Toll-like receptor 3 recognizes incomplete stem structures in single-stranded viral RNA

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• Endosomal Toll-like receptor 3 (TLR3) detects viral RNA and signals danger.
• The specific RNA structures that activate TLR3 during infection are not well understood.
• Understanding TLR3 activation is crucial for developing antiviral and anti-inflammatory therapies.

Purpose of the Study:

• To identify structural features of viral RNA that activate TLR3.
• To investigate the mechanism of TLR3 activation by poliovirus RNA.
• To determine the role of RNA structure and cell uptake in TLR3 signaling.

Main Methods:

• Analysis of poliovirus-derived RNA structures.
• Functional assays in human and mouse cells to measure TLR3 activation.
• Studies on RNA internalization via raftlin-mediated endocytosis.
• Investigation of TLR3's double-stranded RNA-binding sites.

Main Results:

• Single-stranded poliovirus RNA segments with stem-loop structures are potent TLR3 agonists.
• These functional RNAs resist degradation and induce interferon and cytokines in a TLR3-dependent manner.
• TLR3's N- and C-terminal binding sites are essential for activation by poliovirus RNA.
• RNA uptake occurs via raftlin-mediated endocytosis, with RNAs colocalizing to TLR3.

Conclusions:

• TLR3 senses extracellular viral RNA with stable stem structures.
• The topology of RNA duplexes is critical for recognition by TLR3 and raftlin.
• This study elucidates a novel mechanism of TLR3 activation by specific viral RNA structures.