Abstract
The entry of enveloped viruses into host cells is preceded by membrane fusion, which in Epstein-Barr virus (EBV) is thought to be mediated by the refolding of glycoprotein B (gB) from a prefusion to a postfusion state. In our current studies, we characterized a gB C-terminal tail domain (CTD) mutant truncated at amino acid 843 (gB843). This truncation mutant is hyperfusogenic as monitored by syncytium formation and in a quantitative fusion assay and is dependent on gH/gL for fusion activity. gB843 can rescue the fusion function of other glycoprotein mutants that have null or decreased fusion activity in epithelial and B cells. In addition, gB843 requires less gp42 and gH/gL for fusion, and can function in fusion at a lower temperature than wild-type gB, indicating a lower energy requirement for fusion activation. Since a key step in fusion is the conversion of gB from a prefusion to an active postfusion state by gH/gL, gB843 may access this activated gB state more readily. Our studies indicate that the gB CTD may participate in the fusion function by maintaining gB in an inactive prefusion form prior to activation by receptor binding. Importance: Diseases resulting from Epstein-Barr virus (EBV) infection in humans range from the fairly benign disease infectious mononucleosis to life-threatening cancer. As an enveloped virus, EBV must fuse with a host cell membrane for entry and infection by using glycoproteins gH/gL, gB, and gp42. Among these glycoproteins, gB is thought to be the protein that executes fusion. To further characterize the function of the EBV gB cytoplasmic C-terminal tail domain (CTD) in fusion, we used a previously constructed CTD truncation mutant and studied its fusion activity in the context of other EBV glycoprotein mutants. From these studies, we find that the gB CTD regulates fusion by altering the energy requirements for the triggering of fusion mediated by gH/gL or gp42. Overall, our studies may lead to a better understanding of EBV fusion and entry, which may result in novel therapies that target the EBV entry step.
Highlights
The entry of enveloped viruses into host cells is preceded by membrane fusion, which in Epstein-Barr virus (EBV) is thought to be mediated by the refolding of glycoprotein B from a prefusion to a postfusion state
Four viral-membrane-associated proteins are responsible for the entry of the virus into the host cell: glycoprotein 42, gH, gL, and glycoprotein B (gB). gp42 binds to the HLA class II molecules of B cells and determines the EBV infection tropism; it is required for B cell fusion and inhibits epithelial-cell fusion [2,3,4,5,6,7]. gH is a receptor binding protein that interacts with gp42 or integrins, receptors that are important for epithelial-cell fusion [8, 9]. gL is essential for the correct folding of gH and its transport to the cell surface [10], and gB is a class III viral fusogen [6, 11,12,13,14,15]
The entry of enveloped viruses into a host cell is preceded by membrane fusion, which in EBV is triggered either by gp42 binding to HLA class II molecules or by gH/gL binding to integrins [8, 41]
Summary
The entry of enveloped viruses into host cells is preceded by membrane fusion, which in Epstein-Barr virus (EBV) is thought to be mediated by the refolding of glycoprotein B (gB) from a prefusion to a postfusion state. EBV must fuse with a host cell membrane for entry and infection by using glycoproteins gH/gL, gB, and gp42 Among these glycoproteins, gB is thought to be the protein that executes fusion. To further characterize the function of the EBV gB cytoplasmic C-terminal tail domain (CTD) in fusion, we used a previously constructed CTD truncation mutant and studied its fusion activity in the context of other EBV glycoprotein mutants. There is no direct evidence of EBV gB refolding, a model of the prefusion and postfusion states of gB has been proposed, and it is hypothesized that gB may undergo major conformational changes during the fusion process [11]
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