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Review
. 2021 Oct 23;22(21):11435.
doi: 10.3390/ijms222111435.

Deciphering the Biological Significance of ADAR1-Z-RNA Interactions

Taisuke Nakahama  1 , Yukio Kawahara  1   2
Affiliations
Review

Deciphering the Biological Significance of ADAR1-Z-RNA Interactions

Taisuke Nakahama et al. Int J Mol Sci. .

Abstract

Adenosine deaminase acting on RNA 1 (ADAR1) is an enzyme responsible for double-stranded RNA (dsRNA)-specific adenosine-to-inosine RNA editing, which is estimated to occur at over 100 million sites in humans. ADAR1 is composed of two isoforms transcribed from different promoters: p150 and N-terminal truncated p110. Deletion of ADAR1 p150 in mice activates melanoma differentiation-associated protein 5 (MDA5)-sensing pathway, which recognizes endogenous unedited RNA as non-self. In contrast, we have recently demonstrated that ADAR1 p110-mediated RNA editing does not contribute to this function, implying that a unique Z-DNA/RNA-binding domain α (Zα) in the N terminus of ADAR1 p150 provides specific RNA editing, which is critical for preventing MDA5 activation. In addition, a mutation in the Zα domain is identified in patients with Aicardi-Goutières syndrome (AGS), an inherited encephalopathy characterized by overproduction of type I interferon. Accordingly, we and other groups have recently demonstrated that Adar1 Zα-mutated mice show MDA5-dependent type I interferon responses. Furthermore, one such mutant mouse carrying a W197A point mutation in the Zα domain, which inhibits Z-RNA binding, manifests AGS-like encephalopathy. These findings collectively suggest that Z-RNA binding by ADAR1 p150 is essential for proper RNA editing at certain sites, preventing aberrant MDA5 activation.

Keywords: ADAR1; AGS; IGS; MDA5; RNA editing; Z-RNA; interferonopathy.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Adenosine-to-inosine RNA editing. Adenosine deaminases acting on RNA (ADARs) convert adenosine into inosine through a deamination reaction.
Figure 2
Figure 2
Structural representation of active human ADARs. Both ADAR1 and ADAR2 comprise double-stranded (ds)RNA-binding domains (orange), a C-terminal deaminase domain (green), and a nuclear localization signal (NLS; shown in purple). Both ADAR1 p150 and p110 comprise Z-DNA/RNA-binding domain β (Zβ; shown in light blue), which loses binding capacity to Z-DNA/RNA. In contrast, ADAR1 p150-specific Zα (red) can bind to Z-DNA/RNA. A nuclear export signal (NES; shown in light brown) is present only in the p150 isoform, which is predominantly localized in the cytoplasm. Amino acid substitution resulting from point mutations in the ADAR1 gene, identified in patients with Aicardi–Goutières syndrome (AGS), is also shown. Amino acid sequences of a part of Zα in human and mouse ADAR 150 are shown below. Critical residues for Z-DNA/RNA binding and resides mutated in patients with AGS are shown in red.
Figure 3
Figure 3
Structural representation of retinoic acid-inducible gene I (RIG-I)-like receptor family members. Melanoma differentiation-associated protein 5 (MDA5) and RIG-I comprise two caspase activation and recruitment domains (CARDs; shown in blue), which mediate signal transduction through interaction with the mitochondrial antiviral-signaling protein (MAVS), with a DExD/H-box RNA helicase domain (light green) and a C-terminal domain (CTD; shown in pink), both of which are required for RNA binding. LGP2 lacks CARDs.
Figure 4
Figure 4
Crystal structure of Z-RNA bound to Zα of ADAR1 p150. Two Zα domains in blue bind to Z-RNA composed of dUr(CG)3 duplex in brown and green (PDB ID: 2GXB) [59]. Critical residues for Z-DNA/RNA binding (N173 and Y177 in the α helix, and W195 in the β sheet) and residues mutated in patients with AGS (N173 and P193) are shown in red.
Figure 5
Figure 5
Preventing MDA5 sensing of dsRNAs by ADAR1 p150-mediated RNA editing. ADAR1 p150 binds to Z-prone sequences in dsRNAs through Zα, converting to Z-RNA and promoting adenosine (A)-to-inosine (I) RNA editing of dsRNAs. ADAR1 p150-specific RNA editing is required for prevention of sensing unedited dsRNAs by MDA5, leading to filament assembly and activating MAVS.
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