RNA editing and immune control: from mechanism to therapy

Abstract

Adenosine-to-inosine RNA editing, catalyzed by the enzymes ADAR1 and ADAR2, stands as a pervasive RNA modification. A primary function of ADAR1-mediated RNA editing lies in labeling endogenous double-stranded RNAs (dsRNAs) as 'self', thereby averting their potential to activate innate immune responses. Recent findings have highlighted additional roles of ADAR1, independent of RNA editing, that are crucial for immune control. Here, we focus on recent progress in understanding ADAR1's RNA editing-dependent and -independent roles in immune control. We describe how ADAR1 regulates various dsRNA innate immune receptors through distinct mechanisms. Furthermore, we discuss the implications of ADAR1 and RNA editing in diseases, including autoimmune diseases and cancers.

Figure 1.

A schematic drawing of RNA editing and catalytic active ADAR proteins. (a) ADAR catalyzes Adenosine-to-Inosine RNA editing on dsRNAs. (b) The protein domains of ADAR1 and ADAR2.

Figure 2.

The dsRNA-mediated innate immune pathways regulated by ADAR1. Endogenous dsRNAs are bound and edited by ADAR1p150 to evade innate immune sensing by PKR and MDA5. Additionally, ADAR1p150’s Z-RNA binding activity is involved in the suppression of ZBP1.