ADAR1 mutation causes ZBP1-dependent immunopathology

Nicholas W. Hubbard, Joshua M. Ames, Megan Maurano, Lan H. Chu, Kim Y. Somfleth, Nandan S. Gokhale, Margo Werner, Jessica M. Snyder, Katrina Lichauco, Ram Savan, Daniel B. Stetson and Andrew Oberst ()
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Nicholas W. Hubbard: University of Washington
Joshua M. Ames: University of Washington
Megan Maurano: University of Washington
Lan H. Chu: University of Washington
Kim Y. Somfleth: University of Washington
Nandan S. Gokhale: University of Washington
Margo Werner: University of Washington
Jessica M. Snyder: University of Washington
Katrina Lichauco: University of Washington
Ram Savan: University of Washington
Daniel B. Stetson: University of Washington
Andrew Oberst: University of Washington

Nature, 2022, vol. 607, issue 7920, 769-775

Abstract: Abstract The RNA-editing enzyme ADAR1 is essential for the suppression of innate immune activation and pathology caused by aberrant recognition of self-RNA, a role it carries out by disrupting the duplex structure of endogenous double-stranded RNA species1,2. A point mutation in the sequence encoding the Z-DNA-binding domain (ZBD) of ADAR1 is associated with severe autoinflammatory disease3–5. ZBP1 is the only other ZBD-containing mammalian protein6, and its activation can trigger both cell death and transcriptional responses through the kinases RIPK1 and RIPK3, and the protease caspase 8 (refs. 7–9). Here we show that the pathology caused by alteration of the ZBD of ADAR1 is driven by activation of ZBP1. We found that ablation of ZBP1 fully rescued the overt pathology caused by ADAR1 alteration, without fully reversing the underlying inflammatory program caused by this alteration. Whereas loss of RIPK3 partially phenocopied the protective effects of ZBP1 ablation, combined deletion of caspase 8 and RIPK3, or of caspase 8 and MLKL, unexpectedly exacerbated the pathogenic effects of ADAR1 alteration. These findings indicate that ADAR1 is a negative regulator of sterile ZBP1 activation, and that ZBP1-dependent signalling underlies the autoinflammatory pathology caused by alteration of ADAR1.

Date: 2022
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DOI: 10.1038/s41586-022-04896-7

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