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J. Biol. Chem., Vol. 276, Issue 2, 1133-1137, January 12, 2001
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From the Division of Medicinal Chemistry, Leiden/Amsterdam Center
for Drug Research, Vrije Universiteit Amsterdam, 1081 HV Amsterdam,
The Netherlands
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-
Constitutive Signaling of the Human Cytomegalovirus-encoded
Chemokine Receptor US28*
,
B signaling via Gq/11 protein-dependent pathways. Whereas phospholipase C activation is mediated via
G
q/11 subunits, the activation of NF-B strongly
depends on 
subunits with a preference for the
21 dimer. The CC chemokines RANTES (regulated on activation, normal
T cell expressed and
secreted) and MCP-1 (monocyte
chemotactic protein-1) act as neutral
antagonists at US28, whereas the CX3C 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-coupled receptor property to modulate the homeostasis of
infected cells via the early gene product US28.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by Byk Nederland B. V. (Zwanenburg, The Netherlands).
§
Supported by the Netherlands Organization for Scientific
Research (Chemische Wetenschappen).
¶
To whom correspondence should be addressed: Leiden/Amsterdam
Center for Drug Research, Division of Medicinal Chemistry, Faculty of
Chemistry, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands. Tel.: 31-20-4447579; Fax: 31-20-4447610; E-mail:
leurs@chem.vu.nl.
Supported by the Royal Netherlands Academy of Arts and Sciences.
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