RIG-I 对 5'-单磷酸 RNA 具有选择性识别能力。

RIG-I Selectively Discriminates against 5'-Monophosphate RNA.

机构信息

Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT 06520, USA.

Department of Immunobiology, Yale University, New Haven, CT 06520, USA.

出版信息

Cell Rep. 2019 Feb 19;26(8):2019-2027.e4. doi: 10.1016/j.celrep.2019.01.107.

DOI:10.1016/j.celrep.2019.01.107

PMID:30784585

Abstract

The innate immune sensor RIG-I must sensitively detect and respond to viral RNAs that enter the cytoplasm, while remaining unresponsive to the abundance of structurally similar RNAs that are the products of host metabolism. In the case of RIG-I, these viral and host targets differ by only a few atoms, and a molecular mechanism for such selective differentiation has remained elusive. Using a combination of quantitative biophysical and immunological studies, we show that RIG-I, which is normally activated by duplex RNAs containing a 5'-tri- or diphosphate (5'-ppp or 5'-pp RNAs), is actively antagonized by RNAs containing 5'-monophosphates (5'-p RNAs). This is accomplished by a gating mechanism in which an alternative RIG-I conformation blocks the C-terminal domain (CTD) upon 5'-p RNA binding, thereby short circuiting the activation of signaling.

摘要

先天免疫传感器 RIG-I 必须灵敏地检测和响应进入细胞质的病毒 RNA，同时对宿主代谢产物中大量结构相似的 RNA 保持无反应状态。在 RIG-I 的情况下，这些病毒和宿主靶标仅相差几个原子，而这种选择性分化的分子机制仍然难以捉摸。通过定量生物物理和免疫学研究的结合，我们表明，通常被含有 5'-三磷酸或二磷酸（5'-ppp 或 5'-pp RNA）的双链 RNA 激活的 RIG-I 被含有 5'-单磷酸（5'-p RNA）的 RNA 积极拮抗。这是通过一种门控机制来实现的，其中替代的 RIG-I 构象在 5'-p RNA 结合时阻止 C 末端结构域（CTD），从而短路信号的激活。