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GEO help: Mouse over screen elements for information. |
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Status |
Public on Aug 10, 2022 |
Title |
ADAR1 mutation causes ZBP1-dependent immunopathology I |
Organism |
Mus musculus |
Experiment type |
Other
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Summary |
The RNA editing enzyme ADAR1 is essential for 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 species. A point mutation in the Z-nucleic-acid binding domain (ZBD) of ADAR1 is associated with severe autoinflammatory disease. ZBP1 is the only other ZBD-containing mammalian protein and its activation can trigger both cell death and transcriptional responses via the kinases RIPK1 and RIPK3, and the protease caspase-8. Here, we show that the pathology caused by ADAR1 ZBD mutation is driven by activation of ZBP1. We found that ablation of ZBP1 fully rescued the overt pathology caused by ADAR1 mutation, without reversing the underlying inflammatory program caused by this mutation. While 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 mutation. These findings indicate that ADAR1 is a negative regulator of sterile ZBP1 activation, and that ZBP1-dependent signaling underlies the autoinflammatory pathology caused by mutation of ADAR1.
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Overall design |
Mouse embryonic fibroblasts derived from mice of the indicated genotypes were treated with an siRNA targeting ADAR1 (siADAR) or a non-targeting siRNA (siNT) to compare the effect of genotype and ADAR1 deficiency on inflammatory signatures. 3 biological replicates were analyzed for each group. Transcripts were measured using the Mouse inflammation v2 nCounter panel commercially availible from Nanostring Technologies Inc.
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Contributor(s) |
Hubbard NW, Ames JM, Maurano M, Chu LH, Somfleth KY, Gokhale NS, Werner M, Snyder JM, Lichauco K, Savan R, Stetson DB, Oberst A |
Citation(s) |
35859177 |
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Submission date |
Apr 18, 2022 |
Last update date |
Aug 11, 2022 |
Contact name |
Andrew Oberst |
E-mail(s) |
oberst@uw.edu
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Organization name |
University of Washington
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Street address |
750 Republican street
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City |
Seattle |
State/province |
WA |
ZIP/Postal code |
98109 |
Country |
USA |
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Platforms (1) |
GPL20885 |
nCounter Mouse Inflammation panel V2 |
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Samples (12)
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Relations |
BioProject |
PRJNA827812 |
Supplementary file |
Size |
Download |
File type/resource |
GSE200985_RAW.tar |
50.0 Kb |
(http)(custom) |
TAR (of RCC) |
Processed data included within Sample table |
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