Constitutive Receptor Activity series
HCMV-encoded G-protein-coupled receptors as constitutively active modulators of cellular signaling networks

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Several herpesviruses encode G-protein-coupled receptor (vGPCR) proteins that are homologous to human chemokine receptors. In contrast to chemokine receptors, many vGPCRs signal in a ligand-independent (constitutive) manner. Such constitutive signaling is of major significance because various pathologies are associated with activating GPCR mutations. Constitutive activity of the human herpesvirus 8-encoded GPCR (ORF74), for example, is essential for its oncogenic potential to cause angioproliferative Kaposi's sarcoma-like lesions. The human cytomegalovirus (HCMV) encodes four GPCRs, of which US28 and UL33 display constitutive activity in transfected, but also HCMV-infected, cells. In addition, US28 is activated by a broad spectrum of chemokines. Furthermore, both US28 and UL33 show promiscuous G-protein coupling, whereas chemokine receptors activate primarily Gi/o proteins. Thus, these vGPCRs are versatile signaling devices, reprogramming cellular signaling networks to modulate cellular function after infection. By these means, these HCMV-encoded receptors might contribute to HCMV-related pathologies.

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HCMV-encoded GPCRs

Increasing evidence suggests that human cytomegalovirus (HCMV) contributes to the onset or progression of chronic inflammation, vascular diseases and infection with human immunodeficiency virus (HIV) [1]. HCMV is a widely spread β-herpesvirus, infecting 50–80% of the general population, and can persist lifelong in an asymptomatic latent form. However, primary infection or reactivation of the virus in immunocompromised hosts, such as the developing fetus, transplant recipients or acquired immune

Ligand-induced and constitutive signaling activity via promiscuous G-protein coupling

To date, no constitutive and/or ligand-induced signaling has been reported for US27 and UL78. However, their presence on the virion either suggests a role during early stages of infection or infers modulation of cellular signaling pathways upon infection.

Signaling has been reported for US28 and UL33 (Figure 2). CC chemokines, shown to bind to US28, induce increases in intracellular Ca2+ levels and activation of mitogen-activated protein kinase (MAPK) in cells that express US28 [35]. CCL2 and

Future perspectives

Exploitation of the chemokine receptor system through molecular mimicry appears to be an effective means to assist viruses in evading immune surveillance, contribute to viral dissemination and receptor-mediated entry. US28 is by far the best-characterized receptor. In accordance with the ability of US28 to respond to a broad spectrum of chemokines, and the ability of US28 and UL33 to signal in a constitutively active manner, these receptors appear to be versatile signaling devices that modulate

Acknowledgements

H.F.V. was supported by the Technology Foundation STW, and M.J.S. was supported by the Royal Netherlands Academy of Arts and Sciences.

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