ArticleProceedings of the National Academy of Sciences of the United States of America2019
Human cytomegalovirus glycoprotein B variants affect viral entry, cell fusion, and genome stability.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed.
- Comparative insights into the apoptosome, inflammasomes and PIDDosome.Nature reviews. Immunology · 2026Review
- Article
- Integrative immunoinformatics and structural modeling for the rational design of a multi-epitope vaccine candidate against human cytomegalovirus.Scientific reports · 2026Article
- Rapid phylogenomic analysis for viral surveillance and metagenomic profiling with Omni2Tree.bioRxiv : the preprint server for biology · 2026Article
- Virion proteomics of genetically intact HCMV reveals a regulator of envelope glycoprotein composition that protects against humoral immunity.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The viral landscape in metastatic solid cancers.Heliyon · 2025Article
- Article
- Rapid glycoprotein evolution enables variant interactions in herpes simplex virus type 1.Virus evolution · 2025Article
- Role of Non-coding RNAs on the Radiotherapy Sensitivity and Resistance in Cancer Cells.Current gene therapy · 2025Review
- E2F3-dependent activation of FAM111B restricts mouse cytomegalovirus replication in primate cells.Journal of virology · 2024Article
- Human cytomegalovirus glycoprotein variants governing viral tropism and syncytium formation in epithelial cells and macrophages.Journal of virology · 2024Article
- Article
- Virus-Induced Cell Fusion and Syncytia Formation.Results and problems in cell differentiation · 2024Article
- Innate and adaptive effector immune drivers of cytomegalovirus disease in lung transplantation: a double-edged sword.Frontiers in transplantation · 2024Review
- A Virus Genetic System to Analyze the Fusogenicity of Human Cytomegalovirus Glycoprotein B Variants.Viruses · 2023Article
- Recombinant Human Cytomegalovirus Expressing an Analog-Sensitive Kinase pUL97 as Novel Tool for Functional Analyses.Viruses · 2022Article
- Polymorphisms of the cytomegalovirus glycoprotein B genotype in patients with Posner-Schlossman syndrome.The British journal of ophthalmology · 2022Observational
- Human cytomegalovirus hijacks host stress response fueling replication stress and genome instability.Cell death and differentiation · 2022Article
- Human Cytomegalovirus Replication and Infection-Induced Syncytia Formation in Labial, Foreskin, and Fetal Lung Fibroblasts.Viruses · 2021Article
- Review
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human cytomegalovirus (HCMV), like many other DNA viruses, can cause genome instability and activate a DNA damage response (DDR). Activation of ataxia-telangiectasia mutated (ATM), a kinase activated by DNA breaks, is a hallmark of the HCMV-induced DDR. Here we investigated the activation of caspase-2, an initiator caspase activated in response to DNA damage and supernumerary centrosomes. Of 7 HCMV strains tested, only strain AD169 activated caspase-2 in infected fibroblasts. Treatment with an ATM inhibitor or inactivation of PIDD or RAIDD inhibited caspase-2 activation, indicating that caspase-2 was activated by the PIDDosome. A set of chimeric HCMV strains was used to identify the genetic basis of this phenotype. Surprisingly, we found a single nucleotide polymorphism within the AD169 UL55 ORF, resulting in a D275Y amino acid exchange within glycoprotein B (gB), to be responsible for caspase-2 activation. As gB is an envelope glycoprotein required for fusion with host cell membranes, we tested whether gB(275Y) altered viral entry into fibroblasts. While entry of AD169 expressing gB(275D) proceeded slowly and could be blocked by a macropinocytosis inhibitor, entry of wild-type AD169 expressing gB(275Y) proceeded more rapidly, presumably by envelope fusion with the plasma membrane. Moreover, gB(275Y) caused the formation of syncytia with numerous centrosomes, suggesting that cell fusion triggered caspase-2 activation. These results suggest that gB variants with increased fusogenicity accelerate viral entry, cause cell fusion, and thereby compromise genome stability. They further suggest the ATM-PIDDosome-caspase-2 signaling axis alerts the cell of potentially dangerous cell fusion.
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