环状 RNA 的结构和降解调控先天免疫中 PKR 的激活。

Structure and Degradation of Circular RNAs Regulate PKR Activation in Innate Immunity.

机构信息

State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.

CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.

出版信息

Cell. 2019 May 2;177(4):865-880.e21. doi: 10.1016/j.cell.2019.03.046. Epub 2019 Apr 25.

DOI:10.1016/j.cell.2019.03.046

PMID:31031002

Abstract

Circular RNAs (circRNAs) produced from back-splicing of exons of pre-mRNAs are widely expressed, but current understanding of their functions is limited. These RNAs are stable in general and are thought to have unique structural conformations distinct from their linear RNA cognates. Here, we show that endogenous circRNAs tend to form 16-26 bp imperfect RNA duplexes and act as inhibitors of double-stranded RNA (dsRNA)-activated protein kinase (PKR) related to innate immunity. Upon poly(I:C) stimulation or viral infection, circRNAs are globally degraded by RNase L, a process required for PKR activation in early cellular innate immune responses. Augmented PKR phosphorylation and circRNA reduction are found in peripheral blood mononuclear cells (PBMCs) derived from patients with autoimmune disease systemic lupus erythematosus (SLE). Importantly, overexpression of the dsRNA-containing circRNA in PBMCs or T cells derived from SLE can alleviate the aberrant PKR activation cascade, thus providing a connection between circRNAs and SLE.

摘要

环形 RNA（circRNAs）是由前体 mRNA 的外显子反向剪接产生的，广泛表达，但目前对其功能的认识有限。这些 RNA 通常很稳定，被认为具有独特的结构构象，与它们的线性 RNA 同源物不同。在这里，我们表明内源性 circRNAs 倾向于形成 16-26bp 的不完全 RNA 双链，并作为与先天免疫相关的双链 RNA（dsRNA）激活蛋白激酶（PKR）的抑制剂。在多聚（I：C）刺激或病毒感染后，circRNAs 被核糖核酸酶 L 全局降解，这是早期细胞先天免疫反应中 PKR 激活所必需的过程。在自身免疫性疾病系统性红斑狼疮（SLE）患者来源的外周血单核细胞（PBMC）中发现 PKR 磷酸化增强和 circRNA 减少。重要的是，在 SLE 患者的 PBMC 或 T 细胞中过表达含有 dsRNA 的 circRNA 可以缓解异常的 PKR 激活级联反应，从而为 circRNAs 和 SLE 之间提供了联系。