Distinguishing self from non-self RNA by editing-specific inosine patterns

Endogenous double-stranded RNAs are modified by the A to I RNA-editing enzymes of the ADAR family to prevent activation of MDA5. In vivo, the cytoplasmic ADAR1p150 version seems critically required to suppress MDA5 activation in vivo, while the editing signature of all ADAR isoforms seems surprisingly overlapping in mice.

Further, it is not clear, how A to I modifications in dsRNA prevent MDA5 activation. Here we show that 3' UTRs harboring inverted repeat elements when not edited are able to activate MDA5 in vitro and in cells. Interestingly, in vitro editing by either ADAR isoform leads to editing at overlapping hotspot regions and prevents MDA5 activation in vitro and in cells.