Molecular characterization of endosomal self RNA Rmrp-engaged TLR3 dimerization to prime innate activation

Area of Science:

• Immunology
• Structural Biology
• Molecular Biology

Background:

• Toll-like receptor 3 (TLR3) dimerization is essential for innate immune recognition.
• The precise mechanisms of TLR3 pre-dimerization and activation priming remain incompletely understood.

Purpose of the Study:

• To elucidate the mechanism of self RNA-induced TLR3 dimerization and activation.
• To determine the structural basis of the interaction between self RNA Rmrp and TLR3.

Main Methods:

• Cryo-electron microscopy (Cryo-EM) to determine the structure of the Rmrp-TLR3 complex.
• In vitro assays to assess TLR3 dimerization and binding.
• In vivo studies using myeloid-cell specific Rmrp deficiency models.

Main Results:

• Endosome-localized self RNA Rmrp directly binds and induces TLR3 dimerization in a novel lapped conformation.
• A specific structural feature at the 3'-end of Rmrp and the K42 residue of TLR3 are critical for this interaction.
• Rmrp dissociation upon endosomal acidification matures the TLR3 dimer for activation.
• Myeloid-cell deficiency of Rmrp impairs TLR3 dimerization and attenuates antiviral responses.

Conclusions:

• Self RNA Rmrp acts as a specific activator of TLR3 dimerization within early endosomes.
• Endosomal acidification regulates the dissociation of Rmrp, priming TLR3 for innate recognition.
• This study reveals a novel mechanism for TLR activation by self RNA and highlights the role of subcellular RNA localization in innate immunity.