Toll-like Receptor 3 Recognizes Incomplete Stem Structures in Single-Stranded Viral RNA

Nat Commun. 2013;4:1833. doi: 10.1038/ncomms2857.

Abstract

Endosomal Toll-like receptor 3 (TLR3) serves as a sensor of viral infection and sterile tissue necrosis. Although TLR3 recognizes double-stranded RNA, little is known about structural features of virus- or host-derived RNAs that activate TLR3 in infection/inflammatory states. Here we demonstrate that poliovirus-derived single-stranded RNA segments harbouring stem structures with bulge/internal loops are potent TLR3 agonists. Functional poliovirus-RNAs are resistant to degradation and efficiently induce interferon-α/β and proinflammatory cytokines in human and mouse cells in a TLR3-dependent manner. The N- and C-terminal double-stranded RNA-binding sites of TLR3 are required for poliovirus-RNA-mediated TLR3 activation. Like polyriboinosinic:polyribocytidylic acid, a synthetic double-stranded RNA, these RNAs are internalized into cells via raftlin-mediated endocytosis and colocalized with TLR3. Raftlin-associated RNA uptake machinery and the TLR3 RNA-sensing system appear to recognize an appropriate topology of multiple RNA duplexes in poliovirus-RNAs. Hence, TLR3 is a sensor of extracellular viral/host RNA with stable stem structures derived from infection or inflammation-damaged cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • CD11c Antigen / metabolism
  • Cell-Free System
  • DNA-Binding Proteins / metabolism
  • Dendritic Cells / metabolism
  • Endocytosis
  • Endoribonucleases / metabolism
  • Endosomes / metabolism
  • Escherichia coli Proteins / metabolism
  • Fibroblasts / metabolism
  • HEK293 Cells
  • Humans
  • Interferon Type I / biosynthesis
  • Interferon-beta / biosynthesis
  • Mice
  • Nucleic Acid Conformation*
  • Poliovirus / metabolism*
  • RNA Stability
  • RNA, Double-Stranded / metabolism
  • RNA, Viral / chemistry*
  • RNA, Viral / metabolism*
  • Toll-Like Receptor 3 / deficiency
  • Toll-Like Receptor 3 / metabolism*

Substances

  • CD11c Antigen
  • DNA-Binding Proteins
  • Escherichia coli Proteins
  • Interferon Type I
  • MazF protein, E coli
  • RNA, Double-Stranded
  • RNA, Viral
  • Toll-Like Receptor 3
  • Interferon-beta
  • Endoribonucleases