Biology Reference
In-Depth Information
Other functions of IE1 are observed. IE1 apparently functions as an antago-
nist to type1 interferon signal transduction (Paulus et al. 2006). Where this
antagonist interferes is of interest since it may be at several levels of interaction.
It might be the downstream effect of dispersing PML and thus releasing and pos-
sibly changing the Sp100 isotype composition. Circumstantial evidence comes
from work that shows that elimination of PML and thus release of all ND10-
associated proteins strongly reduces the detrimental Sp100 isotypes (Everett
et al. 2006; Negorev et al. 2006).
Effect of ND10-Associated Proteins on CMV
PML
PML is the matrix protein of ND10. Without PML, specifically the SUMO modi-
fied form, the aggregation of various ND10-associated proteins does not take place
(Ishov et al. 1999). Numerous proteins have been shown to accumulate at ND10,
mostly when overexpressed, and many reviews suggest a plethora of supposed
functions of these protein accumulations (Negorev and Maul 2001). There seems to
be no nuclear function that has not been fingered as dependent, influenced or modu-
lated by these structures, except perhaps splicing. This often indiscriminate assign-
ment of function, based on mostly spurious evidence of colocalization after
overexpression, has muddied the field considerably. However, a clearing and clear
effect on the replicative cycle of HCMV has recently been provided by Stamminger's
group, who showed that the depletion of PML through shRNA substantially
increases replicative success. This was all the more convincing because it could be
reversed by the reconstitution of a single PML isotype (Tavalai et al. 2006). The
finding that depletion of PML can enhance the number of cells replicating HCMV
and plaque formation by a factor of 4 shows that IE1 cannot completely overcome
the repressive effect, unlike ICP0 of HSV-1 (Everett et al. 2006). However, the
much higher (20 times) enhancement of replicative success of the IE1 deletion
mutant also shows that IE1 has a suppressive effect on the PML-based inhibition of
immediate early transcriptional events and replicative success.
PML may repress the initiation of immediate early transcription, or its progres-
sion, or both. PML may repress transcription by interfering directly with Daxx-
mediated NFkB binding on the MIEP, or by indirect means such as retaining
repressive factors (Daxx, ATRX, Sp100). IE1 in turn may enhance transcriptional
activity by lowering free PML, as IE1's concentration generally exceeds that of
PML. Observations on HCMV and MCMV show that PML, Daxx and Sp100
initially accumulate in HCMV IE2 or MCMV IE3 domains and the UL112/113
outlined prereplication domains. From there, they disperse at later stages when IE1
is present. In the absence of IE1 in either virus, these ND10-associated proteins
remain in the prereplication domains, and later in the replication domains (Tavalai
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