Virus-Encoded 7 Transmembrane Receptors

Mølleskov-Jensen, Ann-Sofie; Oliveira, Martha Trindade; Farrell, Helen E.; Davis-Poynter, Nicholas

doi:10.1016/bs.pmbts.2014.10.010

Cited by 11 publications

(14 citation statements)

References 182 publications

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“…Homologues of 7TMRs have been identified in all beta- and gammaherpesviruses, promoting interest as potential targets for novel antiviral drugs [ 1 , 2 ]. Phylogenetic analysis suggests six independent gene capture events, three within the betaherpesvirus and three within the gammaherpesvirus lineages [ 3 ]. The prototypes of the betaherpesvirus 7TMR gene families were initially identified in human cytomegalovirus (CMV), namely 1) US28 and the related US27, 2) UL33 and 3) UL78 [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…The US28 gene family is found only in Old World primate CMVs, whereas UL33 and UL78 homologues have been identified in all sequenced betaherpesviruses [ 5 ]. Many of the herpesvirus 7TMRs are most closely homologous to chemokine receptors and several have been demonstrated to conserve functions such as chemokine binding and G protein-coupled signalling [ 1 – 3 ].…”

Section: Introductionmentioning

confidence: 99%

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The Cytoplasmic C-Tail of the Mouse Cytomegalovirus 7 Transmembrane Receptor Homologue, M78, Regulates Endocytosis of the Receptor and Modulates Virus Replication in Different Cell Types

2016

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Virus homologues of seven-transmembrane receptors (7TMR) are encoded by all beta- and gammaherpesviruses, suggesting important functional roles. M78 of mouse cytomegalovirus (MCMV) is representative of a family of 7TMR conserved in all betaherpesviruses. M78 family members have been found to exhibit cell-type specific effects upon virus replication in tissue culture and to affect virus pathogenesis in vivo. We reported previously that M78, for which no ligands are known, undergoes rapid, constitutive endocytosis. In this study, we have investigated the role of the M78 cytoplasmic C-tail in mediating endocytosis and consequences of C-tail deletion upon replication and pathogenesis. Mutations of M78 (C-tail truncations or point mutations) and CCR5-M78 chimeras identified two distinct regions affecting endocytosis. The first was a classical acidic di-leucine motif (DDxxxLL), located close to the C-terminus. The second region, the activity of which was suppressed by downstream sequences, included the putative 8th helix, located close to the 7th transmembrane domain. A recombinant MCMV expressing an endocytosis-deficient M78, lacking most of the C-tail (M78_CΔ155), had a cell-type specific replication phenotype. M78_CΔ155 had restricted replication in bone marrow macrophages, indistinguishable from an M78-null recombinant. In contrast, M78_CΔ155 replicated normally or with enhanced titres to wild type virus in other tested cell-types, whereas M78-null was attenuated. Distinct phenotypes for M78_CΔ155 and M78-null suggest that the C-tail deletion resulted in M78 dysfunction, rather than complete loss of function; furthermore, they highlight a cell-type specific role of M78 during replication. Infection of mice (intranasal) demonstrated that M78_CΔ155, similar to M78-null, was cleared more rapidly from the lungs than wild type virus and was severely attenuated for replication in salivary glands. It may be speculated that attenuation of both M78_CΔ155 and M78-null for replication in macrophages may have contributed to their similar pathogenic phenotypes.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Cytoplasmic C-Tail of the Mouse Cytomegalovirus 7 Transmembrane Receptor Homologue, M78, Regulates Endocytosis of the Receptor and Modulates Virus Replication in Different Cell Types

2016

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“…For this reason, US28 has different sequences requirements for binding and activation of diverse G proteins. In addition, HCMV seems to utilize this context-specific US28 stimulation of ligand-dependent and ligand-independent signaling pathways to maximize their chances for cellular survival (Molleskov-Jensen et al ., 2015). In this regards, US28’s ability to execute this “functional selectivity” could serve as a master switch for HCMV to fine-tune its host cellular environment to its utmost favor (Urban et al ., 2007).…”

Section: Host Signaling Pathways Regulated By Us28mentioning

confidence: 99%

“…First, deletion of the carboxyl terminal domain of US28 resulted in reduced constitutive endocytosis and consequent enhanced signaling capacity of US28 (Melnychuk et al ., 2004). Second, host and other viral GPCRs showed constitutive endocytosis and subsequent perinuclear localization when fused with the carboxyl terminal domain of US28 (Waldhoer et al ., 2003; Molleskov-Jensen et al ., 2015). These two reports further emphasize the critical role of GRKs-dependent phosphorylation on carboxyl terminal domain of US28 in determination of the subcellular localization of US28.…”

Section: Constitutive Internalization Of Us28mentioning

confidence: 99%

US28, a Virally-Encoded GPCR as an Antiviral Target for Human Cytomegalovirus Infection

Lee

Chung

Lee

2017

Biomolecules & Therapeutics

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Viruses continue to evolve a new strategy to take advantage of every aspect of host cells in order to maximize their survival. Due to their central roles in transducing a variety of transmembrane signals, GPCRs seem to be a prime target for viruses to pirate for their own use. Incorporation of GPCR functionality into the genome of herpesviruses has been demonstrated to be essential for pathogenesis of many herpesviruses-induced diseases. Here, we introduce US28 of human cytomegalovirus (HCMV) as the best-studied example of virally-encoded GPCRs to manipulate host GPCR signaling. In this review, we wish to summarize a number of US28-related topics including its regulation of host signaling pathways, its constitutive internalization, its structural and functional analysis, its roles in HCMV biology and pathogenesis, its proliferative activities and role in oncogenesis, and pharmacological modulation of its biological activities. This review will aid in our understanding of how pathogenic viruses usurp the host GPCR signaling for successful viral infection. This kind of knowledge will enable us to build a better strategy to control viral infection by normalizing the virally-dysregulated host GPCR signaling.

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“…vGPCR signalling can be transduced upon ligand interaction, dimerization with other receptors (both viral or host) or constitutive activity Molleskov-Jensen et al, 2015;Tschische et al, 2011;Waldhoer et al, 2002). Remarkably, ligand profile of vGPCR is not necessarily consistent with the ligand profile of host receptors, which are quite specific.…”

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 7 Transmembrane Receptors

Cited by 11 publications

References 182 publications

The Cytoplasmic C-Tail of the Mouse Cytomegalovirus 7 Transmembrane Receptor Homologue, M78, Regulates Endocytosis of the Receptor and Modulates Virus Replication in Different Cell Types

The Cytoplasmic C-Tail of the Mouse Cytomegalovirus 7 Transmembrane Receptor Homologue, M78, Regulates Endocytosis of the Receptor and Modulates Virus Replication in Different Cell Types

US28, a Virally-Encoded GPCR as an Antiviral Target for Human Cytomegalovirus Infection

Cell-type specific activities of cytomegalovirus GPCR homologues

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