The Human Cytomegalovirus UL116 Glycoprotein Is a Chaperone to Control gH-Based Complexes Levels on Virions

Vezzani, Giacomo; Amendola, Diego; Yü, Dong; Chandramouli, Sumana; Frigimelica, Elisabetta; Maione, Domenico; Merola, Marcello

doi:10.3389/fmicb.2021.630121

Cited by 12 publications

(4 citation statements)

References 45 publications

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“…UL47, UL49, UL76 and US22 proteins are known to be part of the tegument, UL77 is located in the capsid; UL105, UL122 and UL89 are found in the nucleus of the host cells [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. In addition, UL4, UL22A and UL116, which were predicted to have one transmembrane domain, were discarded because the transmembrane domain corresponded to the sequence of signal peptide [ 42 , 43 , 44 ]. In addition, RL13TRL14 and US33 (TB40-E_UNC strain) or ORFL27C and ORFL49W.IORF1 (AD169-BAC20) proteins were only found in one of the CMV studied strains and were not considered for further analysis.…”

Section: Resultsmentioning

confidence: 99%

Deciphering the Potential Coding of Human Cytomegalovirus: New Predicted Transmembrane Proteome

Mancebo

Parras-Moltó

García‐Ríos

et al. 2022

IJMS

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CMV is a major cause of morbidity and mortality in immunocompromised individuals that will benefit from the availability of a vaccine. Despite the efforts made during the last decade, no CMV vaccine is available. An ideal CMV vaccine should elicit a broad immune response against multiple viral antigens including proteins involved in virus-cell interaction and entry. However, the therapeutic use of neutralizing antibodies targeting glycoproteins involved in viral entry achieved only partial protection against infection. In this scenario, a better understanding of the CMV proteome potentially involved in viral entry may provide novel candidates to include in new potential vaccine design. In this study, we aimed to explore the CMV genome to identify proteins with putative transmembrane domains to identify new potential viral envelope proteins. We have performed in silico analysis using the genome sequences of nine different CMV strains to predict the transmembrane domains of the encoded proteins. We have identified 77 proteins with transmembrane domains, 39 of which were present in all the strains and were highly conserved. Among the core proteins, 17 of them such as UL10, UL139 or US33A have no ascribed function and may be good candidates for further mechanistic studies.

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Section: Resultsmentioning

confidence: 99%

Deciphering the Potential Coding of Human Cytomegalovirus: New Predicted Transmembrane Proteome

Mancebo

Parras-Moltó

García‐Ríos

et al. 2022

IJMS

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“…Intriguingly, Calo and colleagues have shown that the HCMV UL116 protein is a non-disulfide bound gH-associated factor alternative to gL and that the gH-UL116 complex is inserted into the viral envelope of mature virus particles [ 133 ]. To date, a specific receptor for this glycoprotein complex has not been identified [ 134 ], and it is still under debate whether UL116 is part of a new functional gH complex or rather acts as a chaperone that mainly regulates the availability of gH on the virion envelope [ 135 , 136 ]. Though not fully understood, UL116 conservation between herpesviruses and its features reminiscent of adhesion factors suggest an important role in the process of membrane recognition and fusion.…”

Section: Determinants and Mechanism Of Syncytium Formationmentioning

confidence: 99%

Cell Fusion and Syncytium Formation in Betaherpesvirus Infection

Tang

Frascaroli

Zhou

et al. 2021

Viruses

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Cell–cell fusion is a fundamental and complex process that occurs during reproduction, organ and tissue growth, cancer metastasis, immune response, and infection. All enveloped viruses express one or more proteins that drive the fusion of the viral envelope with cellular membranes. The same proteins can mediate the fusion of the plasma membranes of adjacent cells, leading to the formation of multinucleated syncytia. While cell–cell fusion triggered by alpha- and gammaherpesviruses is well-studied, much less is known about the fusogenic potential of betaherpesviruses such as human cytomegalovirus (HCMV) and human herpesviruses 6 and 7 (HHV-6 and HHV-7). These are slow-growing viruses that are highly prevalent in the human population and associated with several diseases, particularly in individuals with an immature or impaired immune system such as fetuses and transplant recipients. While HHV-6 and HHV-7 are strictly lymphotropic, HCMV infects a very broad range of cell types including epithelial, endothelial, mesenchymal, and myeloid cells. Syncytia have been observed occasionally for all three betaherpesviruses, both during in vitro and in vivo infection. Since cell–cell fusion may allow efficient spread to neighboring cells without exposure to neutralizing antibodies and other host immune factors, viral-induced syncytia may be important for viral dissemination, long-term persistence, and pathogenicity. In this review, we provide an overview of the viral and cellular factors and mechanisms identified so far in the process of cell–cell fusion induced by betaherpesviruses and discuss the possible consequences for cellular dysfunction and pathogenesis.

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“…It seems likely that differences in other viral genes contribute to the phenotype of VR1814 GF . Candidates are, for instance, the variants of gH, a component of the core fusion machinery (55), and UL116, a chaperone promoting the incorporation of gH/gL complexes into virions (56, 57).…”

Section: Discussionmentioning

confidence: 99%

Human cytomegalovirus glycoprotein variants governing viral tropism and syncytium formation in epithelial cells and macrophages

Cimato,

Zhou,

Brune

et al. 2024

Preprint

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Human cytomegalovirus (HCMV) displays a broad cell tropism, and the infection of biologically relevant cells such as epithelial, endothelial, and hematopoietic cells supports viral transmission, systemic spread, and pathogenesis in the human host. HCMV strains differ in their ability to infect and replicate in these cell types, but the genetic basis of these differences has remained incompletely understood. In this study, we investigated HCMV strain VR1814, which is highly infectious for epithelial cells and macrophages and induces cell-cell fusion in both cell types. A VR1814-derived bacterial artificial chromosome (BAC) clone, FIX-BAC, was generated many years ago but has fallen out of favor because of its modest infectivity. By sequence comparison and genetic engineering of FIX, we demonstrate that the high infectivity of VR1814 and its ability to induce syncytium formation in epithelial cells and macrophages depends on VR1814-specific variants of the envelope glycoproteins gB, UL128, and UL130. We also show that UL130-neutralizing antibodies inhibit syncytium formation, and a FIX-specific mutation in UL130 is responsible for its low infectivity by reducing the amount of the pentameric glycoprotein complex in viral particles. Moreover, we found that a VR1814-specific mutation in US28 further increases viral infectivity in macrophages, possibly by promoting lytic rather than latent infection of these cells. Our findings show that variants of gB and the pentameric complex are major determinants of infectivity and syncytium formation in epithelial cells and macrophages. Furthermore, the VR1814-adjusted FIX strains can serve as valuable tools to study HCMV infection of myeloid cells.

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The Human Cytomegalovirus UL116 Glycoprotein Is a Chaperone to Control gH-Based Complexes Levels on Virions

Cited by 12 publications

References 45 publications

Deciphering the Potential Coding of Human Cytomegalovirus: New Predicted Transmembrane Proteome

Deciphering the Potential Coding of Human Cytomegalovirus: New Predicted Transmembrane Proteome

Cell Fusion and Syncytium Formation in Betaherpesvirus Infection

Human cytomegalovirus glycoprotein variants governing viral tropism and syncytium formation in epithelial cells and macrophages

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