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Series GSE200985 Query DataSets for GSE200985
Status Public on Aug 10, 2022
Title ADAR1 mutation causes ZBP1-dependent immunopathology I
Organism Mus musculus
Experiment type Other
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.
 
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.
 
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
Submission date Apr 18, 2022
Last update date Aug 11, 2022
Contact name Andrew Oberst
E-mail(s) oberst@uw.edu
Organization name University of Washington
Street address 750 Republican street
City Seattle
State/province WA
ZIP/Postal code 98109
Country USA
 
Platforms (1)
GPL20885 nCounter Mouse Inflammation panel V2
Samples (12)
GSM6047841 20210827_AOberst-20210826-01_1_01
GSM6047842 20210827_AOberst-20210826-01_2_02
GSM6047843 20210827_AOberst-20210826-01_3_03
Relations
BioProject PRJNA827812

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

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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