Plasma membrane requirements for cell fusion induced by herpes simplex virus type 1 glycoproteins gB, gD, gH and gL

Browne, Helena; Bruun, Birgitte; Minson, Tony

doi:10.1099/0022-1317-82-6-1419

Cited by 82 publications

(78 citation statements)

References 21 publications

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“…This had been demonstrated earlier for the equivalent HSV-1 proteins (38), and the assay was subsequently characterized further (4,30). A similar system was reported for PRV, although in this case, the gD homolog was not required (21).…”

Section: Resultssupporting

confidence: 56%

Truncation of Herpes Simplex Virus Type 2 Glycoprotein B Increases Its Cell Surface Expression and Activity in Cell-Cell Fusion, but These Properties Are Unrelated

Fan

Grantham

Smith

et al. 2002

J Virol

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Formation of small polykaryons by cell-cell fusion is characteristic of herpes simplex virus (HSV) lesions, but the great majority of viruses isolated from such lesions produce only limited cell fusion in tissue culture. Because of this, HSV laboratory strains that produce extensive cell fusion (syncytium formation) in culture are regarded as variants or mutants. Furthermore, the rarity of clinical isolates able to produce syncytia in culture suggests that extensive cell fusion is deleterious in vivo. Mutations that confer a syncytial phenotype can then be regarded as bypassing a mechanism that normally limits cell fusion. Determination of how these mutations, some of which are in the cytoplasmic tail of glycoprotein B (gB), lead to syncytium formation will likely reveal how fusion is controlled. Here we show the following. (i) Truncation of the cytoplasmic tail of HSV type 2 gB (gB-2) by a minimum of 25 residues or a maximum of 49 residues produces a syncytial phenotype. (ii) Truncation by 20 to 49 residues increases cell fusion when gB-2 is coexpressed with only gD-2, gH-2, and gL-2. (iii) Truncation by 25 or more residues removes a potential endocytosis motif and increases gB-2 cell surface expression. (iv) Mutation of this motif increases gB-2 cell surface expression but does not increase fusogenic activity, whereas mutation of another potential endocytosis motif does not increase surface expression but does increase fusogenic activity. Therefore, syncytial mutations in the cytoplasmic tail of gB-2 do not act by increasing cell surface levels of the protein.Membrane fusion is a crucial facet in the life cycle of herpesviruses: in virus entry, in virus spread, probably in virus egress, and for some viruses, in cell-cell fusion. For herpes simplex viruses (HSV), entry into the cell occurs by fusion of the virus envelope with the cell plasma membrane (14, 24, 42) via a process that requires the concerted action of four viral glycoproteins, namely, glycoprotein B (gB), gD, gH, and gL (7,13,23,32). HSV membrane proteins can also cause fusion of infected cells with neighboring cells to produce polykaryocytes or syncytia; this occurs to a limited extent in herpes lesions and in cell cultures infected with wild-type strains of the virus (2, 12, 34, 41), but variants that cause more extensive fusion in tissue culture can be isolated from laboratory stocks without mutagenesis and the resulting syncytia may contain thousands of nuclei (35).Extensive cell-cell fusion in tissue culture requires the four glycoproteins involved in virus entry plus gE, gI, gM, and UL45 (10, 16); it also requires a syn mutation at any one of four loci (35), namely, gB, gK, UL20, or UL24. Because clinical isolates are rarely syncytial, whereas a wild-type virus can acquire a syncytial phenotype by a single conservative amino acid substitution in, for example, gB, it seems likely that a syncytial phenotype is actually deleterious to the virus in vivo. This possibility is supported by the finding that most of the syncytial variants tested are l...

