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首页> 外文OA文献 >The Elk-1 and Serum Response Factor Binding Sites in the Major Immediate-Early Promoter of Human Cytomegalovirus Are Required for Efficient Viral Replication in Quiescent Cells and Compensate for Inactivation of the NF-κB Sites in Proliferating Cells▿
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The Elk-1 and Serum Response Factor Binding Sites in the Major Immediate-Early Promoter of Human Cytomegalovirus Are Required for Efficient Viral Replication in Quiescent Cells and Compensate for Inactivation of the NF-κB Sites in Proliferating Cells▿

机译：人类巨细胞病毒主要早期启动子中的Elk-1和血清反应因子结合位点是在静止细胞中高效病毒复制并补偿增殖细胞中NF-κB位点失活所必需的。

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The major immediate-early promoter (MIEP) region of human cytomegalovirus (HCMV) plays a critical role in the regulation of lytic and latent infections by integrating multiple signals supplied by the infecting virus, the type and physiological state of the host cell, and its extracellular surroundings. The interaction of cellular transcription factors with their cognate binding sites, which are present at high densities within the enhancer upstream from the MIEP core promoter, regulate the rate of IE gene transcription and thus affect the outcome of HCMV infection. We have shown previously that the NF-κB binding sites within the MIEP enhancer and cellular NF-κB activity induced by HCMV infection are required for efficient MIEP activity and viral replication in quiescent cells (P. Caposio, A. Luganini, G. Hahn, S. Landolfo, and G. Gribaudo, Cell. Microbiol. 9:2040-2054, 2007). We now show that the inactivation of either the Elk-1 or serum response factor (SRF) binding site within the enhancer also reduces MIEP activation and viral replication of recombinant HCMV viruses in quiescent fibroblasts. In these cells, we show that the expression of either Elk-1 or SRF is required for optimal IE gene expression, and that the HCMV-stimulated activation of the MEK1/2-ERK1/2 signaling axis leads to Elk-1 transcriptional competency. Furthermore, the replication kinetics of recombinant viruses in which NF-κB, Elk-1, and SRF binding sites all are inactivated demonstrate that the higher levels of Elk-1 and SRF binding to MIEP in proliferating cells can compensate even for a lack of HCMV-induced NF-κB-mediated MIEP transactivation. These observations highlight the importance of the combination of different MIEP binding sites to optimize IE gene expression in cells in different physiological states.
机译：人类巨细胞病毒（HCMV）的主要立即早期启动子（MIEP）区通过整合感染病毒提供的多种信号，宿主细胞的类型和生理状态及其信号，在裂解性和潜伏性感染的调节中起关键作用。细胞外环境。细胞转录因子与其同源结合位点的相互作用，以高密度存在于MIEP核心启动子上游的增强子中，调节IE基因转录的速率，从而影响HCMV感染的结果。先前我们已经证明，MIEP增强子中的NF-κB结合位点和HCMV感染诱导的细胞NF-κB活性是静止细胞中有效MIEP活性和病毒复制所必需的（P. Caposio，A. Luganini，G. Hahn， S.Landolfo和G.Gribaudo，Cell.Microbiol.9：2040-2054，2007）。我们现在显示，增强子内Elk-1或血清反应因子（SRF）结合位点的失活也减少了MIEP激活和静态成纤维细胞中重组HCMV病毒的病毒复制。在这些细胞中，我们显示Elk-1或SRF的表达是最佳IE基因表达所必需的，并且HCMV刺激的MEK1 / 2-ERK1 / 2信号轴的激活导致Elk-1转录能力。此外，其中NF-κB，Elk-1和SRF结合位点均被灭活的重组病毒的复制动力学表明，在增殖细胞中较高水平的Elk-1和SRF与MIEP的结合甚至可以弥补HCMV的缺乏。诱导的NF-κB介导的MIEP反式激活。这些观察结果突出了组合不同MIEP结合位点以优化处于不同生理状态的细胞中IE基因表达的重要性。

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