National Key Laboratory of Medical Molecular Biology, Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China.
MOH Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Beijing 100021, China.
Cell. 2018 May 3;173(4):906-919.e13. doi: 10.1016/j.cell.2018.03.064. Epub 2018 Apr 26.
The innate RNA sensor RIG-I is critical in the initiation of antiviral type I interferons (IFNs) production upon recognition of "non-self" viral RNAs. Here, we identify a host-derived, IFN-inducible long noncoding RNA, lnc-Lsm3b, that can compete with viral RNAs in the binding of RIG-I monomers and feedback inactivate the RIG-I innate function at late stage of innate response. Mechanistically, binding of lnc-Lsm3b restricts RIG-I protein's conformational shift and prevents downstream signaling, thereby terminating type I IFNs production. Multivalent structural motifs and long-stem structure are critical features of lnc-Lsm3b for RIG-I binding and inhibition. These data reveal a non-canonical self-recognition mode in the regulation of immune response and demonstrate an important role of an inducible "self" lncRNA acting as a potent molecular decoy actively saturating RIG-I binding sites to restrict the duration of "non-self" RNA-induced innate immune response and maintaining immune homeostasis, with potential utility in inflammatory disease management.
天然 RNA 传感器 RIG-I 在识别“非自身”病毒 RNA 后，对于启动抗病毒 I 型干扰素 (IFN) 的产生至关重要。在这里，我们鉴定了一种宿主衍生的 IFN 诱导的长非编码 RNA lnc-Lsm3b，它可以与病毒 RNA 竞争 RIG-I 单体的结合，并在先天反应的晚期反馈失活 RIG-I 的先天功能。在机制上，lnc-Lsm3b 的结合限制了 RIG-I 蛋白的构象变化，阻止了下游信号转导，从而终止了 I 型 IFN 的产生。多价结构基元和长茎结构是 lnc-Lsm3b 与 RIG-I 结合和抑制的关键特征。这些数据揭示了免疫反应调节中的一种非典型的自我识别模式，并证明了一种诱导型“自我”lncRNA 的重要作用，它作为一种有效的分子诱饵，主动饱和 RIG-I 结合位点，限制“非自身”RNA 诱导的先天免疫反应的持续时间，维持免疫稳态，在炎症性疾病的管理中具有潜在的应用价值。
