Constitutive signaling of the human cytomegalovirus-encoded chemokine receptor US28

Previously it was shown that the HHV-8-encoded chemokine receptor ORF74 sho ws considerable agonist-independent, constitutive activity giving rise to o ncogenic transformation (Arvanitakis, L., Geras-Raaka, E., Varma, A., Grers hengorn, M. C., and Cesarman, E. (1997) Nature 385, 347-350), In this study we report that a second viral-encoded chemokine receptor, the human cytome galovirus-encoded US28, also efficiently signals in an agonist-independent manner. Transient expression of US28 in COS-7 cells leads to the constituti ve activation of phospholipase C and NF-kappaB signaling via G(q/11) protei n-dependent pathways. Whereas phospholipase C activation is mediated via G alpha (q/11) subunits, the activation of NF-KB strongly depends on py subun its with a preference for the beta (2)gamma (1) dimer. The CC chemokines RA NTES (regulated on activation, normal T cell expressed and secreted) and MC P-1 (monocyte chemotactic protein-1) act as neutral antagonists at US28, wh ereas the CX,C chemokine fractalkine acts as a partial inverse agonist with IC50 values 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-coupl ed receptor property to modulate the homeostasis of infected cells via the early gene product US28.