ADAR1 averts fatal type I interferon induction by ZBP1

Mutations of the ADAR1 gene encoding an RNA deaminase cause severe diseases associated with chronic activation of type I interferon(IFN)responses,including Aicardi-Goutières syndrome and bilateral striatal necrosis1-3.The IFN-inducible p150 isoform of ADAR1 contains a Zαdomain that recognizes RNA with an alternative left-handed double-helix structure,termed Z-RNA4,5.Hemizygous ADAR1 mutations in the Zαdomain cause type I IFN-mediated pathologies in humans2,3 and mice6-8;however,it remains unclear how the interaction of ADAR1 with Z-RNA prevents IFN activation.Here we show that Z-DNA-binding protein 1(ZBP1),the only other protein in mammals known to harbour Zαdomains9,promotes type I IFN activation and fatal pathology in mice with impaired ADAR1 function.ZBP1 deficiency or mutation of its Zαdomains reduced the expression of IFN-stimulated genes and largely prevented early postnatal lethality in mice with hemizygous expression of ADAR1 with mutated Zαdomain(Adar1mZα/-mice).Adar1mZα/-mice showed upregulation and impaired editing of endogenous retroelement-derived complementary RNA reads,which represent a likely source of Z-RNAs activating ZBP1.