RNA sensing via LGP2 is essential for the induction of a type I IFN response in ADAR1 deficiency

RNA editing by the enzyme Adenosine Deaminase Acting on RNA 1 (ADAR1) is an important mechanism by which cells avoid innate immune responses to some endogenous RNAs. In ADAR1-deficient cells, unedited self RNAs can form base-paired structures that resemble viral RNAs and inadvertently activate antiviral innate immune pathways that lead to the induction of type I interferon (IFN). Rare mutations in ADAR1 cause Aicardi-Goutieres Syndrome (AGS), a severe childhood autoinflammatory syndrome that is characterized by chronic and excessive type I IFN production and developmental delay. Conversely, ADAR1 dysfunction and consequent type I IFN production helps restrict tumor growth and potentiates the activity of some chemotherapy drugs. Induction of type I IFN in ADAR1-deficient cells is thought to be due to triggering of the cytosolic RIG-I-like receptor (RLR), MDA5, by unedited self RNAs. Here, we show that another RLR, LGP2, also has an essential role. We demonstrate that ADAR1-deficient human cells fail to mount a type I IFN response in the absence of LGP2 and this involves the canonical function of LGP2 as an RNA sensor and facilitator of MDA5-dependent signaling. Further, we show that the sensitivity of tumor cells to ADAR1 loss requires the presence of LGP2. Finally, we find that type I IFN induction in tumor cells depleted of ADAR1 and treated with some chemotherapeutics is fully dependent on the expression of LGP2. These findings highlight a central role for LGP2 in self RNA sensing with important clinical implications for the treatment of AGS as well as for the potential application of ADAR1-directed anti-tumor therapy. ### Competing Interest Statement CRS has an additional appointment as Professor in the Faculty of Medicine at Imperial College London. CRS is a founder of Adendra Therapeutics and owns stock options and/or is a paid consultant for Adendra Therapeutics, Bicara Therapeutics, Montis Biosciences, Oncurious NV, Bicycle Therapeutics and Sosei Heptares, all unrelated to this work. The other authors declare that they have no conflict of interest.