A Role for Human Cytomegalovirus Glycoprotein O (gO) in Cell Fusion and a New Hypervariable Locus

Paterson, David A.; Dyer, Angela P.; Milne, Richard S. B.; Sevilla-Reyes, Edgar; Gompels, Ursula A.

doi:10.1006/viro.2001.1274

Cited by 47 publications

(66 citation statements)

References 70 publications

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“…Given that the role of gH/gL in entry is highly conserved among the herpesviruses, it seemed likely that gH/gL/gO might be involved in entry into fibroblasts. Consistent with this notion, Paterson et al showed that anti-gO antibodies decreased fusion from without caused by infection of cells with HCMV AD169 (37). These observations supported our working model in which gH/gL/UL128-131 mediates entry into epithelial and endothelial cells, while gH/gL/gO mediates entry into fibroblasts.…”

supporting

confidence: 73%

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Human Cytomegalovirus TR Strain Glycoprotein O Acts as a Chaperone Promoting gH/gL Incorporation into Virions but Is Not Present in Virions

Ryckman

Chase

Johnson

2010

J Virol

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Human cytomegalovirus (HCMV) produces the following two gH/gL complexes: gH/gL/gO and gH/gL/ UL128-131. Entry into epithelial and endothelial cells requires gH/gL/UL128-131, and we have provided evidence that gH/gL/UL128-131 binds saturable epithelial cell receptors to mediate entry. HCMV does not require gH/gL/UL128-131 to enter fibroblasts, and laboratory adaptation to fibroblasts results in mutations in the UL128-131 genes, abolishing infection of epithelial and endothelial cells. HCMV gO-null mutants produce very small plaques on fibroblasts yet can spread on endothelial cells. Thus, one prevailing model suggests that gH/gL/gO mediates infection of fibroblasts, while gH/gL/UL128-131 mediates entry into epithelial/endothelial cells. Most biochemical studies of gO have involved the HCMV lab strain AD169, which does not assemble gH/gL/UL128-131 complexes. We examined gO produced by the low-passage clinical HCMV strain TR. Surprisingly, TR gO was not detected in purified extracellular virus particles. In TR-infected cells, gO remained sensitive to endoglycosidase H, suggesting that the protein was not exported from the endoplasmic reticulum (ER). However, TR gO interacted with gH/gL in the ER and promoted export of gH/gL from the ER to the Golgi apparatus. Pulse-chase experiments showed that a fraction of gO remained bound to gH/gL for relatively long periods, but gO eventually dissociated or was degraded and was not found in extracellular virions or secreted from cells. The accompanying report by P. T. Wille et al. (J. Virol., 84:2585-2596, 2010) showed that a TR gO-null mutant failed to incorporate gH/gL into virions and that the mutant was unable to enter fibroblasts and epithelial and endothelial cells. We concluded that gO acts as a molecular chaperone, increasing gH/gL ER export and incorporation into virions. It appears that gO competes with UL128-131 for binding onto gH/gL but is released from gH/gL, so that gH/gL (lacking UL128-131) is incorporated into virions. Thus, our revised model suggests that both gH/gL and gH/gL/UL128-131 are required for entry into epithelial and endothelial cells.

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supporting

confidence: 73%

“…It is also reasonable to suggest that fibroblast adaptation includes changes in gO. The gO genes (UL74) of several laboratory and clinical strains and clinical isolates are highly variable (up to 25% of amino acids) (10,35,37,47). However, it is important to note that AD169-derived UL131-repair virus can infect epithelial and endothelial cells (52).…”

mentioning

confidence: 99%

Human Cytomegalovirus TR Strain Glycoprotein O Acts as a Chaperone Promoting gH/gL Incorporation into Virions but Is Not Present in Virions

Ryckman

Chase

Johnson

2010

J Virol

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“…For gH/ gL, two alternative complexes have been described: a complex of gH (UL75), gL (UL115), and gO (UL74) (16,24) and a complex of gH, gL, and pUL128, pUL130, and pUL131A (1,56). HCMV gH/gL complexes are supposed to play a role in promoting fusion of the viral envelope and cellular membranes and probably act in concert with gB and potentially through binding to integrin receptors (11,22,36,37,52,58). Recently, the role of the gH/gL/gO complex was analyzed in more detail.…”

mentioning

confidence: 99%

“…gO is N and O glycosylated and contains an amino-terminal hydrophobic membrane anchor which is cleaved off during processing (17,49,50). Data on the contribution of gO to the fusogenic activity of the gH/gL complex are controversial (36,52). It is also not exactly known whether gH/gL/gO complexes are consistently incorporated into HCMV particles or whether gO merely acts as a chaperone to promote incorporation of gH/gL complexes into virions (44,60).…”

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confidence: 99%

The m74 Gene Product of Murine Cytomegalovirus (MCMV) Is a Functional Homolog of Human CMV gO and Determines the Entry Pathway of MCMV

Scrivano

Esterlechner

Mühlbach

et al. 2010

J Virol

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The glycoprotein gO (UL74) of human cytomegalovirus (HCMV) forms a complex with gH/gL. Virus mutants with a deletion of gO show a defect in secondary envelopment with the consequence that virus spread is restricted to a cell-associated pathway. Here we report that the positional homolog of HCMV gO, m74 of mouse CMV (MCMV), codes for a glycosylated protein which also forms a complex with gH (M75). m74 knockout mutants of MCMV show the same spread phenotype as gO knockout mutants of HCMV, namely, a shift from supernatant-driven to cell-associated spread. We could show that this phenotype is due to a reduction of infectious virus particles in cell culture supernatants. m74 knockout mutants enter fibroblasts via an energydependent and pH-sensitive pathway, whereas in the presence of an intact m74 gene product, entry is neither energy dependent nor pH sensitive. This entry phenotype is shared by HCMV expressing or lacking gO. Our data indicate that the m74 and UL74 gene products both codetermine CMV spread and CMV entry into cells. We postulate that MCMV, like HCMV, expresses alternative gH/gL complexes which govern cell-to-cell spread of the virus.

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“…Data about the functional role of the main gB types in HCMV pathogenesis and their relationship with the clinical outcome of HCMV disease and virus cell/tissue tropism are controversial and in some cases, contradictory (4,8,10). The components of the glycoprotein envelope complex, gH, gL and gO, encoded by the ORFs UL75, UL115 and UL74, respectively, have also been shown to be polymorphic (5,20,25).…”

mentioning

confidence: 99%

Genetic Variability of Human Cytomegalovirus UL132 Gene in Strains from Infected Infants

Sun

Yao

Ruan

et al. 2006

Microbiology and Immunology

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A Role for Human Cytomegalovirus Glycoprotein O (gO) in Cell Fusion and a New Hypervariable Locus

Cited by 47 publications

References 70 publications

Human Cytomegalovirus TR Strain Glycoprotein O Acts as a Chaperone Promoting gH/gL Incorporation into Virions but Is Not Present in Virions

Human Cytomegalovirus TR Strain Glycoprotein O Acts as a Chaperone Promoting gH/gL Incorporation into Virions but Is Not Present in Virions

The m74 Gene Product of Murine Cytomegalovirus (MCMV) Is a Functional Homolog of Human CMV gO and Determines the Entry Pathway of MCMV

Genetic Variability of Human Cytomegalovirus UL132 Gene in Strains from Infected Infants

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