Extracellular RNA Sensing by Pattern Recognition Receptors

Abstract

RNA works as a genome and messenger in RNA viruses, and it sends messages in most of the creatures of the Earth, including viruses, bacteria, fungi, plants, and animals. The human innate immune system has evolved to detect single- and double-stranded RNA molecules from microbes by pattern recognition receptors and induce defense reactions against infections such as the production of type I interferons and inflammatory cytokines. To avoid cytokine toxicity causing chronic inflammation or autoimmunity by sensing self-RNA, the activation of RNA sensors is strictly regulated. All of the Toll-like receptors that recognize RNA are localized to endosomes/lysosomes, which require internalization of RNA for sensing through an endocytic pathway. RIG-I-like receptors sense RNA in cytosol. These receptors are expressed in a cell type-specific fashion, enabling sensing of RNA for a wide range of microbial invasions. At the same time, both endosomal and cytoplasmic receptors have strategies to respond only to RNA of pathogenic microorganisms or dying cells. RNA are potential vaccine adjuvants for immune enhancement against cancer and provide a benefit for vaccinations. Understanding the detailed molecular mechanisms of the RNA-sensing system will help us to broaden the clinical utility of RNA adjuvants for patients with incurable diseases.

Keywords: Endosome; Extracellular RNA; Innate immune signaling; RNA uptake; Toll-like receptor.

Fig. 1

Internalization of extracellular ds­RNA. dsRNA in the extracellular milieu bind to uptake receptors on the cell surface and are endocytosed, mediated by Raftlin, in a clathrin-dependent manner. dsRNA activate TLR3 in endosomes and then SIDT2 urgse them to exit from the endosome to the cytosol. In the cytosol, RLR recognize dsRNA.

Fig. 2

Trafficking and maturation in the endosome of TLR3 and TLR8. UNC93B1 interacts with NAS TLR and regulates the COP II-mediated exit from the ER to the Golgi apparatus. Also, LRRC59 promotes the ER-to-Golgi delivery of TLR3 and TLR8. NAS TLR are translocated to the endosomal/lysosomal compartments and cleaved by proteases maturing to recognize ligands effectively.