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

Chu-Xiao Liu; Xiang Li; Fang Nan; Shan Jiang; Xiang Gao; Si-Kun Guo; Wei Xue; Yange Cui; Kaige Dong; Huihua Ding; Bo Qu; Zhaocai Zhou; Nan Shen; Li Yang; Ling-Ling Chen

doi:10.1016/j.cell.2019.03.046

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

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

Authors

Chu-Xiao Liu¹, Xiang Li¹, Fang Nan², Shan Jiang¹, Xiang Gao³, Si-Kun Guo¹, Wei Xue², Yange Cui⁴, Kaige Dong², Huihua Ding⁵, Bo Qu⁵, Zhaocai Zhou¹, Nan Shen⁶, Li Yang⁷, Ling-Ling Chen⁸

Affiliations

¹ 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.
² 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.
³ 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; School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China.
⁴ Laboratory of Molecular Rheumatology, 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.
⁵ Shanghai Institute of Rheumatology, China-Australia Centre for Personalized Immunology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁶ Laboratory of Molecular Rheumatology, 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; Shanghai Institute of Rheumatology, China-Australia Centre for Personalized Immunology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. Electronic address: nanshensibs@gmail.com.
⁷ 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; School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China. Electronic address: liyang@picb.ac.cn.
⁸ 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; School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China. Electronic address: linglingchen@sibcb.ac.cn.

PMID: 31031002
DOI: 10.1016/j.cell.2019.03.046

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.

Keywords: PKR; RNase L; autoimmune disease; circRNA degradation; circRNA structure; circRNAs; circular RNAs; double-stranded RNAs; innate immune responses; systemic lupus erythematosus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Autoimmune Diseases / genetics
Cell Line
Endoribonucleases / metabolism
Female
Humans
Immunity, Innate / genetics
Leukocytes, Mononuclear / immunology
Leukocytes, Mononuclear / metabolism
Lupus Erythematosus, Systemic / genetics
Middle Aged
Phosphorylation
RNA / metabolism
RNA Splicing / genetics
RNA Stability / physiology
RNA, Circular / genetics
RNA, Circular / metabolism*
RNA, Circular / physiology*
RNA, Double-Stranded / metabolism
Virus Diseases / metabolism
eIF-2 Kinase / immunology
eIF-2 Kinase / metabolism*

Substances

RNA, Circular
RNA, Double-Stranded
RNA
eIF-2 Kinase
Endoribonucleases
2-5A-dependent ribonuclease