Double-stranded RNAs containing multiple IU pairs are sufficient to suppress interferon induction and apoptosis

Adenosine deaminases acting on RNA (ADARs) catalyze hyperediting of long double-stranded RNAs (dsRNAs), whereby up to 50% of adenosines are converted to inosine (I). Although hyperedited dsRNAs (IU-dsRNAs) have been implicated in various cellular functions, we now provide evidence for another role. We show that IU-dsRNA suppresses the induction of interferon-stimulated genes (ISGs) and apoptosis by poly(IC). Moreover, we show that IU-dsRNA inhibits the activation of interferon regulatory factor 3 (IRF3), which is essential for the induction of ISGs and apoptosis. Finally, we speculate that the inhibition of IRF3 results from specific binding of IU-dsRNA to MDA-5 or RIG-I, both of which are cytosolic sensors for poly(IC). Although our data are consistent with a previous study in which ADAR1 deletion resulted in increased expression of ISGs and apoptosis, we show that IU-dsRNA per se suppresses ISGs and apoptosis. We therefore propose that any IU-dsRNA generated by ADAR1 can inhibit both pathways.