Oncogenic Ras promotes reovirus spread by suppressing IFN-beta production through negative regulation of RIG-I signaling.
Oncogenic Ras promotes reovirus spread by suppressing IFN-beta production through negative regulation of RIG-I signaling.
复制标题
致癌 Ras 通过 RIG-I 信号传导的负调节抑制 IFN-β 的产生，从而促进呼肠孤病毒传播。
作者：
M. Shmulevitz;L. Pan;Katy A. Garant;D. Pan;Patrick Lee
呼肠孤病毒是第一种天然存在的人类病毒，据报道，它利用宿主细胞中激活的Ras信号转导进行感染，目前正在进行癌症治疗的临床试验。最近的证据表明，Ras转化在第一轮感染期间促进三个呼肠孤病毒复制步骤：进入的病毒体的脱壳，具有增强的感染性的子代病毒的产生，以及通过增强的细胞凋亡的病毒释放。致癌Ras是否也通过其他机制增强呼肠孤病毒在随后几轮感染中的传播尚未研究。在这里，我们表明，与非转化细胞相比，Ras转化细胞严重受损，不仅在他们的反应IFN-β，但也在呼肠孤病毒感染后IFN-β mRNA的诱导。IFN-β产生和应答的缺陷允许病毒在Ras转化细胞中有效传播。我们发现Ras下游的MEK/ERK通路通过阻断识别病毒RNA的视黄酸诱导基因I（RIG-I）的信号传导来抑制IFN-β的表达。野生型RIG-I的过表达恢复了呼肠孤病毒感染的Ras转化细胞中INF-β的表达。体外合成的病毒mRNA也在转染的非转化细胞中引起RIG-I介导的IFN-β产生，但在Ras转化细胞中不引起。总的来说，我们的数据表明，致癌Ras通过抑制病毒RNA诱导的IFN-β的产生，通过负调节RIG-I信号，促进病毒传播。
Reovirus is the first naturally occurring human virus reported to exploit activated Ras signaling in the host cell for infection, and is currently undergoing clinical trials as a cancer therapeutic. Recent evidence suggests that Ras transformation promotes three reoviral replication steps during the first round of infection: uncoating of the incoming virion, generation of progeny viruses with enhanced infectivity, and virus release through enhanced apoptosis. Whether oncogenic Ras also enhances reovirus spread in subsequent rounds of infection through other mechanisms has not been examined. Here, we show that compared with nontransformed cells, Ras-transformed cells are severely compromised not only in their response to IFN-beta, but also in the induction of IFN-beta mRNA following reovirus infection. Defects in both IFN-beta production and response allow for efficient virus spread in Ras-transformed cells. We show that the MEK/ERK pathway downstream of Ras is responsible for inhibiting IFN-beta expression by blocking signaling from the retinoic acid-inducible gene I (RIG-I) which recognizes viral RNAs. Overexpression of wild-type RIG-I restores INF-beta expression in reovirus-infected Ras-transformed cells. In vitro-synthesized viral mRNAs also invoke robust RIG-I-mediated IFN-beta production in transfected nontransformed cells, but not in Ras-transformed cells. Collectively, our data suggest that oncogenic Ras promotes virus spread by suppressing viral RNA-induced IFN-beta production through negative regulation of RIG-I signaling.