Figure 3.

Model for alternative pathways responding to loss of editing by ADAR1 under physiological and pathological states. Under normal homeostatic conditions (a), low levels of dsRNA are produced by the cell, which are edited in both the nucleus and cytoplasm to prevent activation of MDA5. In the absence of editing (b), unedited endogenous dsRNA triggers the activation of MDA5/MAVS resulting in the production of IFN and ISGs. Some cancers have chronic activation of the DNA sensing innate immune pathway, cGAS/STING (c), which leads to increased interferon secretion, induction of ISGs including ADAR1 and PKR and increased dsRNA which is edited by ADAR1. In the absence of editing by ADAR1 in this state (d), the interferon-induced and cellular dsRNA triggers activation of both MDA5/MAVS and PKR leading to further induction of ISGs and translational shutdown. Abbreviations: IFN, interferon. ISGs, interferon-stimulated genes. In (b,d) the active pathway participants are coloured in red.