RNase-L-dependent destabilization of interferon-induced mRNAs - A role forthe 2-5A system in attenuation of the interferon response

The 2-5A system is an interferon-regulated RNA degradation pathway with ant iviral, growth-inhibitory, and pro-apoptotic activities. RNase-L mediates t he antiviral activity through the degradation of viral RNAs, and the antice llular effects of the 2-5A system are thought to be similarly mediated thro ugh the degradation of cellular transcripts. However, specific RNase-L-regu lated cellular RNAs have not been identified. To isolate candidate RNase-L substrates, differential display was used to identify mRNAs that exhibited increased expression in RNase-L-deficient N1E-115 cells as compared with RN ase-L-transfected cells. A novel interferon-stimulated gene encoding a 43-k Da ubiquitin-specific protease, designated ISG43, was identified in this sc reen. ISG43 expression is induced by interferon and negatively regulated by RNase-L. ISG43 induction is a primary response to interferon treatment and requires a functional JAK/STAT signaling pathway. The kinetics of ISG43 in duction were identical in wild type and RNase-L knock-out fibroblasts; howe ver, the decline in ISG43 mRNA following interferon treatment was markedly attenuated in RNase-L knock-out fibroblasts. The delayed shut-off kinetics of ISG43 mRNA corresponded to an increase in its half-life in RNase-L-defic ient cells. ISG15 mRNA also displayed RNase-L-dependent regulation. These f indings identify a novel role for the 2-5A system in the attenuation of the interferon response.