Control of Apoptosis by Human Cytomegalovirus - Human Cytomegalovirus - page 276

encoded by UL36 (Goldmacher et al. 1999; Skaletskaya et al. 2001). Both functions
increase infected cell resistance to apoptosis (Skaletskaya et al. 2001; Menard et al.
2003; Reboredo et al. 2004; McCormick et al. 2005). A direct assessment of IE1 491aa
and IE2 579aa lead to observed impacts on pro-survival signaling mediated by the kinase
Akt (Lukac and Alwine; Yu and Alwine 2002). The mechanisms and direct impact of
these pro-survival activities on viral growth remain unexplored. Viral genetics high-
lighted the contributions of UL38, M45, and m41 to survival from apoptosis induced
by replication (Brune et al. 2001, 2003; Terhune et al. 2007). Although the antiapop-
totic mechanism remains unknown, pUL38 is sufficient to increase survival in apop-
tosis models (Terhune et al. 2007). Lastly, interaction studies revealed the RNA, β2.7,
binds mitochondrial complex I and as a result, controls mitochondrial function and
cell survival following death induced by respiration poisons. Thus, multiple CMV
genes encode pro-survival or antiapoptotic factors. The phenotypes of viral mutants
combined with results of exogenous expression analyses, suggest the UL36-38
genomic region is a cell death suppression locus.

vMIA Controls Mitochondria-Dependent Death

The UL37×1 ORF encoding vMIA is included on multiple viral transcripts. (Tenney
and Colberg-Poley 1990, 1991a, 1991b; Goldmacher et al. 1999) (Fig. 1). The
predominant, unspliced transcript yields the 163 aa vMIA, while splicing to UL37×2
and UL37×3 yields the larger antiapoptotic glycoprotein gpUL37 and pUL37 M
(Goldmacher et al. 1999). Additional less abundant spliced transcripts are predicted to
encode antiapoptotic proteins as well, but have not yet been tested for function (Adair
et al. 2003). vMIA localizes to mitochondria and prevents the release of pro-death

UL36x1 UL37x2

UL37x1

UL36x2 UL37x3 UL38

ORFS:

pUL37x1
pUL38

gpUL37

pUL37 M

pUL36

Fig. 1 A map of the HCMV UL36-UL38 cell death suppression locus indicating the relative
positions of open reading frames (ORFs) and major transcripts of the region. Rectangles represent
the ORFs and include an arrowhead to denote the direction of transcription. Arrows represent the
3′ nontranslated regions. A raised line connecting ORFs indicates splicing. Splicing events pro-
ducing minor transcripts of the UL37 gene (Adair et al. 2003) are not shown