Deciphering the Biological Significance of ADAR1–Z-RNA Interactions

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.

ZBP1: A Powerful Innate Immune Sensor and Double-Edged Sword in Host Immunity

“…Ectopic ADAR1 or E3 expression powerfully impaired the B-DNA-mediated induction of IFN-β mRNA in MEFs [ 12 ]. Additionally, both ADAR1 and E3 had been confirmed to competitively bind Z-RNA with ZBP1 and to block ZBP1-mediated necroptosis via the homotypic Zα domain [ 6 , 33 , 34 ]. The negative regulation of ZBP1 signaling may be beneficial to cellular immune homeostasis or viral immune escape [ 35 ].…”

Generation of a newAdar1p150-/-mouse demonstrates isoform-specific roles in embryonic development and adult homeostasis

“…ADAR1p150 is primarily expressed in the cytoplasm and is inducible in response to stimuli such as viral infection and type IFN (Samuel, 2011; 2019). It has a unique Z-DNA/RNA-binding alpha domain (Zα) at its N-terminus that can bind to and interact with the alternative left-handed conformation of RNA (Z-RNA)(Herbert et al, 1995; Herbert et al, 1998; Nakahama and Kawahara, 2021). The p150 isoform has been considered the key to suppressing MDA5-mediated sensing.…”

Thiophene-Extended Fluorescent Nucleosides as Molecular Rotor-Type Fluorogenic Sensors for Biomolecular Interactions

“…The first single-crystal X-ray structure of DNA was observed as a left-handed double helix of d­(CG) 3 under high-salt conditions. Since then, Z-DNA has been investigated not only in vitro using high-salt conditions but also in vivo with relevance to negative supercoiling. − The discovery of the Z-DNA-binding domain (Zα domain) in the adenosine deaminase acting on the RNA 1 (ADAR1) protein triggered the investigation of Z-DNA under physiological conditions, which led to an effort to elucidate the biological role of Z-DNA . Despite decades of research, structural information on, and the biological relevance of, Z-RNA are still lacking.…”