Biology Reference
In-Depth Information
by arresting cells in the G
1
phase of the cell cycle (Lu and Shenk 1999). Functionally,
UL82 has also been shown to interact with the cellular protein hDaxx resulting in
IE gene transcription and viral replication (Cantrell and Bresnahan 2006a, 2006b;
Saffert and Kalejta 2006; Hwang and Kalejta 2007; see the chapter by R. Kalejta,
this volume).
Other Viral Gene Products That Modulate Signaling
Once viral gene transcription begins, HCMV increases its repertoire of signaling
molecules. For example, the major IE genes (IE1-72/UL123 and IE2/UL122) have
been shown to interact with a multitude of transcription factors to increase tran-
scription of required viral and cellular genes (reviewed in DeMeritt and Yurochko
2006; Mocarski et al. 2007), as well as interact with cell cycle regulators such as
p53, pRB, p107 and others to modulate the cell cycle (reviewed in Kalejta and
Shenk 2002; Castillo and Kowalik 2004). IE1-72 has also been reported to contain
intrinsic kinase activity and to activate cells through the targeted phosphorylation
of members of the E2F family of transcription factors (Pajovic et al. 1997). In addi-
tion, IE1-72 and IE2-86 (Zhu et al. 1995) along with the other IE genes, UL36
(viral inhibitor of caspase activation; Skaletskaya et al. 2001; McCormick et al.
2003) and UL37×1 (viral mitochondrial inhibitor of apoptosis; Goldmacher et al.
1999; McCormick et al. 2003; Reboredo et al. 2004), can modulate various survival
pathways and provide protection from apoptosis (for additional information see
Andoniou and Degli-Esposti 2006). HCMV also encodes other proteins with dis-
tinct signaling capabilities such as UL97, a viral kinase that plays a critical role
during viral infection through its ability to phosphorylate cellular and viral sub-
strates (Prichard et al. 2005); four putative GPCRs (US27, US28, UL33 and UL78)
that have been shown to bind chemokines, activate G proteins in a manner similar
to traditional GPCRs, mediate calcium flux, activate various kinases (MAPKs, Src,
and FAK) and modulate smooth muscle cell migration (reviewed in Streblow et al.
2001b; Stropes and Miller 2004; van Cleef et al. 2006); and a TNF-like receptor,
UL144 that activates NFκ-B through a TRAF6-dependent signaling cascade (Poole
et al. 2006).
Biological Rationale for Modulation of Host Cell Signaling
There is little doubt that HCMV binding and/or infection of multiple cell types
induces a sequence of signaling events (more detail provided in DeMeritt and
Yurochko 2006), of which key points have been discussed briefly above. The
question that remains is why the virus has evolved an elaborate strategy involving
a multitiered approach to activate host target cells? The available evidence sug-
gests the viral-induced signaling serves to promote multiple steps required for an
