Lan Ke, Murakami Masanao, Choudhuri Tathagata, Kuppers Daniel A, Robertson Erle S
Department of Microbiology and the Tumor Virology Program, Abramson Comprehensive Cancer Center, University of Pennsylvania Medical School, 201E Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104, USA.
Virology. 2006 Aug 1;351(2):393-403. doi: 10.1016/j.virol.2006.03.047. Epub 2006 May 15.
Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a predominantly latent infection in the infected host. Importantly, during latency, only a small number of viral encoded genes are expressed. This viral gene expression pattern contributes to the establishment of long-term infection as well as the ability of the virus to evade the immune system. Previous studies have been shown that the replication and transcription activator (RTA) encoded by ORF50 activates it downstream genes and initiates viral lytic reactivation through functional interaction with RBP-Jkappa, the major downstream effector of the Notch signaling pathway. This indicates that RTA can usurp the conserved Notch signaling pathway and mimic the activities of intracellular Notch1 to modulate gene expression. In this report, we show that the activated intracellular domain of Notch1 (ICN) is aberrantly accumulated in KSHV latently infected pleural effusion lymphoma (PEL) cells. ICN activated the RTA promoter in a dose-dependent manner, and forced expression of ICN in latently infected KSHV-positive cells initiated full blown lytic replication with the production of infectious viral progeny. However, latency-associated nuclear antigen (LANA) which is predominantly expressed during latency can specifically down-modulate ICN-mediated transactivation of RTA and so control KSHV for lytic reactivation. These results demonstrate that LANA can inhibit viral lytic replication by antagonizing ICN function and suggest that LANA is a critical component of the regulatory control mechanism for switching between viral latent and lytic replication by directly interacting with effectors of the conserved cellular Notch1 pathway.
卡波西肉瘤相关疱疹病毒（KSHV）在受感染宿主中主要建立潜伏感染。重要的是，在潜伏期间，仅少量病毒编码基因表达。这种病毒基因表达模式有助于建立长期感染以及病毒逃避免疫系统的能力。先前的研究表明，由ORF50编码的复制和转录激活因子（RTA）激活其下游基因，并通过与Notch信号通路的主要下游效应物RBP-Jkappa的功能相互作用启动病毒裂解再激活。这表明RTA可以篡夺保守的Notch信号通路并模拟细胞内Notch1的活性来调节基因表达。在本报告中，我们表明Notch1的活化细胞内结构域（ICN）在KSHV潜伏感染的胸腔积液淋巴瘤（PEL）细胞中异常积累。ICN以剂量依赖性方式激活RTA启动子，并且在潜伏感染的KSHV阳性细胞中强制表达ICN引发了完全成熟的裂解复制，并产生了有传染性的病毒后代。然而，在潜伏期间主要表达的潜伏相关核抗原（LANA）可以特异性下调ICN介导的RTA反式激活，从而控制KSHV的裂解再激活。这些结果表明LANA可以通过拮抗ICN功能来抑制病毒裂解复制，并表明LANA是通过直接与保守的细胞Notch1途径的效应物相互作用在病毒潜伏和裂解复制之间切换的调节控制机制的关键组成部分。
