Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.
Chemistry, Yale University, New Haven, CT, USA.
Immunol Rev. 2021 Nov;304(1):154-168. doi: 10.1111/imr.13022. Epub 2021 Sep 12.
RIG-I is our first line of defense against RNA viruses, serving as a pattern recognition receptor that identifies molecular features common among dsRNA and ssRNA viral pathogens. RIG-I is maintained in an inactive conformation as it samples the cellular space for pathogenic RNAs. Upon encounter with the triphosphorylated terminus of blunt-ended viral RNA duplexes, the receptor changes conformation and releases a pair of signaling domains (CARDs) that are selectively modified and interact with an adapter protein (MAVS), thereby triggering a signaling cascade that stimulates transcription of interferons. Here, we describe the structural determinants for specific RIG-I activation by viral RNA, and we describe the strategies by which RIG-I remains inactivated in the presence of host RNAs. From the initial RNA triggering event to the final stages of interferon expression, we describe the experimental evidence underpinning our working knowledge of RIG-I signaling. We draw parallels with behavior of related proteins MDA5 and LGP2, describing evolutionary implications of their collective surveillance of the cell. We conclude by describing the cell biology and immunological investigations that will be needed to accurately describe the role of RIG-I in innate immunity and to provide the necessary foundation for pharmacological manipulation of this important receptor.
RIG-I 是我们抵御 RNA 病毒的第一道防线，作为一种模式识别受体，它可以识别双链 RNA（dsRNA）和单链 RNA（ssRNA）病毒病原体中的分子特征。RIG-I 以无活性构象存在，因为它在细胞空间中采样致病 RNA。当遇到无末端病毒 RNA 双链体的三磷酸末端时，受体构象发生变化并释放一对信号结构域（CARD），这些结构域被选择性修饰并与衔接蛋白（MAVS）相互作用，从而触发刺激干扰素转录的信号级联反应。在这里，我们描述了病毒 RNA 特异性激活 RIG-I 的结构决定因素，还描述了 RIG-I 在存在宿主 RNA 的情况下保持失活的策略。从初始 RNA 触发事件到干扰素表达的最后阶段，我们描述了支持我们对 RIG-I 信号转导的工作知识的实验证据。我们与相关蛋白 MDA5 和 LGP2 的行为进行了类比，描述了它们对细胞的集体监测的进化意义。最后，我们描述了细胞生物学和免疫学研究，这些研究将有助于准确描述 RIG-I 在先天免疫中的作用，并为该重要受体的药理学干预提供必要的基础。
