Sensing Self and Foreign Circular RNAs by Intron Identity

Mol Cell. 2017 Jul 20;67(2):228-238.e5. doi: 10.1016/j.molcel.2017.05.022. Epub 2017 Jun 15.

Abstract

Circular RNAs (circRNAs) are single-stranded RNAs that are joined head to tail with largely unknown functions. Here we show that transfection of purified in vitro generated circRNA into mammalian cells led to potent induction of innate immunity genes and confers protection against viral infection. The nucleic acid sensor RIG-I is necessary to sense foreign circRNA, and RIG-I and foreign circRNA co-aggregate in cytoplasmic foci. CircRNA activation of innate immunity is independent of a 5' triphosphate, double-stranded RNA structure, or the primary sequence of the foreign circRNA. Instead, self-nonself discrimination depends on the intron that programs the circRNA. Use of a human intron to express a foreign circRNA sequence abrogates immune activation, and mature human circRNA is associated with diverse RNA binding proteins reflecting its endogenous splicing and biogenesis. These results reveal innate immune sensing of circRNA and highlight introns-the predominant output of mammalian transcription-as arbiters of self-nonself identity.

Keywords: Circular RNA; circRNA; innate immunity; introns; self-nonself.

MeSH terms

  • Animals
  • Base Sequence
  • DEAD Box Protein 58 / genetics
  • DEAD Box Protein 58 / immunology
  • DEAD Box Protein 58 / metabolism
  • Encephalitis Virus, Venezuelan Equine / genetics
  • Encephalitis Virus, Venezuelan Equine / immunology*
  • Encephalitis Virus, Venezuelan Equine / metabolism
  • Encephalomyelitis, Venezuelan Equine / genetics
  • Encephalomyelitis, Venezuelan Equine / immunology
  • Encephalomyelitis, Venezuelan Equine / metabolism
  • Encephalomyelitis, Venezuelan Equine / prevention & control*
  • HEK293 Cells
  • HeLa Cells
  • Host-Pathogen Interactions
  • Humans
  • Immune Tolerance* / genetics
  • Immunity, Innate* / genetics
  • Introns*
  • Mice
  • Nucleic Acid Conformation
  • Protein Binding
  • RAW 264.7 Cells
  • RNA / biosynthesis
  • RNA / chemistry
  • RNA / genetics*
  • RNA / immunology*
  • RNA Processing, Post-Transcriptional*
  • RNA, Circular
  • RNA, Messenger / genetics
  • RNA, Messenger / immunology
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / immunology*
  • RNA-Binding Proteins / metabolism
  • Receptors, Immunologic
  • Spliceosomes / immunology
  • Spliceosomes / metabolism
  • Transfection

Substances

  • RNA, Circular
  • RNA, Messenger
  • RNA-Binding Proteins
  • Receptors, Immunologic
  • RNA
  • RIGI protein, human
  • Ddx58 protein, mouse
  • DEAD Box Protein 58