The Human Cytomegalovirus-Specific
            <i>UL1</i>
            Gene Encodes a Late-Phase Glycoprotein Incorporated in the Virion Envelope

Shikhagaie, Medya; Mercé-Maldonado, Eva; Isern, Elena; Muntasell, Aura; Albà, M. Mar; López‐Botet, Miguel; Hengel, Hartmut; Angulo, Ana

doi:10.1128/jvi.06291-11

Cited by 20 publications

(20 citation statements)

References 60 publications

(92 reference statements)

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“…Out of the total number of proteins composing the HCMV virion, approximately 20 have been identified as envelope-associated proteins (10)(11)(12). Notably, all glycoproteins involved in HCMV cell entry were shown to be essential for virus replication in vitro in different cell types: glycoproteins B (gB), M (gM), N (gN), L (gL), H (gH), UL128, UL130, and UL131A (13).…”

mentioning

confidence: 99%

The Human Cytomegalovirus UL116 Gene Encodes an Envelope Glycoprotein Forming a Complex with gH Independently from gL

Caló

Cortese

Ciferri³

et al. 2016

J Virol

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Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality in transplant patients and is the leading viral cause of birth defects after congenital infection. HCMV infection relies on the recognition of cell-specific receptors by one of the viral envelope glycoprotein complexes. Either the gH/gL/gO or the gH/gL/UL128/UL130/UL131A (Pentamer) complex has been found to fulfill this role, accounting for HCMV entry into almost all cell types. We have studied the UL116 gene product, a putative open reading frame identified by in silico analysis and predicted to code for a secreted protein. Virus infection experiments in mammalian cells demonstrated that UL116 is expressed late in the HCMV replication cycle and is a heavily glycosylated protein that first localizes to the cellular site of virus assembly and then inserts into the virion envelope. Transient-transfection studies revealed that UL116 is efficiently transported to the plasma membrane when coexpressed with gH and that gL competes with UL116 for gH binding. Further evidence for gH/UL116 complex formation was obtained by coimmunoprecipitation experiments on both transfected and infected cells and biochemical characterization of the purified complex. In summary, our results show that the product of the UL116 gene is an HCMV envelope glycoprotein that forms a novel gH-based complex alternative to gH/gL. Remarkably, the gH/UL116 complex is the first herpesvirus gH-based gL-less complex. IMPORTANCE HCMV infection can cause severe disease in immunocompromised adults and infants infected in utero.The dissection of the HCMV entry machinery is important to understand the mechanism of viral infection and to identify new vaccine antigens. The gH/gL/gO and gH/gL/UL128/UL130/UL131 (Pentamer) complexes play a key role in HCMV cell entry and tropism. Both complexes are formed by an invariant gH/gL scaffold on which the other subunits assemble. Here, we show that the UL116 gene product is expressed in infected cells and forms a heterodimer with gH. The gH/UL116 complex is carried on the infectious virions, although in smaller amounts than gH/gL complexes. No gH/UL116/gL ternary complex formed in transfected cells, suggesting that the gH/UL116 complex is independent from gL. This new gH-based gL-free complex represents a potential target for a protective HCMV vaccine and opens new perspectives on the comprehension of the HCMV cell entry mechanism and tropism. H uman cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus infecting 40 to 60% of the human population (1).HCMV infection usually is mild or asymptomatic in immunocompetent individuals, while it can cause severe disease in immunocompromised adults. Infants infected in utero can suffer from disseminated HCMV disease and impaired neurological development (2). Transplant patients do not adequately control HCMV infection or reactivation, often resulting in graft rejection and death (3). Preventing primary HCMV infection could significantly decrease the frequency of organ rejection in seronegative recip...

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mentioning

confidence: 99%

The Human Cytomegalovirus UL116 Gene Encodes an Envelope Glycoprotein Forming a Complex with gH Independently from gL

Caló

Cortese

Ciferri³

et al. 2016

J Virol

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“…UL7 has been reported to display sequence similarity to a member of the signaling lymphocyte activation molecule family and apparently modulates the production of proinflammatory cytokines in myeloid cells (31). In addition, UL1 and UL13 may influence the cell tropism of CMV (32,33).…”

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confidence: 99%

Expression of the Human Cytomegalovirus UL11 Glycoprotein in Viral Infection and Evaluation of Its Effect on Virus-Specific CD8 T Cells

