The Interferon Antiviral Response
RNA cleavage is a fundamental host response for controlling viral infections in both plants and animals. In higher vertebrates, this process is often regulated by interferons (IFNs), a family of antiviral cytokines discovered 50 years ago. One of the principal IFN antiviral pathways involves activation of the ubiquitous cellular endoribonuclease RNase L (formerly 2-5A-dependent RNase). 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.
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. 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. IFN signaling induces transcription of the OAS genes through IFN-stimulated response elements in the promoters. 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 only well-established function of 2-5A is activation of RNase L. 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 deleted mice. 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. 2-5A binds to ankyrin repeats 2 and 4, causing catalytically inactive RNase L monomers to form activated dimers with potent RNase activity. 2-5A is degraded within minutes by 2′-phosphodiesterase and 5′-phosphatase activities within cells and in sera. 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. While there is some evidence that RNase L prefers viral to cellular RNA, cellular RNAs, including rRNA in intact ribosomes, are also cleaved by RNase L.
Tags: Biology, Immunology, Medicine, Microbiology, Science, Virology
