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-Goutieres syndrome and bilateral striatal necrosis(1-3). The IFN-inducible p150 isoform of ADAR1 contains a Z alpha domain that recognizes RNA with an alternative left-handeddouble-helix structure, termed Z-RNA(4,5). Hemizygous ADAR1 mutations in the Z alpha domain cause type I IFN-mediated pathologies in humans(2,3) and mice(6-8); 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 Z alpha domains(9), promotes type I IFN activation and fatal pathology in mice with impaired ADAR1 function. ZBP1 deficiency or mutation of its Z alpha domains reduced the expression of IFN-stimulated genes and largely prevented early postnatal lethality in mice with hemizygous expression of ADAR1 with mutated Z alpha domain (Adar1(mZ alpha/-) mice). Adar1(mZ alpha/-) mice showed upregulation and impaired editing of endogenous retroelement-derived complementary RNA reads, which represent a likely source of Z-RNAs activating ZBP1. Notably, ZBP1 promoted IFN activation and severe pathology in Adar1(mZ alpha/-) mice in a manner independent of RIPK1, RIPK3, MLKL-mediated necroptosis and caspase-8-dependent apoptosis, suggesting a novel mechanism of action. Thus, ADAR1 prevents endogenous Z-RNA-dependent activation of pathogenic type I IFN responses by ZBP1, suggesting that ZBP1 could contribute to type I interferonopathies caused by ADAR1 mutations.

Automated summary

Mutations of the ADAR1 gene cause chronic activation of type I interferon responses, leading to severe diseases. The interaction between ADAR1 and another protein called ZBP1 prevents IFN activation. Deficiency or mutation of ZBP1's Z alpha domains reduces expression of IFN-stimulated genes and prevents early postnatal lethality in mice with mutated ADAR1 Z alpha domain.