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ADAR1 mutation causes ZBP1-dependent immunopathology.

Nicholas W Hubbard¹, Joshua M Ames¹, Megan Maurano¹

¹Department of Immunology, University of Washington, Seattle, WA, USA.

|July 21, 2022

Summary

The RNA-editing enzyme ADAR1 normally suppresses innate immunity. Its Z-DNA-binding domain (ZBD) alteration causes autoinflammatory disease by activating ZBP1, a pathway ADAR1 normally inhibits.

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Area of Science:

Immunology
Molecular Biology
Genetics

Background:

ADAR1 (A1) is crucial for preventing self-RNA-induced innate immune activation.
Mutations in ADAR1's Z-DNA-binding domain (ZBD) cause severe autoinflammatory disease.
ZBP1 is another ZBD-containing protein that triggers cell death and inflammation.

Purpose of the Study:

To investigate the role of ZBP1 in ADAR1 ZBD-mutation-associated autoinflammatory pathology.
To elucidate the signaling pathways linking ADAR1 function, ZBP1, and autoinflammation.

Main Methods:

Utilized mouse models with alterations in ADAR1's ZBD.
Performed genetic ablation of ZBP1, RIPK3, caspase-8, and MLKL in these models.
Assessed inflammatory responses and pathological outcomes.

Main Results:

ZBP1 activation drives the pathology observed in ADAR1 ZBD-altered mice.
Ablation of ZBP1 fully rescued the overt pathology, despite incomplete reversal of the inflammatory program.
RIPK3 loss partially mimicked ZBP1 ablation, while combined caspase-8/RIPK3 or caspase-8/MLKL deletion exacerbated pathology.

Conclusions:

ADAR1 acts as a negative regulator of sterile ZBP1 activation.
ZBP1-dependent signaling is the key driver of autoinflammatory pathology resulting from ADAR1 ZBD alterations.
This highlights a critical interplay between ADAR1, ZBP1, and innate immunity in autoinflammatory diseases.