Fusion of epithelial cells by Epstein–Barr virus proteins is triggered by binding of viral glycoproteins gHgL to integrins αvβ6 or αvβ8

Chesnokova, Liudmila S.; Nishimura, Stephen L.; Hutt-Fletcher, Lindsey

doi:10.1073/pnas.0907508106

Cited by 181 publications

(203 citation statements)

References 48 publications

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“…EBV glycoprotein-mediated membrane fusion with epithelial cells does not require gp42 but only gB and gH/gL, and fusion can be completely blocked by saturating amounts of either gp42 or short gp42-derived peptides (13)(14)(15)(16), consistent with the hypothesis that gp42 levels in the virion regulate the cellular tropism of the virus in vivo (16). Recent observations indicate that EBV gH/gL engages integrins αvβ6 and/or αvβ8 on epithelial cells to trigger membrane fusion and entry (17).…”

supporting

confidence: 56%

“…The EBV gH/gL protein has a fourdomain architecture arranged linearly along the length of the polypeptide chain, with the N-terminal D-I being formed by both gH and gL subunits, similar to the structures of HSV-2 gH/gL (28) and a PRV gH fragment (33). Functional regions in EBV gH/gL have been mapped to at least four areas, including D-I, the interface between D-I and D-II, D-IV, and a prominently displayed KGD sequence in D-II implicated in integrin binding and epithelial cell entry (17). The integrin binding loop (residues 188-190) lies next to the functionally important L74 (34).…”

Section: Resultsmentioning

confidence: 99%

“…Recently, the interaction of EBV gH/gL with αvβ6 and αvβ8 integrins has been implicated in triggering viral fusion with epithelial cells (17). In the structure, the identified KGD motif is located in a prominent D-II loop between strands 2β-6 and 2β-7 ( Fig.…”

Section: Resultsmentioning

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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supporting

confidence: 56%

Section: Resultsmentioning

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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“…Remarkably, the use of integrins as receptors is a common feature among herpesviruses. Integrins serve as receptors also for gH/gL of EBV (Epstein Barr virus), of human cytomegalovirus and equine herpesvirus, and for gB of Kaposi's sarcoma-associated herpesvirus (24)(25)(26)(27)(28). Most likely, they play a common role.…”

mentioning

confidence: 99%

Dissociation of HSV gL from gH by αvβ6- or αvβ8-integrin promotes gH activation and virus entry

Gianni

Massaro

Campadelli-Fiume

2015

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

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Herpes simplex virus (HSV) is an important human pathogen. It enters cells through an orchestrated process that requires four essential glycoproteins, gD, gH/gL, and gB, activated in cascade fashion by receptor-binding and signaling. gH/gL heterodimer is conserved across the Herpesviridae family. HSV entry is enabled by gH/gL interaction with αvβ6-or αvβ8-integrin receptors. We report that the interaction of virion gH/gL with integrins resulted in gL dissociation and its release in the medium. gL dissociation occurred if all components of the entry apparatus-receptor-bound gD and gB-were present and was prevented if entry was blocked by a neutralizing monoclonal antibody to gH or by a mutation in gH. We propose that (i) gL dissociation from gH/gL is part of the activation of HSV glycoproteins, critical for HSV entry; and (ii) gL is a functional inhibitor of gH and maintains gH in an inhibited form until receptor-bound gD and integrins signal to gH/gL.herpes simplex virus | glycoprotein | gH | gL | virus entry E ntry of herpesviruses into the cell is an orchestrated process that necessitates a multipartite glycoprotein system, rather than onetwo glycoproteins, as is the case for the vast majority of viruses (1-4). For herpes simplex virus (HSV), the entry-fusion apparatus consists of four essential glycoproteins -gD, the heterodimer gH/gL, and gB-plus cognate cellular receptors. gD is the major determinant of HSV tropism. Structurally, it exhibits an Ig-folded core with N-and C-terminal extensions (5, 6). The structure of the gH/gL heterodimer does not resemble that of any known protein (7-9). The binding site of gL in gH maps to the N-terminal domain I. Whether gH/gL has a profusion activity in itself or is only an intermediate between gD and gB in the chain of activation of the glycoproteins is an open question (10-13). gB is considered the fusogenic glycoprotein, based on structural features, including a trimeric fold and a bipartite fusion loop (14, 15). gH, gL, and gB constitute the conserved-entry glycoproteins across the Herpesviridae family. The ability of gH to heterodimerize with gL is also conserved across the family, highlighting that the heterodimeric structure is critical to the function of two glycoproteins.The prevailing model of HSV entry envisions that following a first virion attachment to cells mediated by heparan sulfate glycosaminoglycans, the interaction of gD with one of its receptors, nectin1 and HVEM (herpesvirus entry mediator), results in conformational changes to gD, in particular to the ectodomain C terminus, which harbors the profusion domain (5,6,16,17). The activated gD recruits gH/gL, which, in turn, recruits gB. gB executes the virus-cell fusion (2-4, 18, 19). We observed that the glycoproteins are already in complex in resting virions (17,18). In contrast with the view that glycoproteins are stepwise-recruited to a complex, we favor the view that the process of activation of the viral glycoproteins results from the interaction of preassembled glycoproteins' complexes with cellu...

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“…8 When infecting epithelial cells, EBV BRMF-2 protein binds to β1 integrin present on the cell membrane while the viral envelope protein gH/gL binds to epithelial αvβ6/8 integrin. 9 In both B-cells and epithelial cells, the virus is engulfed via endocytosis. Once inside the cell, the viral envelope fuses with the engulfed vesicle, releasing the nucleocapsid into the host cell's cytoplasm where the nucleocapsid is subsequently dissolved.…”

Section: Introductionmentioning

confidence: 99%

Epstein-Barr Virus (EBV) and the Effectiveness of Suberoylanilide Hydroxamic Acid (SAHA) as a Treatment for EBV Infection and Associated Cancers

Bart¹,

Johnson²,

DeGol³

et al. 2013

Advances in Tumor Virology

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Since being discovered in 1964, Epstein-Barr virus (EBV) has become a growing concern. Clinically, EBV is responsible for many diseases, most notably infectious mononucleosis. In addition to mononucleosis, EBV causes several cancers such as Hodgkin's lymphoma, Burkitt's lymphoma, and nasopharyngeal carcinoma (NPC). Suberoylanilide hydroxamic acid (SAHA) is an anti-cancer drug that inhibits growth and proliferation of various EBV-related cancers. SAHA acts as a histone deacetylase (HDAC) inhibitor. The responsiveness of SAHA treatment stems from the induction of EBV's lytic cycle.

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Fusion of epithelial cells by Epstein–Barr virus proteins is triggered by binding of viral glycoproteins gHgL to integrins αvβ6 or αvβ8

Cited by 181 publications

References 48 publications

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

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

Dissociation of HSV gL from gH by αvβ6- or αvβ8-integrin promotes gH activation and virus entry

Epstein-Barr Virus (EBV) and the Effectiveness of Suberoylanilide Hydroxamic Acid (SAHA) as a Treatment for EBV Infection and Associated Cancers

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