Virus-Encoded G-Protein-Coupled Receptors: Constitutively Active (Dys)Regulators of Cell Function and Their Potential as Drug Target

Vischer, Henry F.; Hulshof, Janneke W.; Esch, Iwan J. P. de; Smit, Martine J.; Leurs, Rob

doi:10.1007/2789_2006_009

Cited by 15 publications

(21 citation statements)

References 92 publications

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“…Transcriptional activation by these GPCRs is not restricted to NF-κB [87] . These receptors are believed to contribute to their pathological functions including stimulation of angiogenesis in the case of KSHV GPCR, and are potential therapeutic targets [91,92] .…”

Section: Gpcrs and Regulation Of Inflammatory Gene Expressionmentioning

confidence: 99%

Role of G protein-coupled receptors in inflammation

2012

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Section: Gpcrs and Regulation Of Inflammatory Gene Expressionmentioning

confidence: 99%

Role of G protein-coupled receptors in inflammation

2012

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“…Despite expressing vLMP antigens at their membrane surface, these latently infected cells are very poor in initiating effective immune responses in infected individuals, thus facilitating viral persistence in humans (2,17,38). One reason for this poor immunogenicity may be the constitutive cell signaling property reported for these vLMPs in latently infected cells (3,16,35,38). Consequently, unnecessary overexpression and large extracellular domains for ligand binding may facilitate vLMP immune escape (3, 35, 38).…”

mentioning

confidence: 99%

“…One reason for this poor immunogenicity may be the constitutive cell signaling property reported for these vLMPs in latently infected cells (3,16,35,38). Consequently, unnecessary overexpression and large extracellular domains for ligand binding may facilitate vLMP immune escape (3,35,38). Thus, a major therapeutic approach involved the discovery of naturally active compounds or pharmacological agents that specifically block viral receptor functioning (12,35).…”

mentioning

confidence: 99%

“…Consequently, unnecessary overexpression and large extracellular domains for ligand binding may facilitate vLMP immune escape (3,35,38). Thus, a major therapeutic approach involved the discovery of naturally active compounds or pharmacological agents that specifically block viral receptor functioning (12,35). Compounds emerged from high-throughput screening of synthetic chemical libraries, but we still lack specific agents for vLMPs, as they cross-react with cellular chemokine/cytokine receptors and cellular signaling pathways (35).…”

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confidence: 99%

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Induction of Therapeutic Antibodies by Vaccination against External Loops of Tumor-Associated Viral Latent Membrane Protein

Delbende

Verwaerde

Mougel

et al. 2009

J Virol

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Some human herpesviruses (HHV) are etiological contributors to a wide range of malignant diseases. These HHV express latent membrane proteins (LMPs), which are type III membrane proteins consistently exposed at the cell surface in these malignancies. These LMPs have relatively large cytoplasmic domains but only short extracellular loops connecting transmembrane segments that are accessible at the surface of infected cells, but they do not elicit antibodies in the course of natural infection and tumorigenesis. We report here that conformational peptides mimicking two adjacent loops of the Epstein-Barr virus (EBV) LMP1 (2LS peptides) induce high-affinity antibodies with remarkable antitumor activities in mice. In active immunization experiments, LMP1-targeting 2LS vaccine conferred tumor protection in BALB/c mice. Moreover, this tumor protection is dependent upon a humoral anti-2LS immune response as demonstrated in DO11.10 (TCR-OVA) mice challenged with LMP1-expressing tumor and in SCID mice xenografted with human EBV-positive lymphoma cells. These data provide a proof of concept for 2LS immunization against short external loops of viral LMPs. This approach might possibly be extended to other infectious agents expressing type III membrane proteins.After the primary infection, some viruses, especially human herpesviruses (HHV) such as Epstein-Barr virus (EBV), cytomegalovirus, Kaposi's sarcoma herpesvirus (HHV8), varicellazoster virus, and herpes simplex virus, persist lifelong in all infected individuals, most often in an asymptomatic latent form. However, in the long term, some HHV can be involved in the emergence of malignant diseases in a small subset of infected individuals. EBV-associated lymphomas and carcinomas (22, 37), HHV8-associated Kaposi's sarcomas (30), and human cytomegalovirus-associated glioblastomas (24) are examples of beta-and gammaherpesvirus-related human malignancies. All these malignancy-associated viruses encode type III membrane proteins which are expressed during the latent state of infection and thus can be called latent membrane proteins (LMPs). These viral LMPs (vLMPs), or "multipass" membrane proteins, appeared to be necessary for virus-driven host cell survival and/or transforming activity (1, 3, 28, 31). They are regarded by some authors as evolutionary mimics of cellular chemokine/cytokine receptors, and, like cellular receptors, they recruit numerous cytoplasmic adaptors. The several transmembrane domains of these vLMPs seem to mimic activated cellular chemokine/cytokine receptor structures and to function with versatile signaling devices, reprogramming cellular signaling networks to modulate cellular function after infection. They contribute prominently to virus survival in latently infected individuals and to virus-related human pathologies, including cancer (8,14,19,34,36). Despite expressing vLMP antigens at their membrane surface, these latently infected cells are very poor in initiating effective immune responses in infected individuals, thus facilitating viral persistence...

