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.


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*


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