Abstract
Herpes simplex virus (HSV) is an important human pathogen. It enters cells through an orchestrated process that requires four essential glycoproteins, gD, gH/gL, and gB, activated in cascade fashion by receptor-binding and signaling. gH/gL heterodimer is conserved across the Herpesviridae family. HSV entry is enabled by gH/gL interaction with αvβ6- or αvβ8-integrin receptors. We report that the interaction of virion gH/gL with integrins resulted in gL dissociation and its release in the medium. gL dissociation occurred if all components of the entry apparatus-receptor-bound gD and gB-were present and was prevented if entry was blocked by a neutralizing monoclonal antibody to gH or by a mutation in gH. We propose that (i) gL dissociation from gH/gL is part of the activation of HSV glycoproteins, critical for HSV entry; and (ii) gL is a functional inhibitor of gH and maintains gH in an inhibited form until receptor-bound gD and integrins signal to gH/gL.
Keywords:
gH; gL; glycoprotein; herpes simplex virus; virus entry.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Motifs
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Antibodies, Monoclonal / pharmacology
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Antibodies, Neutralizing / pharmacology
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Antigens, Neoplasm / chemistry
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Antigens, Neoplasm / metabolism*
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Brefeldin A / pharmacology
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Cell Adhesion Molecules / metabolism
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Cell Line, Tumor
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Cell Membrane / drug effects
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Cell Membrane / metabolism
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Endocytosis / drug effects
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Epithelial Cells / virology
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Herpes Simplex / metabolism
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Herpes Simplex / virology
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Herpesvirus 1, Human / drug effects
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Herpesvirus 1, Human / physiology*
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Humans
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Integrins / chemistry
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Integrins / metabolism*
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Microscopy, Fluorescence
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Models, Biological
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Mutation / genetics
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Nectins
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Protein Structure, Tertiary
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Proteolysis / drug effects
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Solubility
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Viral Envelope Proteins / metabolism*
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Virion / drug effects
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Virion / metabolism
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Virus Internalization* / drug effects
Substances
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Antibodies, Monoclonal
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Antibodies, Neutralizing
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Antigens, Neoplasm
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Cell Adhesion Molecules
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Integrins
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Nectins
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Viral Envelope Proteins
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glycoprotein H, herpes simplex virus type 1
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glycoprotein L, Human herpesvirus 1
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integrin alphavbeta6
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integrin alphavbeta8
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Brefeldin A