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“…Constitutive activation of these signalling cascades has been associated with many pathologies, including proliferative disorders (Vischer et al, 2006b). serine and threonine residues (Beisser et al, 2008;Vischer et al, 2006a). The human CMV encodes four vGPCR: US27, US28, UL33 and UL78.…”

Section: Murid Cytomegalovirus 1 (Mcmv) Infectionmentioning

confidence: 99%

Cell-type specific activities of cytomegalovirus GPCR homologues

Oliveira¹

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The human cytomegalovirus (HCMV) is the main agent of congenital infection worldwide. Although primary infections or reactivations do not represent a threat to most individuals, they impose a lifethreating event to a developing foetus or immunocompromised individuals. Although we have learnt much about sites of viral replication and cells involved in the end-stage disease, the specific pathway and essential cell types that the virus must go through to later establish a successful infection and latency is still not clear. HCMV encodes four GPCR homologues (vGPCR): US27, US28, UL33 and UL78. vGPCR have been implicated in viral pathogenesis due to their ability to activate signalling pathways and, thus, alter physiological processes to favour infection. US28 and UL33 have been shown to activate several kinases and transcriptional factors. A key component of both US28 and UL33 sequence is the DRY (Asp/Arg/Tyr) motif, a region directly involved with G protein binding.Because Gα protein content is cell type-dependent, signalling activation by vGPCR can differ from cell to cell. Furthermore, these receptors share the particular characteristic of being constitutively Functional studies demonstrated migration induction of HTR-8 following transfection by either US28 or UL33. In order to investigate potential mechanisms, signalling pathways were probed via detection of activated kinases and the secretion of matrix metalloproteinases (MMP) and chemokines (CK) via luminex assays. Although differences in the level of kinases could not be measured by western blot, induction of MMP and CK were detected by Luminex assays, with contrasting results for US28 and UL33 in transfected cells (HTR-8 and HUVEC). An HCMV recombinant disrupted for US28 signalling (DQY) was generated and compared with wild type HCMV and a US28 null mutant for induction of MMP and CK in virus-infected cells. US28-dependent effects were identified for infected human foreskin fibroblasts, but results for HUVEC were equivocal.iii To determine potential bottlenecks to viral dissemination that may require M33 function(s), mice were infected with M33 knockout (M33) viruses by different routes: intranasal, -mimicking the most natural route, footpad -a more compartmentalized route, and intraperitoneal, the most direct route to major organs. To help track viral dissemination, a luciferase tagged M33 was generated and infection was compared to control virus (M78luc). M33 intranasal infection did not result in attenuation for colonisation of the nose, draining (superficial cervical) lymph nodes (dLN) or the lungs. Via footpad route, M33 colonised the footpad and dLN to levels equivalent to control virus, but was significantly attenuated in spread to the spleen and, subsequently, the salivary glands.Following intraperitoneal infection, the virus is readily delivered to major organs due to direct access to the bloodstream, there was no difference in the colonisation of primary organs (spleen, liver) between M33 and control MCMV, but M33 was still unable ...

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Virus-Encoded G-Protein-Coupled Receptors: Constitutively Active (Dys)Regulators of Cell Function and Their Potential as Drug Target

Cited by 15 publications

References 92 publications

Role of G protein-coupled receptors in inflammation

Role of G protein-coupled receptors in inflammation

Induction of Therapeutic Antibodies by Vaccination against External Loops of Tumor-Associated Viral Latent Membrane Protein

Cell-type specific activities of cytomegalovirus GPCR homologues

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