Control of Apoptosis by Human Cytomegalovirus - Human Cytomegalovirus - page 283

m41, Late Infection, and the Golgi Apparatus
The CMV ORFs m41 and r41 are apparently unique to rodent CMVs and, as such,
do not share sequence homology with HCMV ORFs (Chee et al. 1990; Rawlinson
et al. 1996; Mocarski et al. 1997; Vink et al. 2000; Brocchieri et al. 2005). Expression
constructs produce a single protein of 19 kDa while polypeptides of 19 and 21-kDa
polypeptides are produced during infection, suggesting splicing to upstream or
downstream ORFs (Brune et al. 2003). Recombinants that disrupt the m41 ORF
induce apoptosis very late in infection, as suggested both by apoptosis-induced
molecular changes, including phosphatidylserine exposure and nuclease-driven
chromatin alterations, and increased survival in the presence of caspase inhibitors.
A more dramatic impact on replication occurs in endothelial cells where viral yields
are reduced 50-fold. Thus far, neither yield nor death has been directly related to
pm41, but Golgi localization is likely important to pm41 function.
β2.7 and Mitochondrial Respiratory Complex I
The highly abundant early transcript β2.7 (McDonough and Spector 1983;
McDonough et al. 1985) is polysome-associated (Wathen and Stinski 1982); how-
ever, sequence analyses suggest a noncoding RNA (McSharry et al. 2003).
Although the gene is conserved in both laboratory-adapted viral strains and clinical
isolates, the RL4 ORF is not. Northwestern screening suggested β2.7 binds proteins
of the nicotinamide adenine dinucleotide-ubiquinone oxidoreductase (mitochon-
drial respiration complex I) (Reeves et al. 2007). β2.7 also increases survival from
the mitochondrial poison rotenone and maintains ATP production late in infection.
The importance of continued mitochondrial function during CMV infection has
been suggested from several studies that have evaluated mitochondrial DNA
synthesis, mitochondrial protein expression profiles, and ATP production (Furukawa
et al. 1976; Hertel and Mocarski 2004; Reeves et al. 2007). β2.7 contributes to viral
production by maintaining ATP production (Reeves et al. 2007), and in addition,
prevents death that follows intrinsic stresses associated with decreased ATP.
Summary and Perspectives
Several CMV gene products that impact apoptosis have already been identified. vMIA
and vICA are the most extensively characterized with regard to proposed mechanism
and antiapoptotic roles during infection. pUL38, M45, and m41 remain largely
uncharacterized with regard to mechanism, and the contributions of IE1 491aa and
IE2 579aa antiapoptotic functions during replication remain to be addressed. Additional
genes like β2.7, which increase survival in response to stress, are likely to be identified
through efforts that determine viral control of cellular stress responses (see the chapter