The 2–5 A system: Modulation of viral and cellular processes through acceleration of RNA degradation

Abstract

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-clependent 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.