ADAR1 Zα domain P195A mutation activates the MDA5-dependent RNA-sensing signaling pathway in brain without decreasing overall RNA editing.

Variants of the RNA-editing enzyme ADAR1 cause Aicardi-Goutières syndrome (AGS), in which severe inflammation occurs in the brain due to innate immune activation. Here, we analyze the RNA-editing status and innate immune activation in an AGS mouse model that carries the Adar P195A mutation in the N terminus of the ADAR1 p150 isoform, the equivalent of the P193A human Zα variant causal for disease. This mutation alone can cause interferon-stimulated gene (ISG) expression in the brain, especially in the periventricular areas, reflecting the pathologic feature of AGS. However, in these mice, ISG expression does not correlate with an overall decrease in RNA editing. Rather, the enhanced ISG expression in the brain due to the P195A mutant is dose dependent. Our findings indicate that ADAR1 can regulate innate immune responses through Z-RNA binding without changing overall RNA editing. [Display omitted] • The ADAR1 P195A mutation alone causes brain innate immune response in Adar ^{P195A/ P195A} mice • Haploinsufficiency of ADAR1 P195A mutation dramatically enhances ISG expression in the brain • ISGs are highly expressed in the periventricular areas in the brains of P195A mutant mice • The ADAR1 P195A mutation does not affect the overall RNA-editing levels in the brain Guo et al. analyze a mouse model carrying the ADAR1 Zα domain P195A mutation and find that this specific mutation does not affect the overall RNA-editing activity of ADAR1, while it results in activation of the MDA5-dependent RNA-sensing signaling pathway, leading to robust ISG expression in the brain. [ABSTRACT FROM AUTHOR]