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RNA regulation of the antiviral protein 2′‐5′‐oligoadenylate synthetase

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Abstract The innate immune system is a broad collection of critical intra‐ and extra‐cellular processes that limit the infectivity of diverse pathogens. The 2′‐5′‐oligoadenylate synthetase (OAS) family of enzymes are important sensors of cytosolic double‐stranded RNA (dsRNA) that play a critical role in limiting viral infection by activating the latent ribonuclease (RNase L) to halt viral replication and establish an antiviral state. Attesting to the importance of the OAS/RNase L pathway, diverse viruses have developed numerous distinct strategies to evade the effects of OAS activation. How OAS proteins are regulated by viral or cellular RNAs is not fully understood but several recent studies have provided important new insights into the molecular mechanisms of OAS activation by dsRNA. Other studies have revealed unanticipated features of RNA sequence and structure that strongly enhance activation of at least one OAS family member. While these discoveries represent important advances, they also underscore the fact that much remains to be learned about RNA‐mediated regulation of the OAS/RNase L pathway. In particular, defining the full complement of RNA molecular signatures that activate OAS is essential to our understanding of how these proteins maximize their protective role against pathogens while still accurately discriminating host molecules to avoid inadvertent activation by cellular RNAs. A more complete knowledge of OAS regulation may also serve as a foundation for the development of novel antiviral therapeutic strategies and lead the way to a deeper understanding of currently unappreciated cellular functions of the OAS/RNase L pathway in the absence of infection. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications Translation > Translation Regulation
Overview of the 2′‐5′‐oligoadenylate synthetase/ribonuclease L (OAS/RNase L) pathway. (a) Double‐stranded RNA (dsRNA) binding to OAS (here shown as OAS1) promotes synthesis of 2′‐5′‐linked oligoadenylates (2‐5A) which in turn induce dimerization and activation of the latent ribonuclease (RNase L). RNase L degrades viral and cellular RNA targets to promote antiviral responses. (b) Summary of domain organization and activities of the four human OAS proteins: OAS1, OAS2, OAS3, and OASL. For the active OAS proteins (OAS1, OAS2, and OAS3), the domain responsible for 2‐5A catalysis is shown in green; other OAS domains (gray) contribute to dsRNA binding. Splicing isoforms are indicated for OAS1 and OAS2 (OAS3 is expressed as a single isoform); these proteins differ in their C‐terminus (green/ white striped region). Human OASL contains a single noncatalytically active OAS domain appended with tandem ubiquitin‐like domains (U1/U2; blue) and functions in antiviral innate immunity independent of RNase L
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Summary of OAS protein activation by RNA. Current understanding of OAS protein regulation by dsRNA, as discussed in the main text, is summarized in the three vertical panels for OAS1 (purple), OAS2 (blue), and OAS3 (gray). Top: minimum dsRNA lengths required to activate each OAS protein. Center: OAS activation by dsRNA with dsRNA induced organization of the catalytic center (green domain) denoted by the yellow star. OAS1 binds short dsRNAs and can also be strongly activated by longer dsRNAs with multiple binding sites. OAS2 functions as a dimer of currently unknown organization (two potential dimer interactions are shown; also possible are via DII–DII only and DI/DI–DII/DII head–head). Also unknown is whether both OAS2 proteins must bind to dsRNA and whether they function independently or cooperatively. OAS3 is activated only by longer dsRNAs due to the requirement to span three OAS domains; shorter RNAs are unable to induce the conformational change in DIII (inset). Bottom, other RNA sequences and motifs identified to enhance 2‐5A synthesis
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Model for enhancement of OAS1 activation by RNA sequence and structural motifs. OAS1 requires at least ~17 bp dsRNA for binding, shown here on the left for the model 18 bp dsRNA duplex with OAS1 consensus activation sequence (purple) and on the right for the nc886 central stem sequence. Once positioned by the OAS1 binding site, RNA signatures such as the 3′‐ssPy motif (orange) or the tertiary structure of nc886 (red) can dramatically increase OAS1 activation. The mechanism of activation by these RNA features is currently unknown but modeling and mutagenesis analyses suggest the OAS1 loop containing G157 may be important (see main text for details)
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Double‐stranded and structured RNA activators of OAS. Select RNAs discussed in the main text: (a) 18 bp dsRNA used in the OAS1‐dsRNA crystal structure and identification of the 3′‐ssPy motif, (b) adenovirus (Ad2) VA RNAI with sites of Dicer cleavage indicated (black scissors), (c) cellular nc886 RNA with location of OAS1 activating structural motif indicated (red shading), (d) example of ss‐dsRNA (43 bp) with sites of RNase cleavage to generate a minimal 3′‐ssPy motif indicated (orange scissors), (e) WNV 5′‐terminal region, and (f) WNV 3′‐terminal region with OAS1 activating stem‐loop highlighted (red shading). For all RNAs 3′‐ssPy motifs are indicated by the orange text and the OAS1 consensus activation sequence WWN9WG (shown above the 18 bp dsRNA in Panel a) by white text on blue background. The purple background for the 18 bp dsRNA top strand denotes the consensus sequence directly contacted by OAS1 in the OAS1‐dsRNA crystal structure (inset in Panel a)
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Conformational changes induced by double‐stranded RNA (dsRNA) binding promote synthesis of 2′‐5′‐linked oligoadenylates (2‐5A) by OAS1. (a) Cartoon of the OAS1 structure in its dsRNA‐bound state (PDB code 4IG8). ATP binding sites and other structural features described in the main text are indicated. (b) Electrostatic surface potential representation of OAS1 showing the positive (blue) charge of the dsRNA binding surface. (c) Superposition of free porcine OAS1 (PDB code 1PX5; blue) and dsRNA‐bound human OAS1 (green) with a zoomed view showing a secondary structure change induced by dsRNA binding. (d) Reorganization of key residues upon dsRNA binding: a functionally critical positional switch in which K66 replaces R195 in an electrostatic interaction with E233 (right), helps promote reorganization of the OAS1 catalytic triad (D75, D77, and D148; dashed box, left)
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