| Herpes simplex virus type 1 is a kind of serious infectious pathogens for human that is the only host, and there is no vaccine as yet. As a double-stranded DNA virus with a complicated structure, HSV-1 plays a specific role in the cascade effect in gene transcription regulation, and shows characteristics of different levels in its interaction with cells. Analysis on the function of the cellular early gene product will help to understand the interaction between HSV-1 and its receptor, and clarify the model of functioning mechanism of some unknown proteins related infection. In our previous studies, we conducted further research on proteins induced by HSV-1 infection in human fibroblasts using mRNA differential display technology and protein 2D differential technology, and identified a number of HSV-1 infection-related proteins. HTRP (human transcription regulator protein) was one of these proteins. It is associated with transcriptional regulation that interacts with part of the transcriptional co-repressor mSin3A complex SAP30 (mSin3A Association Protein) to promote HSV-1 infection which leads to cell death.Our research focused on the biological function and molecules mechanism of the interaction of HTRP and SAP30 between virus and its receptors. This study revealed the transcriptional inhibitory effect of HTRP on HSV-1 gene transcription, and then confirmed synergic inhibitory effect of HTRP and SAP30. We concluded the close relation and molecules mechanism of the interaction of these two proteins. In cells with HTRP protein over expression, HTRP can suppress the transcription of viral TK and gC gene at different infection phases and this inhibition is more significant as the time is extended. Under a cellular environment which contains simultaneous up-regulated expression of HTRP and SAP30, we further demonstrated that both showed a synergistic inhibition effect on the transcription of TK and gC genes. Data have shown that as one of the major structural components of the co-repressor complex for the transcription and regulation in cells, SAP30 plays a role in mediating HDACs to be bound to the complex. The data have also shown that these can achieve transcriptional repression by chromatin histone deacetylation. To further verify molecules mechanism of this synergistic inhibition effect, in dual-luciferase detection system with the presence of HDACs inhibitor TSA, the transcriptional repression effect of HTRP and SAP30 could be associated with the state of HDAC's enzyme activity. Meanwhile, ChIP experiments also showed that the combination of SAP30 and HTRP caused the activity changes of HDACs. Ultimately, the specific mechanism leading to the inhibition of viral gene transcription is that HDACs increases the degree of deacetylation of ly sines 9 and 14 in histone-H3.Based on these data and according to the working molecular mechanism of HTRP up-regulated by HSV-1 infection in fibroblast cells, we propose the following model:As a transcriptional regulation molecule, HTRP is reactively up-regulated by the HSV-1 infection in cells and may function by combining with SAP30 to increase the enzyme activity of HDACs. These HDACs would function via the co-repressor complex Sin3 A, up-regulating the deacetylation level of lysine 9 and 14 in histone H3 in regions binding to the HSV-1 gene promoter. As a result, the transcriptional process of HSV-1 related genes would be inhibited to some extent and the viral replication and proliferation would be affected. The establishment of this model along with experimental data will help us further understand the interaction between HSV-1 and host cells through a cellular protein modifying enzyme system to influence the transcriptional regulation of viral gene, which causes a variety of pathological results by HSV-1 infection in cells.
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