Different Functional Domains in the Cytoplasmic Tail of Glycoprotein B Are Involved in Epstein–Barr Virus-Induced Membrane Fusion

Haan, Keith M.; Lee, Suk Kyeong; Longnecker, Richard

doi:10.1006/viro.2001.1141

Cited by 120 publications

(157 citation statements)

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“…The purpose of this study was to investigate the requirements for EBV-induced cell fusion with epithelial cells and to examine whether differences exist between B cells and epithelial cells. For B cells, gp350 is not required for EBVinduced cell fusion, but gp42, gB, gH, and gL are necessary and sufficient (8). gp350 is dispensable for entry given that a virus lacking gp350 still infects numerous lymphoid and epithelial cell lines (43).…”

Section: Results Gb Gh and Gl Mediate Efficient Fusion With Some Humentioning

confidence: 99%

“…Additionally, EBV gp350͞220 binds to the B cell-surface receptor CD21͞CR2, and this binding mediates the initial interaction of EBV with B cells and is thought to tether the virus to promote the subsequent binding of gp42 to HLA class II (6,7). The gp42-class II interaction is then proposed to trigger membrane fusion, a reaction mediated by gH (EBV gp85), gL (EBV gp25), and gB (EBV gp110) (8). The exact role each of these glycoproteins plays in fusion is unclear.…”

mentioning

confidence: 99%

“…More recent studies of recombinant viruses with specific deletions in gB has shown that gB is essential for the production of infectious virus (21,22). Finally, gB coexpressed with other viral glycoproteins is required for cell-cell fusion in cell-based fusion assays for pseudorabies virus, HSV-1, HSV-2, HHV-8, and EBV (8,(23)(24)(25)(26)(27).…”

mentioning

confidence: 99%

“…The role of the gB tail in regulating herpesvirus-induced membrane fusion is most apparent because many mutations that modulate fusion are located in the gB C terminus (23,24,(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). For EBV, the C terminus also contains domains that are important for cell fusion and the cellular localization of gB (8,21). Four arginine residues in the C terminus (836-839) are required for the localization of gB primarily to the endoplasmic reticulum (ER)͞nuclear membrane (39).…”

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confidence: 99%

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Cell-surface expression of a mutated Epstein–Barr virus glycoprotein B allows fusion independent of other viral proteins

McShane

Longnecker

2004

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

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Epstein-Barr virus (EBV) infects human B lymphocytes and epithelial cells. We have compared the requirements for EBV glycoprotein-induced cell fusion between Chinese hamster ovary effecter cells and human B lymphoblasts or epithelial cells by using a virus-free cell fusion assay. EBV-encoded gB, gH, gL, and gp42 glycoproteins were required for efficient B cell fusion, whereas EBV gB, gH, and gL glycoproteins were required for Chinese hamster ovary effecter cell fusion with epithelial cell lines (AGS and SCC68) or the human embryonic kidney cell line 293-P. Fusion with human embryonic kidney 293-P cells was greater than fusion observed with B cells, indicative of an important role for cell contact. An antibody directed against the gH and gL complex inhibited epithelial cell fusion. Increased surface expression of gB alone as a result of truncations or point mutants in the carboxyl-terminal tail allowed gB-mediated fusion with epithelial cells, albeit at a lower level than with coexpression of gB, gH, and gL. Overall, gB appears to be the critical component for EBV glycoprotein-mediated cell fusion. viral entry ͉ herpesvirus T he entry process of human herpesviruses entails a two-step process: binding followed by fusion. Specific herpesvirusencoded glycoproteins and cell-surface receptors are important for both events (1-3). Entry may occur by free virus infecting a cell or by cell-cell spread (2). In either case, fusion is a prerequisite for infection. Despite herpesvirus genomes encoding many viral glycoproteins, the glycoproteins implicated in entry and fusion are limited and conserved (1). Most herpesviruses require the conserved glycoproteins gH, gL, and gB, as well as an additional, family-specific viral glycoprotein, such as gD for ␣-herpesviruses or gp42 for the ␥-herpesvirus Epstein-Barr virus (EBV), for efficient entry and fusion (1). These nonconserved glycoproteins result in cell specificity by recognizing distinct cellular receptors. For example, EBV glycoprotein 42 binds to HLA class II on B cells, an interaction essential for the infection of B cells (4, 5). Additionally, EBV gp350͞220 binds to the B cell-surface receptor CD21͞CR2, and this binding mediates the initial interaction of EBV with B cells and is thought to tether the virus to promote the subsequent binding of gp42 to HLA class II (6, 7). The gp42-class II interaction is then proposed to trigger membrane fusion, a reaction mediated by gH (EBV gp85), gL (EBV gp25), and gB (EBV gp110) (8). The exact role each of these glycoproteins plays in fusion is unclear.EBV can enter cells by means of two routes, depending on the host cell type. In primary human lymphocytes, EBV is endocytosed before fusion, whereas, in B cells in culture, the virion envelope directly fuses with the plasma membrane (9, 10). Similarly to B cells in culture, fusion of EBV with epithelial cells occurs by direct fusion of the virion envelope with the plasma membrane. Despite B lymphocytes being the primary site for latency, the tropism of EBV for epithelial cells is suppor...

