Life science
Medical & healthcare, Drug development

Our body recognizes left-handed RNAs as non-self
Department of RNA Biology and Neuroscience, Graduate School of Medicine
Professor Yukio Kawahara

https://researchmap.jp/rnabiology

Assistant Professor Taisuke Nakahama

https://researchmap.jp/Tomato-kiraiLife science

Abstract
Our bodies are equipped with innate immunity that rapidly
detects and eliminates infecting pathogens. Innate immunity recognizes molecular structures common to viruses and other pathogens, including dsRNA structures. However, there is a risk that
endogenous dsRNAs are misrecognized as non-self. To avoid this,endogenous dsRNAs are subjected to RNA editing, which converts
adenosine to inosine, whereas the detailed mechanism of this RNA
editing remains largely unknown. In this study, we found that theRNA-editing enzyme ADAR1 binds to left-handed dsRNAs, whichis essential for proper RNA editing. Furthermore, Adar1 mutant
mice, in which ADAR1 cannot bind to left-handed dsRNAs, manifested the symptoms similar to human genetic immune disease.
Thus, this study provides an epoch-making achievement that clarified the physiological significance of left-handed dsRNAs.

overproduction of interferon. Of note, the Adar1 mutant mice developed AGS-like encephalopathy. These results suggest that ADAR1
p150-binding to left-handed dsRNAs is essential for proper RNA
editing to prevent aberrant MDA5 activation. In addition, given that
mutations in Zα are also found in patients with AGS, these findings
suggest that impaired binding to left-handed dsRNA is involved in
the pathogenesis of AGS.

▍ Background & Results
We have clarified that dsRNAs are sensed through its helicalstructure in vivo. It has been recently revealed that left-handed dsRNAs are also formed in RNA derived from SARS-CoV-2 and influenza viruses. Thus, our findings will be useful for the developmentof methods for early detection and prevention of viral infection. It isalso expected to be applied to safe artificial mRNA synthesis technology, which inhibits unexpected immune responses.

▍ Significance of the research and Future perspective
Mammalian genome contains many repeat sequences derived
from retrotransposons. When these elements are located on thesame RNA, dsRNAs can be formed between repeat sequences. On the other hand, innate immunity senses foreign dsRNA
derived from viruses by dsRNA sensor proteins, such as MDA5,and stimulates interferon production. To prevent MDA5 sensing ofendogenous dsRNAs as non-self, dsRNAs are subjected to RNA
editing, which marks self dsRNAs by inserting inosine. This typeof RNA editing is catalyzed by ADAR1, which is consisted of twoisoforms: the short ADAR1 p110 and the long ADAR1 p150. We
previously reported that ADAR1 p150, but not the p110 isoform,
exerts a regulatory function to suppress aberrant activation of innate immunity, whereas the detailed mechanism remains largely
unknown. In this study, we focused on the left-handed dsRNA-binding domain termed Zα, which is found only in ADAR1 p150.
First, using cultured cells, we found that inserting a mutation in Zα,
which abolishes binding ability to left-handed dsRNA, reduced
RNA editing efficiency. Then, we generated Adar1 mutant micethat had the same mutation in Zα and found that they exhibited
marked growth retardation and high mortality rate. In these mutantmice, MDA5 was abnormally activated, resulting in overproductionof interferon. ADAR1 mutations are a cause of Aicardi-Goutières
syndrome (AGS), which is characterized by encephalopathy andADAR1 p150 binds to left-handed dsRNAs, which is essential for maintaining
the proper level of RNA editing at certain sites to prevent aberrant activation ofMDA5.

Adar1 mutant mice harboring a point mutation in the Zα domain manifest growth
retardation and encephalopathy. MDA5 is aberrantly activated, leading to the increased expression of an interferon-stimulated gene (Ifit1) in various organs.

ADAR1-mediated RNA editing

P a t e n tNakahama, Taisuke; Kawahara, Yukio et al. Mutations in the adenosine deaminase ADAR1 that prevent endogenous Z-RNA binding induce
Aicardi-Goutières-syndrome-like encephalopathy. Immunity. 2021, 54(9), p.1976-1988, doi: 10.1016/j.immuni.2021.08.022
UR
L https://www.med.osaka-u.ac.jp/pub/rna/index.html
K e y w o r d RNA editing, AGS, Z-RNA, autoimmune disease, interferon

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