Rebsamen M, Meylan E, Curran J, Tschopp J
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Cell Death Differ. 2008 Nov;15(11):1804-11. doi: 10.1038/cdd.2008.119. Epub 2008 Aug 29.
The outcome of a viral infection depends on the interplay between the host's capacity to trigger potent antiviral responses and viral mechanisms that counteract them. Although Toll-like receptor (TLR)-3, which recognizes virally derived double-stranded (ds) RNA, transmits downstream antiviral signaling through the TIR adaptor Trif (TICAM-1), viral RNA-sensing RIG-like helicases (RLHs) use the mitochondrial-bound CARD protein Cardif (IPS-1/MAVS/VISA). The importance of these two antiviral signaling pathways is reflected by the fact that both adaptors are inhibited through specific cleavage triggered by the hepatitis C virus serine protease NS3-4A. Here, we show that inactivation can also occur through cellular caspases activated by various pro-apoptotic signals. Upon caspase-dependent cleavage both adaptors loose their capacity to activate the transcription factors interferon regulatory factors (IRF) and NF-kappaB. Importantly, poliovirus infection triggers a caspase-dependent cleavage of Cardif, suggesting that some viruses may activate caspases not only as a mean to facilitate shedding and replication, but also to impair antiviral responses.
病毒感染的结果取决于宿主触发强效抗病毒反应的能力与对抗这些反应的病毒机制之间的相互作用。虽然识别病毒衍生双链（ds）RNA的Toll样受体（TLR）-3通过TIR衔接蛋白Trif（TICAM-1）传递下游抗病毒信号，但病毒RNA感应RIG样解旋酶（RLH）使用线粒体结合的CARD蛋白Cardif（IPS-1/MAVS/VISA）。丙型肝炎病毒丝氨酸蛋白酶NS3-4A触发的特异性切割会抑制这两种衔接蛋白，这一事实反映了这两条抗病毒信号通路的重要性。在此，我们表明，失活也可能通过各种促凋亡信号激活的细胞半胱天冬酶发生。在半胱天冬酶依赖性切割后，这两种衔接蛋白都会丧失激活转录因子干扰素调节因子（IRF）和核因子κB的能力。重要的是，脊髓灰质炎病毒感染会触发Cardif的半胱天冬酶依赖性切割，这表明一些病毒可能激活半胱天冬酶，不仅是为了促进病毒释放和复制，也是为了损害抗病毒反应。