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Section: Resultssupporting

confidence: 56%

Truncation of Herpes Simplex Virus Type 2 Glycoprotein B Increases Its Cell Surface Expression and Activity in Cell-Cell Fusion, but These Properties Are Unrelated

Fan

Grantham

Smith

et al. 2002

J Virol

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“…Mitosis and Ki67 expression are absent in multinucleate myxoma cells, suggesting that these cells may be formed by cell fusion rather than cell proliferation. It is well established that the fusion of infected cells with neighboring cells in herpes lesions induced by several viral glycoproteins including gD, 43 producing polykaryocytes, is one of the pathways by which HSV-1 spreads in vivo.…”

Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus Type 1 Infection Associated with Atrial Myxoma

Pan

et al. 2003

The American Journal of Pathology

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Some findings suggest an infectious factor in cardiac myxoma and certain histopathological features indicate herpes simplex virus type 1 (HSV-1) infection. We hypothesized that HSV-1 may be involved in the pathogenesis of cardiac myxoma. Paraffin-embedded tissue samples from 17 patients with atrial myxoma were investigated for HSV-1 antigen by immunohistochemistry and viral genomic DNA by nested polymerase chain reaction. The histogenesis and oncogenesis of atrial myxoma were assessed by the expression of calretinin, Ki67, and p53 protein, respectively. Autopsy myocardial samples, including endocardium from 12 patients who died by accident or other conditions, were used for comparison. HSV-1 antigen was detected in atrial myxoma from 12 of 17 patients: 8 of these 12 samples were positive also for HSV-1 DNA. No HSV-1 antigen or DNA was found in tissue from the comparison group. Antigens of HSV-2, varicella-zoster virus, Epstein-Barr virus, and cytomegalovirus were not found in atrial myxoma. Calretinin was found in myxoma cells of all 17 cases but Ki67 was present only in smooth muscle cells or infiltrating cells in some cases. p53 was not detectable in any myxoma. Most infiltrating cells were cytotoxic T lymphocytes. These data suggest that HSV-1 infection is associated with some cases of sporadic atrial myxoma and that these may result from a chronic inflammatory lesion of endocardium. Although benign, atrial myxoma is the most common primary cardiac tumor, with an incidence of about one per million population per year and a recurrence rate of 2% to 3%.

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“…A prefusion model of the EBV gB structure has been proposed (18), but there is no experimental evidence to date for this conformational transition in the herpesvirus glycoproteins. In contrast to the VSV and baculovirus fusion proteins, which act independently, herpesvirus gB requires gH/gL for the most efficient membrane fusion (15,26,27).…”

mentioning

confidence: 99%

Crystal structure of the Epstein-Barr virus (EBV) glycoprotein H/glycoprotein L (gH/gL) complex

Matsuura

Kirschner

Longnecker

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

151

205

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The Epstein-Barr virus (EBV) is a γ-herpesvirus that infects B cells and epithelial cells and that has been linked to malignancies in both cell types in vivo. EBV, like other herpesviruses, has three glycoproteins, glycoprotein B (gB), gH, and gL, that form the core membrane fusion machinery mediating viral penetration into the cell. The gH and gL proteins associate to form a heterodimeric complex, which is necessary for efficient membrane fusion and also implicated in direct binding to epithelial cell receptors required for viral entry. To gain insight into the mechanistic role of gH/gL, we determined the crystal structure of the EBV gH/gL complex. The structure is comprised of four domains organized along the longest axis of the molecule. Comparisons with homologous HSV-2 gH/gL and partial pseudorabies virus gH structures support the domain boundaries determined for the EBV gH/gL structure and illustrate significant differences in interdomain packing angles. The gL subunit and N-terminal residues of gH form a globular domain at one end of the structure, implicated in interactions with gB and activation of membrane fusion. The C-terminal domain of gH, proximal to the viral membrane, is also implicated in membrane fusion. The gH/gL structure locates an integrin binding motif, implicated in epithelial cell entry, on a prominent loop in the central region of the structure. Multiple regions of gH/gL, including its two extreme ends, are functionally important, consistent with the multiple roles of gH/gL in EBV entry.

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Plasma membrane requirements for cell fusion induced by herpes simplex virus type 1 glycoproteins gB, gD, gH and gL

Cited by 82 publications

References 21 publications

Truncation of Herpes Simplex Virus Type 2 Glycoprotein B Increases Its Cell Surface Expression and Activity in Cell-Cell Fusion, but These Properties Are Unrelated

Truncation of Herpes Simplex Virus Type 2 Glycoprotein B Increases Its Cell Surface Expression and Activity in Cell-Cell Fusion, but These Properties Are Unrelated

Herpes Simplex Virus Type 1 Infection Associated with Atrial Myxoma

Crystal structure of the Epstein-Barr virus (EBV) glycoprotein H/glycoprotein L (gH/gL) complex

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