Abstract
SummaryNucleic acids are powerful triggers of innate immunity and can adopt the Z-conformation, an unusual left-handed double helix. Here, we studied the biological function(s) of Z-RNA recognition by the adenosine deaminase ADAR1, mutations in which cause Aicardi-Goutières syndrome. Adar1mZα/mZα mice, bearing two point mutations in the Z-nucleic acid binding (Zα) domain that abolish Z-RNA binding, displayed spontaneous induction of type I interferons (IFNs) in multiple organs, including in the lung, where both stromal and hematopoietic cells showed IFN-stimulated gene (ISG) induction. Lung neutrophils expressed ISGs induced by the transcription factor IRF3, indicating an initiating role for neutrophils in this IFN response. The IFN response in Adar1mZα/mZα mice required the adaptor MAVS, implicating cytosolic RNA sensing. Adenosine-to-inosine changes were enriched in transposable elements and revealed a specific requirement of ADAR1’s Zα domain in editing of a subset of RNAs. Thus, endogenous RNAs in Z-conformation have immunostimulatory potential curtailed by ADAR1, with relevance to autoinflammatory disease in humans.
Highlights
The innate immune system monitors the intra- and extracellular environments for unusual nucleic acids (Bartok and Hartmann, 2020)
Our findings suggest that recognition of Z-form RNA by ADAR1 contributes to the suppression of IFN responses
Generation of Z-nucleic acid binding (Za) domain mutated mice To study the role of Z-form nucleic acid binding to the Za domain in ADAR1-p150 in an in vivo setting, we generated mice bearing two missense mutations: p.Asn175Ala and p.Tyr179Ala
Summary
The innate immune system monitors the intra- and extracellular environments for unusual nucleic acids (Bartok and Hartmann, 2020). This process, known as ‘‘nucleic acid sensing’’, detects pathogen invasion and disturbances to homeostasis. It involves a large number of germline encoded nucleic acid sensors. Upon engagement by immunostimulatory DNA or RNA, these sensors signal to initiate a large spectrum of responses, including transcription of the genes encoding type I interferons (IFNs). It is important to understand the molecular mechanisms that prevent activation of nucleic acid sensors by ‘‘normal’’ DNA and RNA present in healthy cells (Bartok and Hartmann, 2020)
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