Constitutive Signaling of the Human Cytomegalovirus-encoded Chemokine Receptor US28*

Previously it was shown that the HHV-8-encoded chemokine receptor ORF74 shows considerable agonist-independent, constitutive activity giving rise to oncogenic transformation (Arvanitakis, L., Geras-Raaka, E., Varma, A., Gershengorn, M. C., and Cesarman, E. (1997) Nature 385, 347–350). In this study we report that a second viral-encoded chemokine receptor, the human cytomegalovirus-encoded US28, also efficiently signals in an agonist-independent manner. Transient expression of US28 in COS-7 cells leads to the constitutive activation of phospholipase C and NF-κB signaling via Gq/11 protein-dependent pathways. Whereas phospholipase C activation is mediated via Gαq/11 subunits, the activation of NF-κB strongly depends on βγ subunits with a preference for the β2γ1 dimer. The CC chemokines RANTES (regulated on activation, normalT cell expressed andsecreted) and MCP-1 (monocytechemotactic protein-1) act as neutral antagonists at US28, whereas the CX3C chemokine fractalkine acts as a partial inverse agonist with IC50values of 1–5 nm. Our data suggest that a high level of constitutive activity might be a more general characteristic of viral G protein-coupled receptors and that human cytomegalovirus might exploit this G protein-coupled receptor property to modulate the homeostasis of infected cells via the early gene product US28.