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Section: Results Gb Gh and Gl Mediate Efficient Fusion With Some Humentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Cell-surface expression of a mutated Epstein–Barr virus glycoprotein B allows fusion independent of other viral proteins

McShane

Longnecker

2004

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

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“…Entry requires fusion of virus with the B-cell membrane, which is mediated by glycoprotein gB (8), and a noncovalently linked complex of three glycoproteins, gH, gL, and gp42 (9,20,37). Glycoprotein gL serves as a chaperone for gH (40), and a recombinant virus with gH deleted also lacks gL (20).…”

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Use of gHgL for Attachment of Epstein-Barr Virus to Epithelial Cells Compromises Infection

Borza

Morgan

Turk

et al. 2004

J Virol

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Epstein-Barr virus (EBV) is a lymphotropic herpesvirus. However, access to B lymphocytes during primary infection may be facilitated by replication in mucosal epithelial cells. Attachment and penetration of EBV into these two cell types are fundamentally different. Both the distribution of receptors and the cellular origin of the virus impact the efficiency of infection. Epithelial cells potentially offer a wide range of receptors with which virus can interact. We report here on analyses of epithelial cells expressing different combinations of receptors. We find that the stoichiometry of the virus glycoprotein complex that includes gHgL and gp42 affects the use of gHgL not just for entry into epithelial cells but also for attachment. Penetration can be mediated efficiently with either a coreceptor for gp42 or gHgL, but the use of gHgL for attachment as well as penetration greatly compromises its ability to mediate entry.Epstein-Barr virus (EBV) is predominantly a lymphotropic herpesvirus. It is the etiologic agent of most cases of infectious mononucleosis and has been implicated in development of immunoblastic lymphoma, endemic Burkitt's lymphoma, and certain types of Hodgkin's disease. However, the virus also has tropism for epithelial cells. It causes oral hairy leukoplakia, a wart-like lesion of the oral cavity, and is associated with development of nasopharyngeal and gastric carcinomas (28). Initiation of infection of these two key targets, B lymphocytes and epithelial cells, is substantially different. It probably involves different routes (18) and certainly involves different envelope glycoproteins and cell receptors.B-cell infection is initiated by attachment of glycoprotein gp350/220 to the complement receptor type 2 (CR2) (6,21,22,34). Entry requires fusion of virus with the B-cell membrane, which is mediated by glycoprotein gB (8), and a noncovalently linked complex of three glycoproteins, gH, gL, and gp42 (9,20,37). Glycoprotein gL serves as a chaperone for gH (40), and a recombinant virus with gH deleted also lacks gL (20). Thus, with few exceptions, the functions of gH and gL cannot be mapped to either one of the two components. However, the third protein, gp42, plays no known role in gHgL maturation and is unique among human herpesviruses. It interacts with HLA class II (32), which functions as an essential coreceptor for B-cell infection (7,14). A monoclonal antibody (MAb) to gp42 that blocks the interaction with HLA class II inhibits virus cell fusion (15,19), and a MAb to HLA class II that blocks gp42 binding neutralizes virus infection. In further support of a critical role for gp42 in B-cell infection, a virus that lacks gp42 fails to infect B cells unless cells and bound virus are fused with polyethylene glycol (37) or a soluble form of gp42 which lacks a transmembrane domain but retains the ability to bind to gH and gL is added in trans (38).In contrast, not only is gp42 completely dispensable for entry into epithelial cells that do not constitutively express HLA class II, its presence is al...

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Epstein–Barr Virus Entry

Longnecker¹,

Hutt-Fletcher²,

Jardetzky³

2008

DNA Tumor Viruses

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Entry of Epstein-Barr virus into human lymphoblastoid cells (Daudi cells) was studied by electron microscopy. At the site of viral attachment, two distinct interactions conducive to penetration of the virus occurred between the viral envelope and cell membrane, namely, (i) simultaneous dissolution of both the envelope and cell membrane, presumably resulting in passage of viral capsids into the cytoplasm and (ii) dissolution confined to the cell membrane with resulting penetration of enveloped virus. In the latter case envelope dissolution appears to occur subsequently in the cytoplasm with release of capsids. Fusion of the viral envelope with the cell membrane was not observed. The capsids exhibited two distinct structural forms one dense, the other translucent or light in appearance. The former disrupted near the cell membrane with release of viral cores into the cytoplasm whereas the light capsids containing dense cores migrated toward the nucleus and accumulated in the perinuclear region. Apparently the process of releasing deoxyribonucleic acid (DNA) from the light capsid is slowed down or prevented in Daudi cells. A hypothesis is presented concerning the manner in which these two types of capsids initiate infection.

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Different Functional Domains in the Cytoplasmic Tail of Glycoprotein B Are Involved in Epstein–Barr Virus-Induced Membrane Fusion

Cited by 120 publications

References 55 publications

Cell-surface expression of a mutated Epstein–Barr virus glycoprotein B allows fusion independent of other viral proteins

Cell-surface expression of a mutated Epstein–Barr virus glycoprotein B allows fusion independent of other viral proteins

Use of gHgL for Attachment of Epstein-Barr Virus to Epithelial Cells Compromises Infection

Epstein–Barr Virus Entry

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