ADAR1p150 RNA binding, independent of A-to-I RNA editing, buffers immunogenicity from the tonic type I IFN induced transcriptome in vivo.

ADAR1 edits adenosine to inosine (A-to-I) in double-stranded RNA to prevent MDA5 sensing of cellular transcripts, its key physiological role. However, editing-independent functions of ADAR1 remain poorly understood. Using a series of Adar1 mutant mice rescued by loss of MDA5 and PKR, we investigated isoform-specific, editing-independent roles of ADAR1 in vivo. We found that the cytoplasmic ADAR1p150 isoform is essential for maintaining peripheral T cell numbers and differentiation of hematopoietic stem and progenitor cells (HSPCs). In bone marrow transplants, ADAR1p150 protein, but not its editing activity, was crucial for T cell regeneration and HSPC repopulation, demonstrating a cell-intrinsic function in hematopoiesis. Experiments with IFN{beta}-treatment of purified HSPCs in vitro and in vivo IFNAR1 neutralization revealed hypersensitivity to tonic type I interferon (IFN) in the absence of ADAR1p150. Using cell lines, we demonstrate that type I IFN activates the OAS-RNaseL pathway, leading to cell death. This study shows that tonic type I IFN induces immunogenic cellular RNAs in sterile conditions. ADAR1p150 suppresses immune sensing of self-dsRNAs through both editing-dependent (MDA5) and editing-independent (PKR, OAS-RNaseL) mechanisms. Thus, ADAR1p150 protein levels and activity combine to set the threshold for tolerance to self-derived dsRNAs.