Abstract
ICP22 is a multifunctional herpes simplex virus 1 (HSV-1) immediate early protein that functions as a general repressor of a subset of cellular and viral promoters in transient expression systems. Although the exact mechanism of repression remains unclear, this protein induces a decrease in RNA polymerase II Serine 2 (RNAPII Ser-2) phosphorylation, which is critical for transcription elongation. To characterize the mechanism of transcriptional repression by ICP22, we established an in vivo transient expression reporter system. We found that ICP22 inhibits transcription of the HSV-1 α, β and γ gene promoters. The viral tegument protein VP16, which plays vital roles in initiation of viral gene expression and viral proliferation, can overcome the inhibitory effect of ICP22 on α-gene transcription. Further immunoprecipitation studies indicated that both ICP22 and VP16 bind to positive transcription elongation factor b (P-TEFb) and form a complex with it in vivo. We extended this to show that P-TEFb regulates transcription of the viral α-gene promoters and affects transcriptional regulation of ICP22 and VP16 on the α-genes. Additionally, ChIP assays demonstrated that ICP22 blocks the recruitment of P-TEFb to the viral promoters, while VP16 reverses this blocking effect by recruiting P-TEFb to the viral α-gene promoters through recognition of the TAATGARAT motif. Taken together, our results suggest that ICP22 interacts with and blocks the recruitment of P-TEFb to viral promoter regions, which inhibits transcription of the viral gene promoters. The transactivator VP16 binds to and induces the recruitment of P-TEFb to viral α-gene promoters, which counteracts the transcriptional repression of ICP22 on α-genes by recruiting p-TEFb to the promoter region.
Highlights
Herpes simplex virus 1 (HSV-1) is a member of the herpes virus family and has a 152 kb double-stranded DNA genome that encodes for more than 80 proteins and possesses complex transcriptional regulation mechanisms [1,2]
The immediate early proteins are involved during the regulation of viral gene transcription in the HSV-1 infection process, the function of ICP22 is not yet clear
ICP22 had an inhibitory effects on ICP4 and ICP0 expression, which was overcome by the expression of VP16, indicating that the effects of ICP22 and VP16 on viral proliferation might be mediated by effects on viral transcription (Fig. 1C)
Summary
Herpes simplex virus 1 (HSV-1) is a member of the herpes virus family and has a 152 kb double-stranded DNA genome that encodes for more than 80 proteins and possesses complex transcriptional regulation mechanisms [1,2]. Three gene classes, known as the immediate early genes (a-genes), the early genes (b-genes), and the late genes (cgenes), are sequentially expressed following the comprehensive transcriptional regulation of viral and host cell proteins [5,6,7]. The immediate early protein ICP22, which may have multiple functions in viral proliferation [11], inhibits the transcription of many cellular and viral gene promoters in transient expression system [15]. Fraser et al suggest that during HSV-1 infection ICP22 triggers a decrease in RNAPII Ser-2 phosphorylation and induces an intermediate status (RNAPIII), which causes abnormalities in cellular-related gene transcription and optimal expression of viral genes [21,37,38,39,40]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.