The 2-5A system: modulation of viral and cellular processes through acceleration of RNA degradation.
The 2-5A system is an RNA degradation pathway that can be induced by the interferons (IFNs). Treatment of cells with IFN activates genes encoding several double-stranded RNA (dsRNA)-dependent synthetases. These enzymes generate 5'-triphosphorylated, 2',5'-phosphodiester-linked oligoadenylates (2-5A) from ATP. The effects of 2-5A in cells are transient since 2-5A is unstable in cells due to the activities of phosphodiesterase and phosphatase. 2-5A activates the endoribonuclease 2-5A-dependent RNase L, causing degradation of single-stranded RNA with moderate specificity. The human 2-5A-dependent RNase is an 83.5 kDa polypeptide that has little, if any, RNase activity, unless 2-5A is present. 2-5A binding to RNase L switches the enzyme from its off-state to its on-state. At least three 2',5'-linked oligoadenylates and a single 5'-phosphoryl group are required for maximal activation of the RNase. Even though the constitutive presence of 2-5A-dependent RNase is observed in nearly all mammalian cell types, cellular amounts of 2-5A-dependent mRNA and activity can increase after IFN treatment. One well-established role of the 2-5A system is as a host defense against some types of viruses. Since virus infection of cells results in the production and secretion of IFNs, and since dsRNA is both a frequent product of virus infection and an activator of 2-5A synthesis, the replication of encephalomyocarditis virus, which produces dsRNA during its life cycle, is greatly suppressed in IFN-treated cells as a direct result of RNA decay by the activated 2-5A-dependent RNase. This review covers the organic chemistry, enzymology, and molecular biology of 2-5A and its associated enzymes. Additional possible biological roles of the 2-5A system, such as in cell growth and differentiation, human immunodeficiency virus replication, heat shock, atherosclerotic plaque, pathogenesis of Type I diabetes, and apoptosis, are presented.
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Section on Biomedical Chemistry, Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0805, USA.
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D000227:Adenine Nucleotides / Q000737:chemistry* / Q000378:metabolism*; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism*; D002468:Cell Physiological Phenomena / Q000187:drug effects*; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D009843:Oligoribonucleotides / Q000737:chemistry* / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D012330:RNA, Double-Stranded / Q000187:drug effects*; D014780:Viruses / Q000187:drug effects*
D000227:Adenine Nucleotides; D000998:Antiviral Agents; D009843:Oligoribonucleotides; D011500:Protein Synthesis Inhibitors; D012330:RNA, Double-Stranded; C023505:2',5'-oligoadenylate; D007372:Interferons