Interferon action may be mediated by activation of a nuclease by pppA2′p5′A2′p5′A

Abstract

EXPOSURE of cells to the antiviral agent interferon inhibits virus replication¹. In interferon-treated cells the adsorption, penetration and uncoating of infecting viruses is not affected, but the synthesis of virus-specific mRNA and viral proteins is inhibited^2,3. We have studied a mechanism for degradation of mRNA which may be activated in interferon-treated cells by the presence of double-stranded RNA (dsRNA) of viral origin. Lengyel et al. have reported that an endonuclease present in extracts of cells treated with interferon is activated by dsRNA and ATP^4–6. The endonuclease degrades mRNA by a process which can be divided into two phases: an activation phase requiring the presence of both ATP and dsRNA but not of mRNA, and an endonucleolytic phase, which does not require either ATP or dsRNA⁶. Kerr et al. have at the same time reported that protein synthesis is inhibited in extracts of cells treated with interferon after incubation with dsRNA and ATP⁷. In these incubation conditions a low molecular weight inhibitor is formed from ATP^8,9. The mechanism of action of this inhibitor, the structure of which has recently been determined as pppA2′p5′A2′p5′A (pppApApA)¹⁰, is not known. Our results indicate that this trinucleotide mediates the activation of a nuclease which degrades mRNA and may therefore inhibit protein synthesis in this way.