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

Viruses ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 594 ◽  
Author(s):  
Jeffrey R. van Senten ◽  
Maarten P. Bebelman ◽  
Puck van Gasselt ◽  
Nick D. Bergkamp ◽  
Jelle van den Bor ◽  
...  
Keyword(s):  
G Protein ◽  
Human Cytomegalovirus ◽  
Parental Virus ◽  
Growth Defect ◽  
Similar Degree ◽  
Virus Spread ◽  
G Protein Coupled Receptor ◽  
Fibroblast Cultures ◽  
Hcmv Strain ◽  
G Protein Coupled

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.

scholarly journals The human cytomegalovirus G-protein coupled receptor US28 promotes latency by attenuating c-fos

2018 ◽  
Author(s):  
Benjamin A. Krishna ◽  
Monica S. Humby ◽  
William E. Miller ◽  
Christine M. O’Connor
Keyword(s):  
Host Cell ◽  
G Protein ◽  
Human Cytomegalovirus ◽  
Latent Infection ◽  
Lytic Replication ◽  
Wild Type ◽  
G Protein Coupled Receptor ◽  
In Trans ◽  
G Protein Coupled

AbstractHuman cytomegalovirus (HCMV) is a ubiquitous pathogen that undergoes latency in cells of the hematopoietic compartment, though the mechanisms underlying establishment and maintenance of latency remain elusive. We previously reported that the HCMV-encoded G-protein coupled receptor (GPCR) homolog,US28is required for successful latent infection. We now show that US28 protein (pUS28) providedin transcomplements the US28Δ lytic phenotype in myeloid cells, suggesting that sustained US28 expression is necessary for long-term latency. Furthermore, expression of pUS28 at the time of infection represses transcription from the major immediate early promoter (MIEP) within 24 hours. However, this repression is only maintained in the presence of continual pUS28 expression providedin trans. Our data also reveal that pUS28-mediated signaling attenuates both expression and phosphorylation of cellular fos (c-fos), an AP-1 transcription factor subunit, to repress MIEP-driven transcription. AP-1 binds to the MIEP and promotes lytic replication, and in line with this, we find that US28Δ infection results in an increase in AP-1 binding to the MIEP, compared to wild type latent infection. Pharmacological inhibition of c-fos represses the MIEP during US28Δ infection to similar levels we observe during wild type latent infection. Together, our data reveal that US28 is required for both establishment and long-term maintenance of HCMV latency, which is modulated, at least in part, by repressing functional AP-1 binding to the MIEP.Significance StatementHuman cytomegalovirus (HCMV) is a wise-spread pathogen that remains with an individual for life in a quiescent/latent state, posing little threat to an otherwise healthy person. However, when an individual’s immune system is severely compromised, HCMV can reactivate to its active/lytic state, resulting in viral spread and disease that is often fatal. The biological mechanisms underlying HCMV latency and reactivation remain poorly understood. Herein we show that the viral-encoded G-protein coupled receptor (GPCR)US28aids in the establishment and the maintenance of viral latency. Furthermore, we find that US28 modulates host cell proteins to suppress viral processes associated with active/lytic replication, thereby promoting latent infection. This work provides mechanism by which HCMV modulates the host cell environment to its advantage.

Human cytomegalovirus encodes three G protein-coupled receptor homologues

Nature ◽  
1990 ◽  
Vol 344 (6268) ◽  
pp. 774-777 ◽  
Author(s):  
M. S. Chee ◽  
S. C. Satchwell ◽  
E. Preddie ◽  
K. M. Weston ◽  
B. G. Barrell
Keyword(s):  
G Protein ◽  
Human Cytomegalovirus ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

