A central role for RNA in the induction and biological activities of type 1 interferons

In mammals the type 1 interferon (IFN) system functions as the primary innate antiviral defense and more broadly as a stress response and regulator of diverse homeostatic mechanisms. RNA plays a central role in the induction of IFN and in its biologic activities. Cellular toll-like receptors (TLR), RIG-I-like receptors (RLR), and nucleotide organization domain-like receptors (NLR) sense pathogen- and danger-associated RNAs as nonself based on structural features and subcellular location that distinguish them from ubiquitous host RNAs. Detection of nonself RNAs activates signaling pathways to induce IFN transcription and secretion. In turn, IFN binds cell surface receptors to initiate signaling that results in the induction of IFN-stimulated genes (ISGs) that mediate its biologic activities. RNA also plays a critical role in this effector phase of the IFN system, serving as an activator of enzyme activity for protein kinase RNA-dependent (PKR) and oligoadenylate synthetase (OAS), and as a substrate for 2('), 5(') -linked oligoadenylate dependant-endoribonuclease (RNase-L). In contrast to the transcriptional response induced by RNA receptors, these key ISGs mediate their activities primarily through post transcriptional mechanisms to regulate the translation and stability of host and microbial RNAs. Together RNA-sensing and RNA-effector molecules comprise a network of coordinately regulated proteins with integrated feedback and feed-forward loops that tightly regulate the cellular response to RNA. This stringent regulation is essential to prevent deleterious effects of uncontrolled IFN expression and effector activation. In light of this extensive crosstalk, targeting key mediators of the cellular response to RNA represents a viable strategy for therapeutic modulation of immune function and treatment of diseases in which this response is dysregulated (e.g., cancer).