Epstein-Barr Virus Entry

Hutt-Fletcher, Lindsey

doi:10.1128/jvi.00445-07

Cited by 243 publications

(244 citation statements)

References 72 publications

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“…A well characterized example is that of Epstein-Barr virus (EBV) (reviewed in ref. 37). The EBV gH/gL complex can be modified by the addition of gp42.…”

Section: Discussionmentioning

confidence: 99%

HCMV gH/gL/UL128–131 interferes with virus entry into epithelial cells: Evidence for cell type-specific receptors

Ryckman

Chase

Johnson

2008

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

150

159

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Human cytomegalovirus (HCMV) forms two different membrane protein complexes, gH/gL/gO and gH/gL/UL128/UL130/UL131, that function in different cell types. gH/gL/gO appears to be important for HCMV entry into or spread between fibroblasts, processes that occur at neutral pH. We demonstrated that HCMV entry into epithelial and endothelial cells requires gH/gL/UL128 -131 and involves endocytosis and low pH. A complex of all five HCMV proteins, gH, gL, UL128, UL130, and UL131, is the functionally important mediator of this entry pathway into epithelial/endothelial cells. Here, we report that expression of gH/gL/UL128 -131 in ARPE-19 epithelial cells causes the cells to be resistant to HCMV infection. Another HCMV glycoprotein, gB, did not interfere, and expression of all five gH/gL/UL128 -131 proteins was required for this interference. gH/gL/UL128 -131 interference was at the stage of virus entry into cells rather than the initial adsorption onto cell surfaces or after-entry defects. By contrast, expression of gH/gL/ UL128 -131 in primary human fibroblasts did not block HCMV infection. Previously, interference by retrovirus and herpes-simplex-virus entry mediators resulted from sequestration or obstruction of receptors. We concluded that epithelial cells express gH/ gL/UL128 -131 receptors that mediate HCMV entry. Fibroblasts either lack the gH/gL/UL128 -131 receptors, the receptors are more numerous, or fibroblasts express other functional receptors.HCMV glycoproteins ͉ receptor interference

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“…A well characterized example is that of Epstein-Barr virus (EBV) (reviewed in ref. 37). The EBV gH/gL complex can be modified by the addition of gp42.…”

Section: Discussionmentioning

confidence: 99%

HCMV gH/gL/UL128–131 interferes with virus entry into epithelial cells: Evidence for cell type-specific receptors

Ryckman

Chase

Johnson

2008

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

150

159

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“…Burkitt lymphoma, as well as NPC, an epithelial carcinoma (19). Complexes of pIgA bound to a surface protein of EBV are efficiently transcytosed across pIgR-expressing hepatocytes and polarized MDCK cells without causing EBV infection (9).…”

Section: Discussionmentioning

confidence: 99%

Reduced Immunoglobulin A Transcytosis Associated with Immunoglobulin A Nephropathy and Nasopharyngeal Carcinoma

Chapin

Bryant

et al. 2011

Journal of Biological Chemistry

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Background:The A580V human pIgR polymorphism is associated with IgA nephropathy and nasopharyngeal carcinoma. Results: A580V mutation reduces pIgR/pIgA transcytosis and seemingly pIgR cleavage and release from the apical surface. Conclusion: The A580V polymorphism regulates pIgR and IgA-pIgR complex transcytosis across cells. Significance: Defects in pIgR trafficking and processing may underlie the pathogenesis of IgA nephropathy and nasopharyngeal carcinoma.Polymeric IgA (pIgA) is transcytosed by the pIgA receptor (pIgR) across mucosal epithelial cells. After transcytosis to the apical surface, the extracellular, ligand-binding portion of the pIgR is proteolytically cleaved. A missense mutation in human pIgR, A580V, is associated with IgA nephropathy and nasopharyngeal carcinoma. We report that this mutation reduces the rate of transcytosis of pIgR and pIgA, and seemingly the rate of pIgR cleavage. We propose that the defects in pIgR trafficking caused by the A580V mutation may underlie the pathogenesis of both diseases.The polymeric immunoglobulin receptor (pIgR) 5 is a singlespanning transmembrane protein expressed on many epithelial cells lining mucosal surfaces (1-3). At the basolateral (BL) cell surface, the pIgR binds its ligand, polymeric IgA (pIgA). The pIgA can in turn be bound to its antigen. The pIgR-pIgA complex is endocytosed and transcytosed through a series of endocytic vesicles to the apical (AP) surface. There, the extracellular, ligand binding domain of pIgR is proteolytically cleaved and released together with the pIgA into external secretions. This cleaved fragment of pIgR is termed secretory component (SC).A missense mutation (pIgR-A580V) in the extracellular region of human pIgR is associated with increased risk of IgA nephropathy (IgAN) in Japan (4). IgAN is the main cause of primary glomerulonephritis worldwide, especially in east Asia; 20 -40% of patients progress to end stage renal failure (5). The pIgR-A580V mutation has also been associated in two studies with increased risk of nasopharyngeal carcinoma (NPC) in Thai and southern Chinese populations, where NPC is a leading form of cancer (6 -8). This result is intriguing, because EpsteinBarr virus (EBV), the causative agent of NPC, can enter epithelial cells via binding to the pIgR of pIgA antibodies directed against EBV (9, 10). EXPERIMENTAL PROCEDURES Plasmids, Viral Production and Transduction, and CellCulture-Human pIgR in pcDNA3.1 was kindly provided by C. Kaetzel (University of Kentucky). The A580V point mutation was made by QuikChange mutagenesis (Stratagene). pIgR (WT and A580V) coding sequence was transferred to pLZRS-MS/ IRES-GFP retroviral vector (A. Reynolds, Vanderbilt University), giving expression of hpIgR and GFP under IRES control. Viral production and transduction were performed as described (11), with some modifications. pLZRS vectors were transfected into 293-GPG packaging cells (O. Weiner, University of California San Francisco). The following day, fresh medium was added, and viral supernatants collected 3 days ...

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“…For both cell types, the minimal viral glycoprotein components that mediate membrane fusion have been identified (4,5). As with other herpesviruses, EBV uses the core viral entry glycoproteins, glycoprotein B (gB) and the gH/gL complex.…”

mentioning

confidence: 99%

“…As with other herpesviruses, EBV uses the core viral entry glycoproteins, glycoprotein B (gB) and the gH/gL complex. For the infection of B lymphocytes, EBV requires an additional protein, gp42, which binds to host HLA class II molecules, triggering the membrane fusion step (4,5). gp42 has multiple functional sites for interaction with gH/gL, HLA class II, and potentially, another unknown binding ligand that could be engaged through a large surface-exposed hydrophobic pocket (6)(7)(8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

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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.

146

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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Epstein-Barr Virus Entry

Cited by 243 publications

References 72 publications

HCMV gH/gL/UL128–131 interferes with virus entry into epithelial cells: Evidence for cell type-specific receptors

HCMV gH/gL/UL128–131 interferes with virus entry into epithelial cells: Evidence for cell type-specific receptors

Reduced Immunoglobulin A Transcytosis Associated with Immunoglobulin A Nephropathy and Nasopharyngeal Carcinoma

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

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