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

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Abstract 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). WIREs RNA 2011 2 58–78 DOI: 10.1002/wrna.32 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Turnover and Surveillance > Regulation of RNA Stability RNA in Disease and Development > RNA in Disease

(A) RNA as trigger of host sensors and IFN transcription (refer to the section on RNA as a Trigger for Host Sensors and the Induction of IFN). RNA agonists and their cognate receptors are indicated (the CpG DNA receptor TLR9 is also shown to depict the full complement of endosomal TLRs); repeated arrowheads denote intermediate steps in signaling that are not shown (reviewed in 5). (B) Domain organization of RNA sensors and effectors; RD, repressor domain; UBL, ubiquitin‐like domain; ANK, ankyrin repeat domain; other domains depicted are defined in the text.

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The cellular RNA response network. RNA functions as a trigger for cellular receptors to induce IFN, and as an activator and substrate of IFN effectors. Crosstalk between these components coordinates the response to RNA; as depicted in the figure, IFN induces RLRs, and RNase‐L generates RLR activators to amplify IFN production. See text for additional examples.

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Model of RNase‐L activation by 2‐5A (refer to the section on RNA as a Substrate of the IFN‐Regulated Endoribonuclease RNase‐L). 2‐5A binding to ankyrin repeats 2‐4 releases an intramolecular interaction resulting in a conformational change that exposes the catalytic and dimerization domains in the active homodimer; note that the active enzyme contains two 2‐5A molecules; see text for details.

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The IFN‐regulated dsRNA‐dependent OAS/RNase‐L and PKR pathways (refer to the section on RNA as an Activator of Host Antiviral and Stress Response Pathways). IFN induces PKR and OAS that are latent until activated by dsRNA‐binding. Activated OAS produces the 2‐5A activator of RNase‐L, and activated PKR phosphorylates eIF2α and other substrates (see text).

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Model of RIG‐I activation by RNA (refer to the section on RLRs and NLRs Sense Nonself RNA in the Cytosol). Binding of short dsRNA or 5 ppp‐containing ssRNA (shown) induces an ATP‐dependent conformational change in RIG‐I resulting in multimerization and IPS1 binding; see text for details.

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IFN‐stimulated signaling and induction of ISGs. IFN‐receptor binding activates Jak/STAT signaling and results in the transcriptional induction of ISGs as described in the text. Of the hundreds of ISGs induced, only those that are regulated by RNA or mediate RNA‐activated pathways are shown.

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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Turnover and Surveillance > Regulation of RNA Stability
RNA in Disease and Development > RNA in Disease
RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition

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