title: Insulin degrading enzyme induces a conformational change in varicella-zoster virus gE, and enhances virus infectivity and stability.
abstract: Varicella-zoster virus (VZV) glycoprotein E (gE) is essential for virus infectivity and binds to a cellular receptor, insulin-degrading enzyme (IDE), through its unique amino terminal extracellular domain. Previous work has shown IDE plays an important role in VZV infection and virus cell-to-cell spread, which is the sole route for VZV spread in vitro. Here we report that a recombinant soluble IDE (rIDE) enhances VZV infectivity at an early step of infection associated with an increase in virus internalization, and increases cell-to-cell spread. VZV mutants lacking the IDE binding domain of gE were impaired for syncytia formation and membrane fusion. Pre-treatment of cell-free VZV with rIDE markedly enhanced the stability of the virus over a range of conditions. rIDE interacted with gE to elicit a conformational change in gE and rendered it more susceptible to proteolysis. Co-incubation of rIDE with gE modified the size of gE. We propose that the conformational change in gE elicited by IDE enhances infectivity and stability of the virus and leads to increased fusogenicity during VZV infection. The ability of rIDE to enhance infectivity of cell-free VZV over a wide range of incubation times and temperatures suggests that rIDE may be useful for increasing the stability of varicella or zoster vaccines.
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Qingxue
authors.initials: Q
authors.lastname: Li
authors.forename: Mir A
authors.initials: MA
authors.lastname: Ali
authors.forename: Kening
authors.initials: K
authors.lastname: Wang
authors.forename: Dean
authors.initials: D
authors.lastname: Sayre
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Hamel
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Fischer
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bennett
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Cohen
mesh_terms: D000818:Animals; D002474:Cell-Free System; D014645:Herpesvirus 3, Human / Q000235:genetics / Q000472:pathogenicity*; D007339:Insulysin / Q000378:metabolism*; D009154:Mutation; D011487:Protein Conformation; D014759:Viral Envelope Proteins / Q000737:chemistry*; D014774:Virulence
chemical_list: D014759:Viral Envelope Proteins; C056913:glycoprotein E, varicella-zoster virus; D007339:Insulysin