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

2019 ◽  
Vol 294 (44) ◽  
pp. 16297-16308 ◽  
Author(s):  
Jeffrey R. van Senten ◽  
Maarten P. Bebelman ◽  
Tian Shu Fan ◽  
Raimond Heukers ◽  
Nick D. Bergkamp ◽  
...  
Keyword(s):  
G Protein ◽  
Human Cytomegalovirus ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals Human Cytomegalovirus-Encoded G Protein-Coupled Receptor US28 Mediates Smooth Muscle Cell Migration through Gα12

2004 ◽  
Vol 78 (15) ◽  
pp. 8382-8391 ◽  
Author(s):  
Ryan M. Melnychuk ◽  
Daniel N. Streblow ◽  
Patricia P. Smith ◽  
Alec J. Hirsch ◽  
Dora Pancheva ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
G Protein ◽  
G Proteins ◽  
Muscle Cell ◽  
Human Cytomegalovirus ◽  
Signaling Molecules ◽  
Cellular Migration ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

ABSTRACT Coupling of G proteins to ligand-engaged chemokine receptors is the paramount event in G-protein-coupled receptor signal transduction. Previously, we have demonstrated that the human cytomegalovirus-encoded chemokine receptor US28 mediates human vascular smooth muscle cell (SMC) migration in response to either RANTES or monocyte chemoattractant protein 1. In this report, we identify the G proteins that couple with US28 to promote vascular SMC migration and identify other signaling molecules that play critical roles in this process. US28-mediated cellular migration was enhanced with the expression of the G-protein subunits Gα12 and Gα13, suggesting that US28 may functionally couple to these G proteins. In correlation with this observation, US28 was able to activate RhoA, a downstream effector of Gα12 and Gα13 in cell types with these G proteins but not in those without them and activation of RhoA was dependent on US28 stimulation with RANTES. In addition, inactivation of RhoA or the RhoA-associated kinase p160ROCK with a dominant-negative mutant of RhoA or the small molecule inhibitor Y27632, respectively, abrogated US28-induced SMC migration. The data presented here suggest that US28 functionally signals through Gα12 family G proteins and RhoA in a ligand-dependent manner and these signaling molecules are important for the ability of US28 to induce cellular migration.

scholarly journals Human cytomegalovirus G protein-coupled receptor US28 promotes latency by attenuating c-fos

2019 ◽  
Vol 116 (5) ◽  
pp. 1755-1764 ◽  
Author(s):  
Benjamin A. Krishna ◽  
Monica S. Humby ◽  
William E. Miller ◽  
Christine M. O’Connor
Keyword(s):  
G Protein ◽  
Human Cytomegalovirus ◽  
Latent Infection ◽  
Lytic Replication ◽  
G Protein Coupled Receptor ◽  
Time Of Infection ◽  
In Trans ◽  
G Protein Coupled ◽  
Major Immediate Early Promoter

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that undergoes latency in cells of the hematopoietic compartment, although the mechanisms underlying establishment and maintenance of latency remain elusive. We previously reported that the HCMV-encoded G protein-coupled receptor (GPCR) homologUS28is required for successful latent infection. We now show that US28 protein (pUS28) providedin transcomplements the US28Δ lytic phenotype in myeloid cells, suggesting that sustained US28 expression is necessary for long-term latency. Furthermore, expression of pUS28 at the time of infection represses transcription from the major immediate early promoter (MIEP) within 24 h. However, this repression is only maintained in the presence of continual pUS28 expression providedin trans. Our data also reveal that pUS28-mediated signaling attenuates both expression and phosphorylation of cellular fos (c-fos), an AP-1 transcription factor subunit, to repress MIEP-driven transcription. AP-1 binds to the MIEP and promotes lytic replication, and in line with this we find that US28Δ infection results in an increase in AP-1 binding to the MIEP, compared with WT latent infection. Pharmacological inhibition of c-fos represses the MIEP during US28Δ infection to levels similar to those we observe during WT latent infection. Together, our data reveal that US28 is required for both establishment and long-term maintenance of HCMV latency, which is modulated, at least in part, by repressing functional AP-1 binding to the MIEP.

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