Proteasome inhibitor differentially regulates expression of the major immediate early genes of human cytomegalovirus in human central nervous system-derived cell lines

Proteasome Subunits Relocalize during Human Cytomegalovirus Infection, and Proteasome Activity Is Necessary for Efficient Viral Gene Transcription

“…A significant delay in early (i.e., UL57) and late (i.e., UL99) protein expression was also observed. These results are consistent with previous studies (31,46,50) that showed that the addition of protea- HCMV TRANSCRIPTION REQUIRES PROTEASOME ACTIVITY 3081…”

“…Previous studies have shown HCMV infection to be negatively affected by inhibition of the proteasome (31,46,50), and in the experiments presented here, we have elucidated the temporal and molecular basis of this inhibition. We show that proteasome proteolytic activity is important for viral transcription and that as the infection progresses, the proteasome subunits accumulate in regions of RNA synthesis at the periphery of the viral DNA replication center in the nucleus.…”

“…It was unclear whether the decrease in early or late gene expression could be attributed to a specific defect in viral DNA synthesis and/or gene transcription or to the decrease in IE expression, which would subsequently affect transactivation of the early genes required for viral DNA synthesis. The block in IE protein expression was later shown to be MOI dependent (31,50), while early and late protein expression remained significantly impaired at all MOIs tested (31), further indicating that the stages of viral gene expression may be differentially affected by proteasome inhibition. Another potential complication that needs to be considered when studying the effects of proteasome inhibitors on HCMV gene expression is the time at which the virus and inhibitor are added in relation to the cell cycle.…”

“…had little effect on IE gene expression, although IE2-86 expression decreased thereafter either after release from the drug or when the inhibitor was added at later times during the infection. Previous studies reported a decrease in both IE1-72 and IE2-86 expression when the proteasome inhibitor was added at the onset of infection and maintained throughout the infection time course (31,46,50). This discrepancy, especially with regard to IE1-72 expression, may be attributed to a difference in the MOI (31) and/or cell lines (50) used in these assays.…”

“…HCMV has also been shown to inhibit the degradation of several cell cycle proteins by inactivating the anaphase-promoting complex, an E3 ubiquitin ligase (4,59,61,62). In general, inhibition of the proteasome appears to impact negatively on viral replication (31,46,50). Viral gene expression is temporally regulated into three different kinetic classes: immediate early (IE), early, and late (for a review, see reference 41).…”