Biology Reference
In-Depth Information
All CMV vGPCRs, with the exception of those encoded by UL78-like genes, contain
the hallmarks of chemokine receptors (Ahuja et al. 1993; Davis-Poynter et al. 1997):
1. An N-linked glycosylation site and several negatively charged amino acid
residues located in the extracellular N-terminal region
2. Two cysteine residues, which are likely to form a disulfide bridge, thereby
joining the N-terminal region with the third extracellular loop (Fig. 1)
3. Several positively charged amino acid residues within the third intracellular
loop
4. Invariant amino acids within the transmembrane regions
5. Several serine and threonine residues in the intracellular C-terminal region
The sequences of US27/US28-like genes have the highest similarity with those
of chemokine receptors of the host. The sequences of UL33-like genes are also
related to those of chemokine receptors, albeit to a lesser extent. The sequences
of UL78-like GPCR genes possess none of the chemokine receptor hallmarks.
Interestingly, the HCMV genome contains several putative genes encoding
7-transmembrane proteins: UL100 (the putative structural glycoprotein
M
),
US12, US13, US14, US15, US16, US17, US18, US19, US20, and US21 (possi-
bly a multiplication of a US12-like ancestor). These genes share some sequence
similarity with genes of well-characterized GPCRs (Rigoutsos et al. 2003). Yet,
their predicted amino acid sequences lack the cysteine residues that join the
second and third extracellular loop of all known GPCRs and are therefore not
considered vGPCRs. Nevertheless, it remains tempting to speculate that these
genes have arisen from host GPCR genes.
Modulation of Intracellular Signaling by CMV vGPCRs
Various CMV vGPCRs have been investigated for their putative role in the activa-
tion of signal transduction pathways. Attempts have been made to identify ligands
that bind to these vGPCRs, as well as to identify the downstream intracellular
signaling pathways. The most common signaling factors studied were:
1. Ca
2+
mobilization
2. Increase of inositol phosphate (InsP) by phospholipase C (PLC)
3. Increase of cAMP by adenylyl cyclase (AC) and subsequent CREB-mediated
gene transcription
4. NFk-B-mediated gene transcription
In some cases, other signaling factors were addressed. The results of these studies
are summarized in Table 3. The consequences of modulation of these intermediates by
vGPCRs may include either activation or inhibition of immune-related responses, such
as cell differentiation and maturation, cell proliferation, cytoskeletal remodeling, cell
migration, cytokine release, and cytotoxicity. Apparently, viruses benefit from altering
these responses by utilizing their own vGPCRs.
