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RNA cleavage is a fundamental host response for controlling viral infections in both plants and animals (26). In higher vertebrates, this process is often regulated by interferons (IFNs), a family of antiviral cytokines discovered 50 years ago (50). One of the principal IFN antiviral pathways involves activation of the ubiquitous cellular endoribonuclease RNase L (formerly 2-5A-dependent RNase) (125). Recently, there has been progress in understanding how RNase L affects a range of different types of viral infections and how viruses counteract RNase L. Understanding how RNase L and viruses interact in vivo could contribute to therapeutic strategies for controlling pathogenic viruses (113).  The 2′,5′-oligoadenylate synthetase (OAS)/RNase L system is an innate immunity pathway that responds to a pathogen-associated molecular pattern to induce degradation of viral and cellular RNAs and thereby block viral infections (Fig. ​(Fig.1A).1A). The pathogen-associated molecular pattern is double-stranded RNA (dsRNA), a type of nonself-RNA produced during infections by both RNA and DNA viruses. Viral dsRNAs include replicative intermediates of single-stranded RNA (ssRNA) viruses, viral dsRNA genomes, annealed viral RNAs of opposite polarities, and stem structures in otherwise single-stranded viral RNAs. dsRNA activates the pathogen recognition receptor 2-5A synthetase, or OAS, resulting in production of 2-5A [px5′A(2′p5′A)n; x = 1 to 3; n ≥ 2] from ATP (Fig. ​(Fig.1)1) (45, 46, 55). IFN signaling induces transcription of the OAS genes through IFN-stimulated response elements in the promoters (94). Therefore, cells exposed to IFN as a result of ongoing viral infections have elevated levels of OAS that contribute to the IFN-induced antiviral state. The trimeric and tetrameric species [(2′-5′)p3A3 and (2′-5′)p3A4] are the principal forms of 2-5A produced in IFN-treated, virus-infected cells (57). Needless to say, 2-5A species are very unusual nucleic acids because of their adjacent 2′ to 5′ phosphodiester bonds. In humans, OAS is a family of 8 to 10 different isoforms encoded by three functional genes (OAS1 to OAS3) and a single OASL gene encoding a related protein with two C-terminal ubiquitin-like domains that does not synthesize 2-5A (42, 52, 75, 88). In mice, there are eight oas1 genes, in addition to oas2, oas3, and two oasl genes (54). OAS1 species (p40/p46) have one catalytic domain and form tetramers, OAS2 species (p69/p71) have two catalytic domains and form dimers, while OAS3 (p100) has three catalytic domains and is a monomer (48, 88). The different forms of OAS occupy different subcellular locations, have different dsRNA optima for activation, and synthesize 2-5A oligomers of different lengths (17, 47, 73). A crystal structure of porcine OAS1 has led to structural and functional insight into the OAS proteins (41).    FIG. 1.  (A) The OAS/RNase L system, an innate immunity pathway that acts against viral infections. PPi, pyrophosphate; 2′PDE, 2′-phosphodiesterase; P'tase, phosphatase; IFN-R, IFN receptor. (B) Domain structure of human RNase L. (Copyright, The ...    The only well-established function of 2-5A is activation of RNase L (125). RNase L was detected by cross-linking to radiolabeled 2-5A in extracts of several different mouse organs. In contrast, no 2-5A binding proteins were detected in organs of RNase L−/− mice (126). Those findings suggested that 2-5A is a unique ligand for RNase L. Human RNase L is a 741-amino-acid polypeptide containing, from the N to the C termini, nine ankyrin repeats, several protein kinase-like motifs, and the RNase domain (Fig. ​(Fig.1B).1B). 2-5A binds to ankyrin repeats 2 and 4 (112), causing catalytically inactive RNase L monomers to form activated dimers with potent RNase activity (19, 28). Specifically, RNase L cleaves within single-stranded regions of RNA, principally on the 3′ sides of UpAp and UpUp dinucleotides, leaving 3′-phosphoryl and 5′-hydroxyl groups at the termini of the RNA cleavage products (31, 119). 2-5A is degraded within minutes by 2′-phosphodiesterase and 5′-phosphatase activities within cells and in sera (51, 59, 101, 107). Therefore, 2-5A is an early transient-response molecule or alarmone that signals antiviral innate immunity through RNase L activation. RNase L function is dampened by the RNase L inhibitor (RLI), an ATP binding cassette protein also known as ABCE1 (7). While there is some evidence that RNase L prefers viral to cellular RNA (65), cellular RNAs, including rRNA in intact ribosomes, are also cleaved by RNase L (106, 118).  Lessons learned from studying interactions between the OAS/RNase L system and many different types of RNA and DNA viruses are considered in the following sections, with an emphasis on more-recent in vivo studies.

Viral Encounters with 2′,5′-Oligoadenylate Synthetase and RNase L during the Interferon Antiviral Response