Fine-Tuning of the Kaposi's Sarcoma-Associated Herpesvirus Life Cycle in Neighboring Cells through the RTA-JAG1-Notch Pathway.
Fine-Tuning of the Kaposi's Sarcoma-Associated Herpesvirus Life Cycle in Neighboring Cells through the RTA-JAG1-Notch Pathway.
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通过 RTA-JAG1-Notch 途径微调邻近细胞中卡波西肉瘤相关疱疹病毒的生命周期
DOI：
10.1371/journal.ppat.1005900
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发表时间：
2016-10
期刊：
影响因子：
6.7
通讯作者：
Lan K
中科院分区：
文献类型：
--
作者：
Li S;Hu H;He Z;Liang D;Sun R;Lan K
卡波西肉瘤(KS)相关疱疹病毒(KSHV)是一种具有潜伏和溶解生命周期的致癌病原体。在KS皮损中，渗透的免疫细胞、分泌的病毒和/或细胞因子以及低氧协调了一个可促进KSHV重新激活的慢性促溶解微环境。然而，在这种溶血的微环境中，只有一小部分病毒自发地进行裂解复制，而大多数病毒仍处于潜伏状态。在这里，我们证明了Notch配体JAG1的表达是由KSHV编码的复制和转录激活因子(RTA)在重新激活过程中诱导的。JAG1上调激活邻近细胞中的Notch信号，防止病毒裂解复制。在RTA诱导或低氧条件下，用抑制剂或小干扰RNA抑制JAG1和Notch1促进裂解复制。其潜在的机制涉及Notch下游效应毛发和裂解1增强子(Hes1)，它直接结合裂解基因启动子并减弱病毒裂解基因的表达。RTA与淋巴增强因子1(LEF1)相互作用，破坏LEF1/Groucho/TLE抑制复合体，释放LEF1激活JAG1表达。综上所述，我们的结果表明，具有病毒裂解复制的细胞可以通过RTA-JAG1-Notch途径抑制相邻细胞中KSHV的重新激活。这些数据提供了对病毒在促进肿瘤微环境中维持裂解感染和潜伏感染之间的平衡的机制的洞察。在普遍的促溶炎性环境中，感染KSHV的细胞在病毒裂解复制方面表现出显著的异质性，这表明潜伏期和重新激活之间的平衡受到仔细的调节。这种微调的调节机制对于KSHV在宿主体内的持续存在和驱使细胞恶性变是必不可少的。在目前的研究中，我们发现KSHV可以篡改Notch信号通路来抑制邻近细胞中病毒的裂解生命周期。在KSHV被重新激活的细胞中，周围细胞中的Notch信号可以通过RTA-JAG1-Notch途径被激活。激活的Notch通过其下游效应器Hes1抑制KSHV的重新激活。这些发现表明，Notch决定相邻细胞命运的能力被KSHV劫持以维持其生命周期，为在常见的溶血微环境中只有一小部分病毒进入裂解复制的现象提供了机制解释。
Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) is an oncogenic pathogen that displays latent and lytic life cycles. In KS lesions, infiltrated immune cells, secreted viral and/or cellular cytokines, and hypoxia orchestrate a chronic pro-lytic microenvironment that can promote KSHV reactivation. However, only a small subset of viruses spontaneously undergoes lytic replication in this pro-lytic microenvironment while the majority remains in latency. Here, we show that the expression of the Notch ligand JAG1 is induced by KSHV-encoded replication and transcription activator (RTA) during reactivation. JAG1 up-regulation activates Notch signaling in neighboring cells and prevents viral lytic replication. The suppression of JAG1 and Notch1 with inhibitors or small interfering RNA promotes lytic replication in the presence of RTA induction or under conditions of hypoxia. The underlying mechanism involves the Notch downstream effector hairy and enhancer of split 1 (Hes1), which directly binds lytic gene promoters and attenuates viral lytic gene expression. RTA interacts with lymphoid enhancer-binding factor 1 (LEF1), disrupts LEF1/Groucho/TLE suppressive complexes and releases LEF1 to activate JAG1 expression. Taken together, our results suggest that cells with viral lytic replication can inhibit KSHV reactivation in neighboring cells through an RTA-JAG1-Notch pathway. These data provide insight into the mechanism by which the virus maintains the balance between lytic and latent infection in the pro-lytic tumor microenvironment. KSHV infected cells display significant heterogeneity in viral lytic replication within the universal pro-lytic inflammatory milieu, suggesting that the balance between latency and reactivation is carefully regulated. This fine-tuned regulatory mechanism is essential for KSHV to persist in the host and drive cells to malignancy. In the present study, we show that KSHV can usurp the Notch signaling pathway to inhibit the viral lytic life cycle in neighboring cells. Notch signaling in surrounding cells can be activated through an RTA-JAG1-Notch pathway initiated by cells in which KSHV is reactivated. Activated Notch inhibits KSHV reactivation through its downstream effector Hes1. These findings suggest that the ability of Notch to determine the fate of adjacent cells is hijacked by KSHV to maintain its life cycle, providing a mechanistic explanation for the phenomenon by which only a small fraction of viruses enters lytic replication in the common pro-lytic microenvironment.
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