ADAR1 averts fatal type I interferon induction by ZBP1

Nature. 2022 Jul;607(7920):776-783. doi: 10.1038/s41586-022-04878-9. Epub 2022 Jul 20.

Abstract

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 Zα domain that recognizes RNA with an alternative left-handed double-helix structure, termed Z-RNA4,5. Hemizygous ADAR1 mutations in the Zα domain 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 Zα domains9, promotes type I IFN activation and fatal pathology in mice with impaired ADAR1 function. ZBP1 deficiency or mutation of its Zα domains reduced the expression of IFN-stimulated genes and largely prevented early postnatal lethality in mice with hemizygous expression of ADAR1 with mutated Zα domain (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. Notably, ZBP1 promoted IFN activation and severe pathology in Adar1mZα/- 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.

MeSH terms

  • Adenosine Deaminase* / genetics
  • Adenosine Deaminase* / metabolism
  • Animals
  • Apoptosis
  • Caspase 8 / metabolism
  • Interferon Type I* / antagonists & inhibitors
  • Interferon Type I* / immunology
  • Mice
  • Mutation
  • Necroptosis
  • RNA, Double-Stranded / metabolism
  • RNA-Binding Proteins* / chemistry
  • RNA-Binding Proteins* / genetics
  • RNA-Binding Proteins* / metabolism

Substances

  • Interferon Type I
  • RNA, Double-Stranded
  • RNA-Binding Proteins
  • Zbp1 protein, mouse
  • Caspase 8
  • ADAR1 protein, mouse
  • Adenosine Deaminase