The RNA-editing enzyme ADAR1: a regulatory hub that tunes multiple dsRNA-sensing pathways

Area of Science:

• Molecular Biology
• Immunology
• Genetics

Background:

• Adenosine deaminase acting on RNA 1 (ADAR1) is a critical RNA-editing enzyme.
• ADAR1 has two isoforms: nuclear p110 and cytoplasmic p150.
• ADAR1 p150 possesses a Zα domain that binds Z-RNAs, distinguishing it from p110.

Purpose of the Study:

• To elucidate the role of ADAR1 isoforms in preventing innate immune sensing of endogenous dsRNAs.
• To investigate the mechanism by which ADAR1 p150 specifically edits and regulates dsRNA recognition.
• To establish the link between ADAR1 mutations, RNA editing, and diseases like Aicardi-Goutières syndrome.

Main Methods:

• Comparative analysis of ADAR1 p110 and p150 functions.
• Investigating ADAR1 p150's interaction with Z-RNAs via its Zα domain.
• Utilizing a mouse model with an ADAR1 Zα domain mutation to study Aicardi-Goutières syndrome pathogenesis.

Main Results:

• ADAR1 p150-mediated RNA editing, but not p110, inhibits MDA5 sensing of endogenous dsRNAs.
• The Zα domain and Z-RNA interaction are crucial for ADAR1 p150's specificity.
• ADAR1 p150 also prevents ZBP1 and PKR from sensing endogenous dsRNAs, averting cell death and translational shutdown.

Conclusions:

• ADAR1 functions as a central regulator, preventing self-dsRNA recognition by multiple innate immune sensors.
• Impaired ADAR1 p150 RNA editing is a key mechanism in ADAR1 mutation-associated Aicardi-Goutières syndrome.
• ADAR1 is a potential therapeutic target for inflammatory diseases and cancer.