Biology Reference
In-Depth Information
For at least one member of each family included in Table 3, one or more ligands
were identified. Interestingly, all of these ligands are CC chemokines, of which
RANTES appears to be the most common. Some vGPCRs, most notably those
encoded by the HHV-6 U51 and CMV US28, interact with more than one CC
chemokine species. The combinations of chemokines that interact with each of
these vGPCRs are unique and unrelated to those specific for chemokine receptors
of the host. The most direct way of determining ligand-dependent vGPCR signal-
ing, as well as subsequent vGPCR desensitization, is measuring intracellular Ca
2+
mobilization (Table 3). In addition to Ca
2+
mobilization, cytoplasmic accumulation
of inositol phosphates (InsP) was measured in cells that expressed a member of
either of the three betaherpesvirus vGPCR families. Interestingly, in all of these
studies, vGPCRs were reported to induce a G
q/11
-mediated increase of InsP in a
ligand-independent manner (Table 3). Thus, all vGPCRs were found to be consti-
tutively active, a property that is not shared by chemokine receptors of the host.
Constitutive signaling was also demonstrated by subjecting betaherpesvirus
vGPCRs to reporter gene assays specific for either cAMP/CREB- or NFk-B-driven
modulation of gene transcription. Most notably, the results of these assays were
inconsistent when comparing the activities of members of the UL33 vGPCR fam-
ily: expression of HCMV UL33 and MCMV M33 resulted in an increase in cAMP-
mediated gene transcription, whereas expression of RCMV R33 resulted in a
decrease (Table 3). The most important factor responsible for this inconsistency is
p38/MAPK, which is activated in cells expressing either HCMV UL33 or MCMV
M33, but not in cells expressing RCMV R33 (Table 3). Additionally, expression
of M33- and R33-encoded vGPCRs resulted in an increase in NFk-B-mediated
gene transcription, whereas expression of HCMV UL33 had no effect (Table 3).
Interestingly, NFk-B-mediated signaling is also increased in cells expressing
HCMV US28. These findings support the hypothesis that the primate UL33-like
vGPCRs have lost some signaling properties as similar functions might have become
redundantly available upon hijacking US28-like genes. Alternatively, the rodent
UL33-like vGPCRs may have gained NFk-B-stimulating activity following the loss
of US28-like genes from their corresponding genomes. Gain and loss of genes as
well as activities during evolution of the CMVs has become apparent by comparing
HCMV US28 with RhCMV US28-like genes. None of the vGPCRs encoded by
the five different US28-like genes within the RhCMV genome possess constitutive
signaling activities, nor do they signal in the presence of chemokine ligands that
are known to modulate HCMV US28-mediated signaling (Penfold et al. 2003b).
Moreover, neither of the InsP-, CREB- and NFk-B-mediated signaling factors
were affected by HCMV US27 expression (Table 3).
A recent study has indicated that the HCMV US28-encoded vGPCR not only
acts individually by modulating intracellular signaling, but also constitutes a regu-
latory switch for signal transduction by other Gi/o-coupled receptors (Bakker
et al. 2004). In addition, when either HHV-7 U12 or U51 were expressed together
with the host chemokine receptors CCR4 and CCR7, they had a broader ligand
specificity than when each of these chemokines were expressed individually
(Table 3). This suggested that the gene products of U12 and U51 can interact with
