The lytic switch protein of KSHV activates gene expression via functional interaction with RBP-Jκ (CSL), the target of the Notch signaling pathway
The lytic switch protein of KSHV activates gene expression via functional interaction with RBP-Jκ (CSL), the target of the Notch signaling pathway
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DOI：
10.1101/gad.996502
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发表时间：
2002-08-01
影响因子：
10.5
通讯作者：
Ganem, D
中科院分区：
文献类型：
--
作者：
Liang, YY;Chang, J;Ganem, D
Kaposi肉瘤相关疱疹病毒(KSHV)的RTA蛋白负责从潜伏复制到裂解复制的转换，这是病毒传播和KS发病所必需的反应。RTA是一种序列特异性转录激活剂，但其靶点的多样性表明它也可能通过与宿主DNA结合蛋白的相互作用发挥作用。在这里，我们发现KSHV RTA与RBP-Jkappa蛋白相互作用，RBP-Jkappa蛋白是Notch信号通路的主要靶点。这种相互作用将RTA靶向DNA上的RBP-Jkappa识别位点，并导致RBP-Jkappa的内在抑制作用被RTA的C末端结构域介导的激活所取代。靶启动子中这些位点的突变会严重削弱RTA的响应性。同样，在RBP-Jkappa(-/-)小鼠的成纤维细胞中，RTA诱导的这种靶基因很差，甚至根本不诱导，这一缺陷可以通过表达RBP-Jkappa来逆转。在体外，RTA与RBP-Jkappa的两个相邻区域结合，其中一个区域与结合Notch效应器片段的中心抑制域相同。这些结果表明，KSHV已经进化出一种非配体依赖的Notch通路成分激活机制，作为其潜伏期重新激活策略的一部分。
The RTA protein of the Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is responsible for the switch from latency to lytic replication, a reaction essential for viral spread and KS pathogenesis. RTA is a sequence-specific transcriptional activator, but the diversity of its target sites suggests it may act via interaction with host DNA-binding proteins as well. Here we show that KSHV RTA interacts with the RBP-Jkappa protein, the primary target of the Notch signaling pathway. This interaction targets RTA to RBP-Jkappa recognition sites on DNA and results in the replacement of RBP-Jkappa's intrinsic repressive action with activation mediated by the C-terminal domain of RTA. Mutation of such sites in target promoters strongly impairs RTA responsiveness. Similarly, such target genes are induced poorly or not at all by RTA in fibroblasts derived from RBP-Jkappa(-/-) mice, a defect that can be reversed by expression of RBP-Jkappa. In vitro, RTA binds to two adjacent regions of RBP-Jkappa, one of which is identical to the central repression domain that binds the Notch effector fragment. These results indicate that KSHV has evolved a ligand-independent mechanism for constitutive activation of the Notch pathway as a part of its strategy for reactivation from latency.