The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I
The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I
复制标题
DOI：
10.4049/jimmunol.175.8.5260
复制
发表时间：
2005-10-15
影响因子：
4.4
通讯作者：
Fitzgerald, KA
中科院分区：
文献类型：
--
作者：
Rothenfusser, S;Goutagny, N;Fitzgerald, KA
仙台副粘病毒 (SV) 是一种成熟的 IFN-αβ 基因表达诱导剂。在本研究中，我们发现，在含有 Toll-IL-1 抗性结构域的接头 MyD88、Mal、Toll/IL-1R 结构域的接头诱导 IFN-β (TRIF) 和 TRIF 相关接头分子 TLR3 或 E3 泛素连接酶、TNFR 相关因子 6 的靶向删除的小鼠细胞中，SV 正常诱导 IFN-α β 基因表达。SV 感染后，这种不依赖于 TLR 的 IFN-α β 诱导。是复制依赖性的，并由 RNA 解旋酶、视黄酸诱导基因-I (RIG-1) 介导，而不是相关的家族成员、黑色素瘤分化相关基因 5。此外，我们还描述了一种类似 RIG-I 的 RNA 解旋酶 Lgp2。与 RIG-I 或黑色素瘤分化相关基因 5 相比，Lgp2 缺乏信号半胱天冬酶募集和激活结构域。 Lgp2 的过表达会抑制 SV 和新城疫病毒向 IFN 刺激的调节元件和 NF-κ B 依赖性途径发出的信号。重要的是，Lgp2 不会阻止 TLR3 信号传导。与 RIG-I 一样，Lgp2 结合双链 RNA，但不结合单链 RNA。定量 PCR 分析表明，Lgp2 在未刺激的细胞中的存在水平低于 RIG-1，尽管两种解旋酶在病毒感染后都被诱导至相似的水平。我们提出 Lgp2 通过隔离 RIG-I 的 dsRNA 来充当抗病毒信号传导的负反馈调节剂。
The paramyxovirus Sendai (SV), is a well-established inducer of IFN-alpha beta gene expression. In this study we show that SV induces IFN-alpha beta gene expression normally in cells from mice with targeted deletions of the Toll-IL-1 resistance domain containing adapters MyD88, Mal, Toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF), and TRIF-related adaptor molecule TLR3, or the E3 ubiquitin ligase, TNFR-associated factor 6. This TLR-independent induction of IFN-alpha beta after SV infection is replication dependent and mediated by the RNA helicase, retinoic acid-inducible gene-I (RIG-1) and not the related family member, melanoma differentiation-associated gene 5. Furthermore, we characterize a RIG-I-like RNA helicase, Lgp2. In contrast to RIG-I or melanoma differentiation-associated gene 5, Lgp2 lacks signaling caspase recruitment and activation domains. Overexpression of Lgp2 inhibits SV and Newcastle disease virus-signaling to IFN-stimulated regulatory element- and NF-kappa B-dependent pathways. Importantly, Lgp2 does not prevent TLR3 signaling. Like RIG-I, Lgp2 binds double-stranded, but not single-stranded, RNA. Quantitative PCR analysis demonstrates that Lgp2 is present in unstimulated cells at a lower level than RIG-1, although both helicases are induced to similar levels after virus infection. We propose that Lgp2 acts as a negative feedback regulator of antiviral signaling by sequestering dsRNA from RIG-I.