Biology Reference
In-Depth Information
stimuli in a species-dependent fashion as well. Thus, vMIA fails to prevent
mitochondrial damage induced by staurosporine in wild type murine fibroblasts,
apparently due to the role of murine Bak in that setting (Arnoult et al. 2004) but
prevents staurosporine-induced death in HeLa cells (Andreau et al. 2004). Thus,
properties of the antiapoptotic proteins encoded by these viruses reflect the
evolutionary divergence of the host. In fact, one aspect of the species barrier
that restricts CMVs is reportedly due to functions that for MCMV can be pro-
vided by vMIA (Jurak and Brune 2006). Given the genomic organization and
studies thus far, it is likely that m38.5 will retain vMIA functions relevant to
survival in the host and that all CMVs rely on vMIA function.
vICA Controls Caspase-8
vICA, the UL36 gene product, interferes with caspase-8-dependent apoptosis by
binding procaspase-8 and preventing proteolytic activation (Skaletskaya et al.
2001) (Fig. 2). The role of caspase-8 as an initiator protease activated by extrinsic,
immune-regulated signals implies vICA is important to survival in the host
(Skaletskaya et al. 2001). vICA is highly conserved among mammalian betaherpes-
viruses both in sequence and function, suggesting a conserved biologic role
(McCormick et al. 2003a; Menard et al. 2003). In contrast, passage in tissue culture
has promoted adventitious mutations that impact antiapoptotic function (Skaletskaya
et al. 2001). Although early work employed a recombinant virus made in
AD169
var
ATCC, a laboratory strain that had already acquired mutations in vICA
(Patterson and Shenk 1999; Skaletskaya et al. 2001), deletion of the gene from
Towne-BAC, a viral strain that retains vICA function, confirmed that both the
UL36 gene and vICA function can be altered without impacting replication in cul-
tured fibroblasts (Dunn et al. 2003). MCMV mutants impacting M36 also grow in
fibroblasts; however, this gene is required for growth in cultured macrophages
(Menard et al. 2003) and in mice (Cicin-Sain et al. 2005). Importantly, infected
macrophages elevated caspase-8 activity only in the absence of M36 (Menard et al.
2003). These observations are consistent with the expectation that vICA prevents
caspase-8 activation, thereby performing a critical role for survival in the host.
IE1
491aa
, IE2
579aa
, and Akt-Dependent Pro-survival Pathways
Pathways leading to death are balanced by pro-survival pathways, including those
regulated by trophic factors that signal through phosphatidylinositide 3′-OH kinase
(PI3K)/Akt kinase (Datta et al. 1999). Evidence suggests CMV requires the PI3K/
Akt pathway for replication (Johnson et al. 2001). The IE1
491aa
and IE2
579aa
are
nuclear proteins that regulate transcription and have important roles in viral repli-
cation (see the chapter by M.F. Stinski and D.T. Petrik, this volume and Stinski and
