Kaposi's Sarcoma-Associated Herpesvirus G-Protein-Coupled Receptor Prevents AU-Rich-Element-Mediated mRNA Decay
Kaposi's Sarcoma-Associated Herpesvirus G-Protein-Coupled Receptor Prevents AU-Rich-Element-Mediated mRNA Decay
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DOI：
10.1128/jvi.00597-12
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发表时间：
2012-08-01
影响因子：
5.4
通讯作者：
McCormick, Craig
中科院分区：
文献类型：
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作者：
Corcoran, Jennifer A.;Khaperskyy, Denys A.;McCormick, Craig
在裂解性卡波西肉瘤相关疱疹病毒（KSHV）感染期间，宿主基因表达受到称为宿主关闭的整体mRNA降解过程的严重限制，该过程将翻译机制重新致力于病毒蛋白的表达。宿主mRNA的一个子集免于关闭，并且其中许多在其3'非翻译区含有顺式作用富含AU的元件（战神）。战神存在于编码细胞因子、生长因子和原癌基因的不稳定mRNA中。p38/MK2信号转导途径的激活逆转了ARE-mRNA的组成性衰变，导致蛋白质产量增加。病毒G蛋白偶联受体（vGPCR）被认为在促进KSHV感染细胞在裂解复制过程中分泌血管生成分子方面发挥重要作用，但迄今为止，vGPCR如何规避宿主关闭尚不清楚。在这里，我们证明了vGPCR激活p38/MK2通路并稳定ARE-mRNA，增加其蛋白质产物的水平。使用MK2缺陷细胞，我们证明了MK2对于最大vGPCR介导的ARE-mRNA稳定是必不可少的。ARE-mRNA通常被递送到称为加工体（PB）的细胞质核糖核蛋白颗粒，用于翻译沉默和衰变。我们证明，PB的形成是防止在KSHV裂解复制或响应vGPCR介导的激活RhoA亚家族GTP酶。总之，这些数据首次表明vGPCR在转录后水平影响基因表达，协调对宿主mRNA降解机制的攻击。通过抑制ARE-mRNA周转，vGPCR可以促进某些靶mRNA从宿主关闭中逃逸，并允许血管生成因子从裂解感染的细胞中分泌。
During lytic Kaposi's sarcoma-associated herpesvirus (KSHV) infection, host gene expression is severely restricted by a process of global mRNA degradation known as host shutoff, which rededicates translational machinery to the expression of viral proteins. A subset of host mRNAs is spared from shutoff, and a number of these contain cis-acting AU-rich elements (AREs) in their 3' untranslated regions. AREs are found in labile mRNAs encoding cytokines, growth factors, and proto-oncogenes. Activation of the p38/MK2 signal transduction pathway reverses constitutive decay of ARE-mRNAs, resulting in increased protein production. The viral G-protein-coupled receptor (vGPCR) is thought to play an important role in promoting the secretion of angiogenic molecules from KSHV-infected cells during lytic replication, but to date it has not been clear how vGPCR circumvents host shutoff. Here, we demonstrate that vGPCR activates the p38/MK2 pathway and stabilizes ARE-mRNAs, augmenting the levels of their protein products. Using MK2-deficient cells, we demonstrate that MK2 is essential for maximal vGPCR-mediated ARE-mRNA stabilization. ARE-mRNAs are normally delivered to cytoplasmic ribonucleoprotein granules known as processing bodies (PBs) for translational silencing and decay. We demonstrate that PB formation is prevented during KSHV lytic replication or in response to vGPCR-mediated activation of RhoA subfamily GTPases. Together, these data show for the first time that vGPCR impacts gene expression at the posttranscriptional level, coordinating an attack on the host mRNA degradation machinery. By suppressing ARE-mRNA turnover, vGPCR may facilitate escape of certain target mRNAs from host shutoff and allow secretion of angiogenic factors from lytically infected cells.