RNase L releases a small RNA from HCV RNA that refolds into a potent PAMP
RNase L releases a small RNA from HCV RNA that refolds into a potent PAMP
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DOI：
10.1261/rna.2244210
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发表时间：
2010-11-01
期刊：
影响因子：
4.5
通讯作者：
Silverman, Robert H.
中科院分区：
文献类型：
--
作者：
Malathi, Krishnamurthy;Saito, Takeshi;Silverman, Robert H.
触发和传播细胞内先天免疫应答对于控制病毒感染是必不可少的。RNase L是一种宿主核糖核酸内切酶，也是先天免疫的关键组分，其切割单链环内的病毒和细胞RNA，释放具有5 '-羟基（5'-OH）和3 '-单磷酰基（3'-p）基团的小结构RNA。在2007年，我们报道了RNase L切割自身RNA以产生小RNA，其作为病原体相关分子模式（PAMP）起作用。然而，由RNase L产生的PAMP RNA的精确序列和结构是未知的。在这里，我们使用丙型肝炎病毒RNA作为底物来表征RNase L介导的切割产物[命名为病毒RNA抑制因子（svRNA）]，以确定其激活RIG-I样受体（RLR）的能力。HCV RNA的NS 5 B区域被RNase L切割以释放与RIG-I结合的svRNA，置换其阻遏物结构域并刺激其ATP酶活性，同时向完整细胞中的IFN-β基因发出信号。所有这三种RIG-I功能都依赖于svRNA中3 '-p的存在。此外，svRNA通过涉及IFN产生的机制在体外抑制HCV复制，并在小鼠中触发RIG-I依赖性肝脏先天免疫应答。RNA酶L和OAS（其激活所需的）都在HCV感染患者的肝细胞中表达，提高了OAS/RNA酶L途径可能抑制HCV体内复制的可能性。有人提出RNA酶L介导的HCV RNA切割产生激活RIG-I的svRNA，从而将先天免疫信号传导至IFN-β基因。
Triggering and propagating an intracellular innate immune response is essential for control of viral infections. RNase L is a host endoribonuclease and a pivotal component of innate immunity that cleaves viral and cellular RNA within single-stranded loops releasing small structured RNAs with 5'-hydroxyl (5'-OH) and 3'-monophosphoryl (3'-p) groups. In 2007, we reported that RNase L cleaves self RNA to produce small RNAs that function as pathogen-associated molecular patterns (PAMPs). However, the precise sequence and structure of PAMP RNAs produced by RNase L is unknown. Here we used hepatitis C virus RNA as substrate to characterize RNase L mediated cleavage products [named suppressor of virus RNA (svRNA)] for their ability to activate RIG-I like receptors (RLR). The NS5B region of HCV RNA was cleaved by RNase L to release an svRNA that bound to RIG-I, displacing its repressor domain and stimulating its ATPase activity while signaling to the IFN-beta gene in intact cells. All three of these RIG-I functions were dependent on the presence in svRNA of the 3'-p. Furthermore, svRNA suppressed HCV replication in vitro through a mechanism involving IFN production and triggered a RIG-I-dependent hepatic innate immune response in mice. RNase L and OAS (required for its activation) were both expressed in hepatocytes from HCV-infected patients, raising the possibility that the OAS/RNase L pathway might suppress HCV replication in vivo. It is proposed that RNase L mediated cleavage of HCV RNA generates svRNA that activates RIG-I, thus propagating innate immune signaling to the IFN-beta gene.