Modulation of cellular signaling by herpesvirus-encoded G protein-coupled receptors

Munnik, Sabrina M. de; Smit, Martine J.; Leurs, Rob; Vischer, Henry F.

doi:10.3389/fphar.2015.00040

Cited by 45 publications

(47 citation statements)

References 334 publications

(448 reference statements)

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“…In the present study, we show that when RhoB is silenced, both parental and their derivative-IE1 cells show a reduction in spread area compared to the RhoA or RhoC knockdown cells, an effect which has attributed to subsequent reduction of total surface levels of b1 integrin [67,68]. Moreover, in the presence of HCMV, an increased number of cellular projections was formed, a phenomenon which has also been observed in HCMV infected primary HFF cells, particularly at the late stages of lytic infection [49]. These findings further corroborate the idea of a key role for RhoB in the regulation of cell shape.…”

Section: Discussionmentioning

confidence: 65%

“…Throughout the years, human herpes viruses have employed genes encoding viral G protein-coupled receptors (vGPCRs), which are expressed in infected host cells. HCMV encodes four GPCRs [48] which have been modified to be used by the virus to take over the control of the host cell for its own benefit [49]. Rho GTPases which are activated through coupling of G proteins to GEFs in order to stimulate proliferation, differentiation, and inflammation in a variety of cell and types [50], are also used from HCMV for the interaction of viral components with cellular proteins.…”

Section: Introductionmentioning

confidence: 99%

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The Role of RhoA, RhoB and RhoC GTPases in Cell Morphology, Proliferation and Migration in Human Cytomegalovirus (HCMV) Infected Glioblastoma Cells

Tseliou

Al‐Qahtani²,

Alarifi

et al. 2016

Cell Physiol Biochem

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Background/Aims: Rho GTPases are crucial regulators of the actin cytoskeleton, membrane trafficking and cell signaling and their importance in cell migration and invasion is well- established. The human cytomegalovirus (HCMV) is a widespread pathogen responsible for generally asymptomatic and persistent infections in healthy people. Recent evidence indicates that HCMV gene products are expressed in over 90% of malignant type glioblastomas (GBM). In addition, the HCMV Immediate Early-1 protein (IE1) is expressed in >90% of tumors analyzed. Methods: RhoA, RhoB and RhoC were individually depleted in U373MG glioblastoma cells as well as U373MG cells stably expressing the HCMV IE1 protein (named U373MG-IE1 cells) shRNA lentivirus vectors. Cell proliferation assays, migration as well as wound-healing assays were performed in uninfected and HCMV-infected cells. Results: The depletion of RhoA, RhoB and RhoC protein resulted in significant alterations in the morphology of the uninfected cells, which were further enhanced by the cytopathic effect caused by HCMV. Furthermore, in the absence or presence of HCMV, the knockdown of RhoB and RhoC proteins decreased the proliferation rate of the parental and the IE1-expressing glioblastoma cells, whereas the knockdown of RhoA protein in the HCMV infected cell lines restored their proliferation rate. In addition, wound healing assays in U373MG cells revealed that depletion of RhoA, RhoB and RhoC differentially reduced their migration rate, even in the presence or the absence of HCMV. Conclusion: Collectively, these data show for the first time a differential implication of Rho GTPases in morphology, proliferation rate and motility of human glioblastoma cells during HCMV infection, further supporting an oncomodulatory role of HCMV depending on the Rho isoforms' state.

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

The Role of RhoA, RhoB and RhoC GTPases in Cell Morphology, Proliferation and Migration in Human Cytomegalovirus (HCMV) Infected Glioblastoma Cells

Tseliou

Al‐Qahtani²,

Alarifi

et al. 2016

Cell Physiol Biochem

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“…Receptor bias has been well- characterized at atypical and viral CKRs [203]. For instance, CXCL12 binding to CXCR4 elicits both G protein and β-arrestin signaling [176, 204], whereas binding to ACKR3 (a.k.a.…”

Section: Beyond Canonical Chemokine Receptor Signalingmentioning

confidence: 99%

New paradigms in chemokine receptor signal transduction: Moving beyond the two-site model

