ebolavirus / Q000502:physiology*; D057809:HEK293 Cells; D019142:Hemorrhagic Fever, Ebola / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D010718:Phosphatidylserines / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000378:metabolism; D019065:Virus Assembly / Q000502:physiology*; D057074:Virus Release / Q000502:physiology*
chemical_list: D010718:Phosphatidylserines; C080981:VP40 protein, virus; D014763:Viral Matrix Proteins