Gabaev

Elbasani

Ameres

et al. 2014

J Virol

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The human cytomegalovirus (CMV) UL11 open reading frame (ORF) encodes a putative type I transmembrane glycoprotein which displays remarkable amino acid sequence variability among different CMV isolates, suggesting that it represents an important virulence factor. In a previous study, we have shown that UL11 can interact with the cellular receptor tyrosine phosphatase CD45, which has a central role for signal transduction in T cells, and treatment of T cells with large amounts of a soluble UL11 protein inhibited their proliferation. In order to analyze UL11 expression in CMV-infected cells, we constructed CMV recombinants whose genomes either encode tagged UL11 versions or carry a stop mutation in the UL11 ORF. Moreover, we examined whether UL11 affects the function of virus-specific cytotoxic T lymphocytes (CTLs). We found that the UL11 ORF gives rise to several proteins due to both posttranslational modification and alternative translation initiation sites. Biotin labeling of surface proteins on infected cells indicated that only highly glycosylated UL11 forms are present at the plasma membrane, whereas less glycosylated UL11 forms were found in the endoplasmic reticulum. We did not find evidence of UL11 cleavage or secretion of a soluble UL11 version. Cocultivation of CTLs recognizing different CMV epitopes with fibroblasts infected with a UL11 deletion mutant or the parental strain revealed that under the conditions applied UL11 did not influence the activation of CMV-specific CD8 T cells. For further studies, we propose to investigate the interaction of UL11 with CD45 and the functional consequences in other immune cells expressing CD45. IMPORTANCEHuman cytomegalovirus (CMV) belongs to those viruses that extensively interfere with the host immune response, yet the precise function of many putative immunomodulatory CMV proteins remains elusive. Previously, we have shown that the CMV UL11 protein interacts with the leukocyte common antigen CD45, a cellular receptor tyrosine phosphatase with a central role for signal transduction in T cells. Here, we examined the proteins expressed by the UL11 gene in CMV-infected cells and found that at least one form of UL11 is present at the cell surface, enabling it to interact with CD45 on immune cells. Surprisingly, CMVexpressed UL11 did not affect the activity of virus-specific CD8 T cells. This finding warrants investigation of the impact of UL11 on CD45 functions in other leukocyte subpopulations.

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“…For example, CEACAM1 has a broad cell expression, which includes epithelial, endothelial, lymphoid and myeloid cells, and has been reported to provide inhibitory signals to these diverse cell types through the ITIMs present in its cytoplasmic tail . The first viral CEACAM homolog identified was the UL1 protein of HCMV . UL1 is an HCMV‐specific gene that encodes a type I transmembrane glycoprotein with an extracellular IgV domain that shows a 22% amino acid identity with the IgV domain of the human CEACAM1 .…”

Section: Ceacam Homologsmentioning

confidence: 99%

“…The first viral CEACAM homolog identified was the UL1 protein of HCMV . UL1 is an HCMV‐specific gene that encodes a type I transmembrane glycoprotein with an extracellular IgV domain that shows a 22% amino acid identity with the IgV domain of the human CEACAM1 . This protein is a component of the virion and has been reported to be necessary for efficient viral growth in epithelial cells.…”

Section: Ceacam Homologsmentioning

confidence: 99%

“…Some of the vIgSF molecules have also been optimized to change their cellular localization or to form part of the virion particle, as demonstrated for a number of the herpesviral FcγR homologs or the CEACAM homolog UL1 of HCMV (Fig. C) . Notably, a large number of the described viral homologs are soluble versions of the host ancestors, with the capacity to function as decoy receptors.…”

Section: Viral Homologs Of Host Genes As a Source Of Functional Divermentioning

confidence: 99%

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Immunoglobulin superfamily members encoded by viruses and their multiple roles in immune evasion

et al. 2017

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Pathogens have developed a plethora of strategies to undermine host immune defenses in order to guarantee their survival. For large DNA viruses, these immune evasion mechanisms frequently rely on the expression of genes acquired from host genomes. Horizontally transferred genes include members of the immunoglobulin superfamily, whose products constitute the most diverse group of proteins of vertebrate genomes. Their promiscuous immunoglobulin domains, which comprise the building blocks of these molecules, are involved in a large variety of functions mediated by ligand-binding interactions. The flexible structural nature of the immunoglobulin domains makes them appealing targets for viral capture due to their capacity to generate high functional diversity. Here, we present an up-to-date review of immunoglobulin superfamily gene homologs encoded by herpesviruses, poxviruses, and adenoviruses, that include CD200, CD47, Fc receptors, interleukin-1 receptor 2, interleukin-18 binding protein, CD80, carcinoembryonic antigen-related cell adhesion molecules, and signaling lymphocyte activation molecules. We discuss their distinct structural attributes, binding properties, and functions, shaped by evolutionary pressures to disarm specific immune pathways. We include several novel genes identified from extensive genome database surveys. An understanding of the properties and modes of action of these viral proteins may guide the development of novel immune-modulatory therapeutic tools.

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The Human Cytomegalovirus-Specific UL1 Gene Encodes a Late-Phase Glycoprotein Incorporated in the Virion Envelope

Cited by 20 publications

References 60 publications

The Human Cytomegalovirus UL116 Gene Encodes an Envelope Glycoprotein Forming a Complex with gH Independently from gL

The Human Cytomegalovirus UL116 Gene Encodes an Envelope Glycoprotein Forming a Complex with gH Independently from gL

Expression of the Human Cytomegalovirus UL11 Glycoprotein in Viral Infection and Evaluation of Its Effect on Virus-Specific CD8 T Cells

Immunoglobulin superfamily members encoded by viruses and their multiple roles in immune evasion

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