Biology Reference
In-Depth Information
viral protein expression, but antagonistically to autoregulate the MIEP (Cherrington
and Mocarski 1989; Pizzorno and Hayward 1990; Stenberg et al. 1990; Cherrington
et al. 1991; Liu et al. 1991). Both activate or augment viral and host gene transcrip-
tion (Hagemeier et al. 1992). Most transactivators become part of the basal tran-
scription machinery when they bind to DNA in the promoter region. Apparently,
IE1 and IE2 are no exceptions. IE2 binds to specific sequences on early promoters
(Cherrington et al. 1991; Meier and Stinski 1997). Some, but not all, transcription
factors (TBP, TFIIB) accumulate in the domain adjacent to ND10 together with IE2,
where there is just one viral genome (Ishov et al. 1997). IE2 is therefore the likely
accumulator of pretranscription complexes, although it might create this enriched
microenvironment in some association with the UL112/113 gene products.
IE1's mechanisms of action are not understood as well as those of IE2.
Apparently, IE1 is not essential to produce viral progeny, but is necessary for the
more natural mode of infection involving low levels of particles. Fibroblasts
infected with an IE1-deletion mutant of HCMV require a much larger number of
mutant viral particles to achieve the same degree of replicative success as that
of wild type viruses, indicating the necessity of multiple genomes of the IE1
mutant. Mocarski and colleagues also found that viral transactivators, such as
tegument proteins can compensate for IE1 at high multiplicities of infection
(moi) (Mocarski et al. 1996). At low moi, infected cells produce no replication
compartments, despite the nearly equal amount of IE2 synthesis (Greaves and
Mocarski 1998). This does not support the idea that IE1 is a necessary component
of the transcription machinery as IE2 is. The temporal localization of IE1 in spe-
cific nuclear compartments, along with the potential interactions of IE1 with
nuclear proteins in these compartments, points to additional functions of IE1 that
are in line with the often noted augmentation of transcription observed in trans-
fection experiments.
Intuitively, one might suppose that the nuclear site with the highest concentration
of a protein is where it functions. IE1 should therefore function in all ND10, and IE2
should function beside a few ND10. However, because not all ND10 have transcribing
viral genomes, it follows that IE1 would not act on viral genomes. IE1 does not act
on host genes as no host genes have been found in ND10. IE1 must therefore have
functions other than transactivation with the basal transcription machinery.
Identifying proteins that interact with IE1 is one way to determine its other
functions. IE1 colocalization with ND10 proteins has been used to identify IE1
interaction partners. The interaction between IE1 and PML in HCMV (Ahn et al.
1998) has also been confirmed in MCMV (Tang and Maul 2003). In immunopre-
cipitation analyses, both of the ND10-associated proteins, PML and Daxx,
co-immunoprecipitate with MCMV IE1, suggesting that all three proteins form a
complex. At present, no functional assay exists for examining the interaction
between IE1 and Daxx. However, MCMV replicates more successfully in Daxx
-/-
cells (Tang and Maul 2006). However, analysis of the influence of the ND10-
associated proteins on overall replicative success has just begun in cells where
these proteins and another ND10-associated protein, such as Sp100, have been
eliminated or strongly downregulated by siRNA.
