dsRNAs containing multiple IU pairs are sufficient to suppress interferon induction and apoptosis

Adenosine deaminases acting on RNA (ADARs) catalyse hyper-editing of long dsRNAs, whereby up to 50% of adenosines are converted to inosine (I). While hyper-edited dsRNAs (IU-dsRNAs) have been implicated in various cellular functions, we now provide evidence suggesting a novel role. We show that IU-dsRNA suppresses induction of interferon-stimulated genes (ISGs) and apoptosis in response to poly(IC). Moreover, we demonstrate that IU-dsRNA inhibits activation of IRF3, which is essential for induction of ISGs and apoptosis. Finally, we speculate that IRF3 inhibition results from specific binding of IU-dsRNA to MDA-5 or RIG-I, cytosolic sensors for poly(IC). While 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.