Lytic but not latent infection by Kaposi's sarcoma-associated herpesvirus requires host CSL protein, the mediator of Notch signaling
Lytic but not latent infection by Kaposi's sarcoma-associated herpesvirus requires host CSL protein, the mediator of Notch signaling
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DOI：
10.1073/pnas.1432843100
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发表时间：
2003-07-08
影响因子：
11.1
通讯作者：
Ganem, D
中科院分区：
文献类型：
--
作者：
Liang, YY;Ganem, D
卡波西肉瘤（KS）相关疱疹病毒（KSHV）感染是KS发展的关键因素。在KS肿瘤细胞中观察到潜伏性和溶解性KSHV感染，并且这两种遗传程序都对KS发病机制有重要贡献。病毒复制和转录激活因子（RTA）蛋白是控制从潜伏期到裂解性复制的转换的转录因子。我们以前已经表明，RTA可以激活几个裂解病毒基因在转染细胞中的表达，通过与重组信号序列结合蛋白-Jkappa（RBP-Jkappa，也称为CSL），在未感染的细胞是一个转录抑制因子，是Notch信号通路的目标相互作用。许多KSHV裂解基因，包括RTA本身，含有RBP-Jkappaw结合位点的认识，提出了RBP-Jkappa介导的抑制可能是建立潜伏期的核心。在这里，我们已经测试了这一假设，通过检查KSHV感染的RBP-Jkappa-null鼠成纤维细胞。我们的研究结果表明，KSHV潜伏期是有效地诱导在这样的细胞，然而，裂解基因表达，病毒DNA复制，并释放后代病毒的再激活显着抑制在RBP-Jkappa的情况下。因此，RBP-J κ介导的抑制对于建立潜伏感染不是必需的，但是RTA介导的RBP-J κ活性从抑制到激活的重定向对于裂解性病毒复制是关键的。
Infection by Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is a key factor in the development of KS. Both latent and lytic KSHV infection is observed in KS tumor cells, and both genetic programs contribute importantly to KS pathogenesis. The viral replication and transcription activator (RTA) protein is a transcription factor that controls the switch from latency to lytic replication. We have previously shown that RTA can activate the expression of several lytic viral genes in transfected cells by interaction with recombination signal sequence-binding protein-Jkappa (RBP-Jkappa, also called CSL), which in uninfected cells is a transcriptional repressor that is the target of the Notch-signaling pathway. The recognition that many KSHV lytic genes, including RTA itself, contain RBP-Jkappaw-binding sites raised the possibility that RBP-Jkappa-mediated repression may be central to the establishment of latency. Here, we have tested this hypothesis by examining KSHV infection of RBP-Jkappa-null murine fibroblasts. Our results show that KSHV latency is efficiently induced in such cells; however, the reactivation of lytic gene expression, viral DNA replication, and the release of progeny viruses are dramatically inhibited in the absence of RBP-Jkappa. RBP-Jkappa-mediated repression is therefore not essential for establishment of latent infection, but the RTA-mediated redirection of RBP-Jkappa activity from repression to activation is critical for lytic viral replication.