ADAR1 and ZBP1 in innate immunity, cell death, and disease

ADAR1 and ZBP1 are mammalian interferon-inducible proteins containing Zα domains that regulate innate immune responses across development and disease.Mutations in ADAR1 are associated with several autoimmune and autoinflammatory disorders in humans, such as Aicardi-Goutières Syndrome 6, systemic lupus erythematosus, and bilateral striatal necrosis.There is a regulatory relationship between ADAR1 and ZBP1 in mammalian cells, where ADAR1 suppresses ZBP1-mediated inflammatory cell death, PANoptosis.ZBP1-mediated PANoptosis contributes to the pathology caused by impaired ADAR1 function in mice.Using nuclear export inhibitors to sequester ADAR1 in the nucleus and disrupt the cytoplasmic interaction between ADAR1 and ZBP1, and activating ZBP1 through the induction of dsRNA have shown promise in preclinical mouse models.