ADAR1 averts fatal type I interferon induction by ZBP1.

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Mutations in the ADAR1 gene cause severe diseases linked to chronic type I interferon (IFN) activation.
• The ADAR1 p150 isoform binds Z-RNA via its Zα domain, but how this interaction prevents IFN activation is unknown.
• Z-DNA-binding protein 1 (ZBP1) also has Zα domains and is implicated in IFN responses.

Purpose of the Study:

• To investigate the role of ZBP1 in type I interferon activation and pathology in the context of ADAR1 deficiency.
• To elucidate the mechanism by which ADAR1 normally prevents Z-RNA-mediated IFN activation.

Main Methods:

• Utilized mouse models with impaired ADAR1 function (Adar1^mZα/- mice).
• Assessed the impact of ZBP1 deficiency or Zα domain mutation on IFN-stimulated gene expression and survival in these mice.
• Analyzed endogenous retroelement-derived RNA reads for Z-RNA characteristics and editing status.

Main Results:

• ZBP1 deficiency or Zα domain mutation significantly reduced IFN-stimulated gene expression and prevented lethality in Adar1^mZα/- mice.
• Adar1^mZα/- mice exhibited increased and improperly edited endogenous retroelement-derived complementary RNA reads, a potential Z-RNA source.
• ZBP1 promoted IFN activation and pathology independently of necroptosis and apoptosis pathways.

Conclusions:

• ADAR1 prevents pathogenic type I interferon responses triggered by endogenous Z-RNAs interacting with ZBP1.
• ZBP1 plays a critical role in mediating type I interferonopathies associated with ADAR1 mutations.
• This suggests a novel mechanism of ZBP1-mediated IFN activation independent of known cell death pathways.