Molecular mechanisms of nonself nucleic acid recognition by the innate immune system

Nucleic acids (NAs) represent one of the most important classes of molecules recognized by the innate immune system. However, NAs are not limited to pathogens, but are also present within the host. As such, the immune system has evolved an elaborate set of pathogen recognition receptors (PRRs) that employ various strategies to recognize distinct types of NAs, while reliably distinguishing between self and nonself. The here-employed strategies encompass the positioning of NA-sensing PRRs in certain subcellular compartments that potentially come in contact with pathogens but not host NAs, the existence of counterregulatory measures that keep endogenous NAs below a certain threshold, and also the specific identification of certain nonself patterns. Here, we review recent advances in the molecular mechanisms of NA recognition by TLRs, RLRs, and the cGAS-STING axis. We highlight the differences in NA-PRR interfaces that confer specificity and selectivity toward an NA ligand, as well as the NA-dependent induced conformational changes required for signal transduction.

Automated summary

The innate immune system recognizes nucleic acids through a complex mechanism, distinguishing between self and nonself by positioning NA-sensing receptors in specific subcellular compartments, employing counterregulatory measures against endogenous NAs, and identifying specific nonself patterns. Recent advances in molecular mechanisms of NA recognition by TLRs, RLRs, and the cGAS-STING axis highlight differences in NA-PRR interfaces that confer specificity and selectivity towards NA ligands, along with NA-dependent induced conformational changes necessary for signal transduction.