Kleist

Getschman

Ziarek

et al. 2016

Biochemical Pharmacology

114

113

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Chemokine receptor (CKR) signaling forms the basis of essential immune cellular functions, and dysregulated CKR signaling underpins numerous disease processes of the immune system and beyond. CKRs, which belong to the seven transmembrane domain receptor (7TMR) superfamily, initiate signaling upon binding of endogenous, secreted chemokine ligands. Chemokine-CKR interactions are traditionally described by a two-step/two-site mechanism, in which the CKR N-terminus recognizes the chemokine globular core (i.e. site 1 interaction), followed by activation when the unstructured chemokine N-terminus is inserted into the receptor TM bundle (i.e. site 2 interaction). Several recent studies challenge the structural independence of sites 1 and 2 by demonstrating physical and allosteric links between these supposedly separate sites. Others contest the functional independence of these sites, identifying nuanced roles for site 1 and other interactions in CKR activation. These developments emerge within a rapidly changing landscape in which CKR signaling is influenced by receptor PTMs, chemokine and CKR dimerization, and endogenous non-chemokine ligands. Simultaneous advances in the structural and functional characterization of 7TMR biased signaling have altered how we understand promiscuous chemokine-CKR interactions. In this review, we explore new paradigms in CKR signal transduction by considering studies that depict a more intricate architecture governing the consequences of chemokine-CKR interactions.

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“…US28 is one of four HCMVencoded G-protein coupled receptor (GPCR) homologs and is expressed during both the latent (5,32,44,45) and lytic (46,47) cycles. Although many studies have focused on understanding US28's functions during lytic replication (reviewed in reference 48), there is little known about the role US28 plays during latency although it is one of only a few genes associated with latent transcription. US28 transcripts have been detected both during natural latency (32,45) and during ex vivo latent infection studies (4-6, 44, 49).…”

mentioning

confidence: 99%

Human Cytomegalovirus US28 Is Important for Latent Infection of Hematopoietic Progenitor Cells

Humby

O’Connor

2016

J Virol

102

163

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Human cytomegalovirus (HCMV) resides latently in hematopoietic progenitor cells (HPCs). During latency, only a subset of HCMV genes is transcribed, including one of the four virus-encoded G protein-coupled receptors (GPCRs), US28. Although US28 is a multifunctional lytic protein, its function during latency has remained undefined. We generated a panel of US28 recombinant viruses in the bacterial artificial chromosome (BAC)-derived clinical HCMV strain TB40/E-mCherry. We deleted the entire US28 open reading frame (ORF), deleted all four of the viral GPCR ORFs, or deleted three of the HCMV GPCRs but not the US28 wild-type protein. Using these recombinant viruses, we assessed the requirement for US28 during latency in the Kasumi-3 in vitro latency model system and in primary ex vivo-cultured CD34 ؉ HPCs. Our data suggest that US28 is required for latency as infection with viruses lacking the US28 ORF alone or in combination with the remaining HCMV-encoded GPCR results in transcription from the major immediate early promoter, the production of extracellular virions, and the production of infectious virus capable of infecting naive fibroblasts. The other HCMV GPCRs are not required for this phenotype as a virus expressing only US28 but not the remaining virus-encoded GPCRs is phenotypically similar to that of wild-type latent infection. Finally, we found that US28 copurifies with mature virions and is expressed in HPCs upon virus entry although its expression at the time of infection does not complement the US28 deletion latency phenotype. This work suggests that US28 protein functions to promote a latent state within hematopoietic progenitor cells. IMPORTANCEHuman cytomegalovirus (HCMV) is a widespread pathogen that, once acquired, remains with its host for life. HCMV remains latent, or quiescent, in cells of the hematopoietic compartment and upon immune challenge can reactivate to cause disease. HCMV-encoded US28 is one of several genes expressed during latency although its biological function during this phase of infection has remained undefined. Here, we show that US28 aids in promoting experimental latency in tissue culture. The betaherpesvirus human cytomegalovirus (HCMV) is a ubiquitous pathogen that, once acquired, remains with its host for life. HCMV establishes a latent infection in CD34 ϩ hematopoietic progenitor cells (HPCs), and individuals with a competent immune system are, for the most part, asymptomatic for disease. Under weakened immune conditions, however, the virus can reactivate, causing severe morbidity and often mortality. In developed countries, such as the United States, approximately 80% of the population is HCMV positive by 40 years of age (reviewed in reference 1). In adults, HCMV-associated disease is due mostly to reactivation of latent infection, whereas primary infections rarely cause significant health burdens in this population (reviewed in reference 1). Current treatments administered in clinical settings to sequester HCMV infection include those that predominantly target la...

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Modulation of cellular signaling by herpesvirus-encoded G protein-coupled receptors

Cited by 45 publications

References 334 publications

The Role of RhoA, RhoB and RhoC GTPases in Cell Morphology, Proliferation and Migration in Human Cytomegalovirus (HCMV) Infected Glioblastoma Cells

The Role of RhoA, RhoB and RhoC GTPases in Cell Morphology, Proliferation and Migration in Human Cytomegalovirus (HCMV) Infected Glioblastoma Cells

New paradigms in chemokine receptor signal transduction: Moving beyond the two-site model

Human Cytomegalovirus US28 Is Important for Latent Infection of Hematopoietic Progenitor Cells

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