Biology Reference
In-Depth Information
alters cell intrinsic defenses employing apoptosis, and multiple viral gene products
together control death-inducing stimuli to promote survival.
Introduction
Apoptosis is an evolutionarily conserved process that removes cells during
development and homeostasis and that can limit viral replication (Roulston et al.
1999). Apoptosis results from the hierarchical activation of a family of cysteine
proteases, the caspases, that follows extrinsic or intrinsic pro-death signaling
(Festjens et al. 2006). Extrinsic signals engage death receptors, a subset of the
TNF superfamily, promoting the recruitment of cytoplasmic proteins and activa-
tion of initiator caspase-8. This caspase is highly regulated, including by c-FLIP
proteins that can prevent proteolytic activation (Barnhart et al. 2003). Intrinsic
signals following DNA damage, ER stress, or other stresses alter mitochondria
membrane permeability, promote release of cytochrome c and additional pro-
death factors, and activate initiator caspase-9 (Festjens et al. 2006). Both extrin-
sic and intrinsic pathways converge on downstream executioner caspase-3,
which targets specific proteins. For most types of cells, extrinsic signals are also
amplified by way of mitochondrial alterations and caspase-9 activation (Barnhart
et al. 2003). The cellular Bcl-2 family proteins tightly regulate the mitochondria
membrane permeability transition (Kuwana and Newmeyer 2003; Green and
Kroemer 2004; Sharpe et al. 2004; Antignani and Youle 2006). Proteins in this
family include one of four distinct amino acid sequence domains, known as Bcl-
2 homology (BH) domains that are important to function (Petros et al. 2004).
The balance of pro- and antiapoptotic Bcl-2 proteins determines whether a cell
undergoes apoptosis (Kuwana and Newmeyer 2003; Green and Kroemer 2004;
Sharpe et al. 2004; Antignani and Youle 2006). The proapoptotic proteins Bax
and Bak are directly linked to the release of pro-death factors from mitochon-
dria. While still controversial, one suggested mechanism employs the inherent
pore-forming properties of these proteins. The actions of the proapoptotic Bcl-
2-related proteins are balanced by antiapoptotic Bcl-2 and Bcl-x
L
. Likewise,
pro-death signals can be balanced by more global pro-survival signals. Sensors
located in various organelles, including the nucleus, endoplasmic reticulum,
lysosomes, and the Golgi apparatus can promote death through apoptosis (Ferri
and Kroemer 2001); thus, events leading to death can occur from multiple cellu-
lar sites. Many viral factors that counteract caspase-dependent apoptosis are
homologs of key cellular regulatory proteins, including the Bcl-2 related pro-
teins and the c-FLIP proteins (Irusta et al. 2003; Polster et al. 2004).
CMV genes that impact apoptosis have been identified by three different strate-
gies. In the first, the antiapoptotic designation followed transient expression and
increased cell survival in well-defined models of apoptosis. A random search employ-
ing this strategy uncovered the viral mitochondria-localized inhibitor of apoptosis
(vMIA) encoded by UL37×1 and the viral inhibitor of caspase-8 activation (vICA),
