Abstract
Self/foreign discrimination by the innate immune system depends on receptors that identify molecular patterns as associated to pathogens. Among others, this group includes endosomal Toll-like receptors, among which Toll-like receptors (TLR) 3, 7, 8, and 13 recognize and discriminate mammalian from microbial, potentially pathogen-associated, RNA. One of the discriminatory principles is the recognition of endogenous RNA modifications. Previous work has identified a couple of RNA modifications that impede activation of TLR signaling when incorporated in synthetic RNA molecules. Of note, work that is more recent has now shown that RNA modifications in their naturally occurring context can have immune-modulatory functions: Gm, a naturally occurring ribose-methylation within tRNA resulted in a lack of TLR7 stimulation and within a defined sequence context acted as antagonist. Additional RNA modifications with immune-modulatory functions have now been identified and recent work also indicates that RNA modifications within the context of whole prokaryotic or eukaryotic cells are indeed used for immune-modulation. This review will discuss new findings and developments in the field of immune-modulatory RNA modifications.
Highlights
Detection of pathogens by the innate immune system relies on a small subset of germline-encoded pattern recognition receptors that recognize structurally conserved microbial molecules
Beside cytosolic receptors including amongst others retinoic acid inducible gene I (RIG-I), melanoma differentiation antigen 5 (MDA-5), absent in melanoma 2 (AIM2) and cyclic GMP-AMP synthase, nucleic acids (NAs) are recognized by the Toll-like receptors (TLRs) 3, TLR7, TLR8, TLR9, and TLR13 which reside in the endosome
At a structural level it was shown that TLR8 recognizes two degradation products of RNA at two different sites [27]: Site 1 was bound by uridine at the TLR dimerization interface
Summary
Detection of pathogens by the innate immune system relies on a small subset of germline-encoded pattern recognition receptors (in contrast to re-arranged receptors of the adaptive immune system) that recognize structurally conserved microbial molecules. Beside cell wall components of bacteria and fungi, nucleic acids (NAs) have been identified as potent stimuli initiating a robust immune response. As both ‘self’ and ‘non-self’ nucleic acids are composed of the same basic building blocks, the ability to identify the origin of DNA and RNA is a crucial necessity for the innate immune system. Three main principles have been described that allow the innate immune system to avoid recognition of host (‘self’) NAs but allow stimulation by microbial (‘foreign’) NAs: First, discrimination can be based on spatial restriction of NA-sensing receptors to specific subcellular compartments. Failures in any of the three described principles can result in autoimmunity and a closer understanding of the molecular principles underlying NA recognition bears therapeutic options
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