The human cytomegalovirus-encoded G protein–coupled receptor UL33 exhibits oncomodulatory properties

Senten, Jeffrey R. van; Bebelman, Maarten P.; Fan, Tian Shu; Heukers, Raimond; Bergkamp, Nick D.; Gasselt, Puck Van; Langemeijer, Ellen; Slinger, Erik; Lagerweij, Tonny; Rahbar, Afsar; Walsum, Marijke Stigter Van; Maussang, David; Leurs, Rob; Musters, René J.P.; Dongen, Guus A.M.S. van; Söderberg‐Nauclér, Cecilia; Würdinger, Thomas; Siderius, Marco; Smit, Martine J.

doi:10.1074/jbc.ra119.007796

Cited by 22 publications

(33 citation statements)

References 66 publications

(112 reference statements)

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“…Expression and signaling of UL33 receptor mutants were assessed in transiently transfected HEK293T cells, as previously described [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

“…HCMV Merlin UL33-HA, ΔUS28, and ΔUL33 bacterial artificial chromosomes (BACs) were described before [ 22 ] and derived from pAL1502, kindly provided by Richard J. Stanton. BAC recombineering using galK selection [ 32 ] was performed to reintroduce UL33-HA or US28 in the ΔUL33 or ΔUS28 BAC, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…UL33 is an orphan receptor that signals constitutively by coupling to and activating Gα s , Gα i and Gα q proteins [ 21 ]. Even though UL33’s signaling properties are for the most part similar to US28’s [ 22 ], UL33 has not been reported to contribute to the viral life cycle. Several studies demonstrated that HCMV growth in tissue culture is UL33 independent [ 7 , 14 , 21 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

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Human Cytomegalovirus-Encoded G Protein-Coupled Receptor UL33 Facilitates Virus Dissemination via the Extracellular and Cell-to-Cell Route

Bebelman

Gasselt

Bergkamp

et al. 2020

Viruses

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Human cytomegalovirus (HCMV) encodes four G protein-coupled receptor (GPCR) homologs. Three of these receptors, UL78, US27 and US28, are known for their roles in HCMV dissemination and latency. Despite importance of its rodent orthologs for viral replication and pathogenesis, such a function is not reported for the HCMV-encoded GPCR UL33. Using the clinical HCMV strain Merlin, we show that UL33 facilitates both cell-associated and cell-free virus transmission. A UL33-deficient virus derivative revealed retarded virus spread, formation of less and smaller plaques, and reduced extracellular progeny during multi-cycle growth analysis in fibroblast cultures compared to parental virus. The growth of UL33-revertant, US28-deficient, and US28-revertant viruses were similar to parental virus under multistep growth conditions. UL33- and US28-deficient Merlin viruses impaired cell-associated virus spread to a similar degree. Thus, the growth defect displayed by the UL33-deficient virus but not the US28-deficient virus reflects UL33’s contribution to extracellular transmission. In conclusion, UL33 facilitates cell-associated and cell-free spread of the clinical HCMV strain Merlin in fibroblast cultures.

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“…Expression and signaling of UL33 receptor mutants were assessed in transiently transfected HEK293T cells, as previously described [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human Cytomegalovirus-Encoded G Protein-Coupled Receptor UL33 Facilitates Virus Dissemination via the Extracellular and Cell-to-Cell Route

Bebelman

Gasselt

Bergkamp

et al. 2020

Viruses

Self Cite

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“…US28 induces the angiogenic phenotype in patients with colorectal cancer (Maussang et al, 2006). Meanwhile, US33 activates the proliferation and angiogenesis and inflammatory signaling pathways in glioblastoma cells (Heukers et al, 2018;van Senten et al, 2019). UL111A affects the survival time of gastric carcinoma patients by altering the number of infiltrating T cells (Liu et al, 2020).…”

Section: Neoplastic Diseasesmentioning

confidence: 99%

Functional Profile of Human Cytomegalovirus Genes and Their Associated Diseases: A Review

Qian

et al. 2020

Front. Microbiol.

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The human cytomegalovirus (HCMV), whose genome is 235 ± 1.9 kbp long, is a common herpesvirus. However, the functions of many of its genes are still unknown. HCMV is closely associated with various human diseases and infects 60-90% of the global population. It can infect various human cells, including fibroblasts, epithelial cells, endothelial cells, smooth muscle cells, and monocytes. Although HCMV infection is generally asymptomatic and causes subtle clinical symptoms, it can generate a robust immune response and establish a latent infection in immunocompromised individuals, including those with AIDS, transplant recipients, and developing fetuses. Currently available antivirals approved for the treatment of HCMV-associated diseases are limited by dose-limiting toxicity and the emergence of resistance; however, vaccines and immunoglobulins are unavailable. In this review, we have summarized the recent literature on 43 newly identified HCMV genes. We have described their novel functions on the viral replication cycle, latency, and host immune evasion. Further, we have discussed HCMV-associated diseases and current therapeutic targets. Our review may provide a foundational basis for studies aiming to prevent and develop targeted therapies for HCMV-associated diseases.

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“…Chemokine receptors are one class of the G protein-coupled receptor (GPCR) superfamily. While most GPCRs require ligand binding for activation, the HCMV GPCRs are constitutively active and can induce signaling in a ligand-independent fashion [ 68 ].…”

Section: Introductionmentioning

confidence: 99%

Control of Cytokines in Latent Cytomegalovirus Infection

et al. 2020

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Human cytomegalovirus (HCMV) has evolved a number of mechanisms for long-term co-existence within its host. HCMV infects a wide range of cell types, including fibroblasts, epithelial cells, monocytes, macrophages, dendritic cells, and myeloid progenitor cells. Lytic infection, with the production of infectious progeny virions, occurs in differentiated cell types, while undifferentiated myeloid precursor cells are the primary site of latent infection. The outcome of HCMV infection depends partly on the cell type and differentiation state but is also influenced by the composition of the immune environment. In this review, we discuss the role of early interactions between HCMV and the host immune system, particularly cytokine and chemokine networks, that facilitate the establishment of lifelong latent infection. A better understanding of these cytokine signaling pathways could lead to novel therapeutic targets that might prevent latency or eradicate latently infected cells.

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The human cytomegalovirus-encoded G protein–coupled receptor UL33 exhibits oncomodulatory properties

Cited by 22 publications

References 66 publications

Human Cytomegalovirus-Encoded G Protein-Coupled Receptor UL33 Facilitates Virus Dissemination via the Extracellular and Cell-to-Cell Route

Human Cytomegalovirus-Encoded G Protein-Coupled Receptor UL33 Facilitates Virus Dissemination via the Extracellular and Cell-to-Cell Route

Functional Profile of Human Cytomegalovirus Genes and Their Associated Diseases: A Review

Control of Cytokines in Latent Cytomegalovirus Infection

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