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RNA editing at a limited number of sites is sufficient to prevent MDA5 activation in the mouse brain

Kim, Jung In ; Nakahama, Taisuke ; Yamasaki, Ryuichiro ; Costa Cruz, Pedro Henrique ; Vongpipatana, Tuangtong ; Inoue, Maal ; Kanou, Nao ; Xing, Yanfang ; Todo, Hiroyuki ; Shibuya, Toshiharu ; Kato, Yuki ; Kawahara, Yukio Hunter, Kent

PLoS genetics, 2021-05, Vol.17 (5), p.e1009516-e1009516 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
RNA editing at a limited number of sites is sufficient to prevent MDA5 activation in the mouse brain
Autor: Kim, Jung In ; Nakahama, Taisuke ; Yamasaki, Ryuichiro ; Costa Cruz, Pedro Henrique ; Vongpipatana, Tuangtong ; Inoue, Maal ; Kanou, Nao ; Xing, Yanfang ; Todo, Hiroyuki ; Shibuya, Toshiharu ; Kato, Yuki ; Kawahara, Yukio
Hunter, Kent
Assuntos: 3' Untranslated Regions - genetics ; Adenosine ; Adenosine Deaminase - deficiency ; Adenosine Deaminase - genetics ; Adenosine Deaminase - metabolism ; Animals ; Animals, Newborn ; Biology and life sciences ; Brain ; Brain - metabolism ; Editing ; Engineering and Technology ; Female ; Fetuses ; Gene expression ; Glyceraldehyde-3-phosphate dehydrogenase ; Interferon-Induced Helicase, IFIH1 - metabolism ; Introns - genetics ; Isoenzymes - metabolism ; Medicine and Health Sciences ; Methods ; Mice ; Mice, Knockout ; Mutation ; Organ Specificity ; Protein expression ; Proteins ; Research and analysis methods ; RNA Editing ; RNA sequencing ; RNA-Binding Proteins - genetics ; Rodents ; Spleen ; Survival Rate ; Thymus gland
É parte de: PLoS genetics, 2021-05, Vol.17 (5), p.e1009516-e1009516
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
The authors have declared that no competing interests exist.
Descrição: Adenosine deaminase acting on RNA 1 (ADAR1), an enzyme responsible for adenosine-to-inosine RNA editing, is composed of two isoforms: nuclear p110 and cytoplasmic p150. Deletion of Adar1 or Adar1 p150 genes in mice results in embryonic lethality with overexpression of interferon-stimulating genes (ISGs), caused by the aberrant recognition of unedited endogenous transcripts by melanoma differentiation-associated protein 5 (MDA5). However, among numerous RNA editing sites, how many RNA sites require editing, especially by ADAR1 p150, to avoid MDA5 activation and whether ADAR1 p110 contributes to this function remains elusive. In particular, ADAR1 p110 is abundant in the mouse brain where a subtle amount of ADAR1 p150 is expressed, whereas ADAR1 mutations cause Aicardi-Goutières syndrome, in which the brain is one of the most affected organs accompanied by the elevated expression of ISGs. Therefore, understanding RNA editing-mediated prevention of MDA5 activation in the brain is especially important. Here, we established Adar1 p110-specific knockout mice, in which the upregulated expression of ISGs was not observed. This result suggests that ADAR1 p150-mediated RNA editing is enough to suppress MDA5 activation. Therefore, we further created Adar1 p110/Adar2 double knockout mice to identify ADAR1 p150-mediated editing sites. This analysis demonstrated that although the elevated expression of ISGs was not observed, only less than 2% of editing sites were preserved in the brains of Adar1 p110/Adar2 double knockout mice. Of note, we found that some sites were highly edited, which was comparable to those found in wild-type mice, indicating the presence of ADAR1 p150-specific sites. These data suggest that RNA editing at a very limited sites, which is mediated by a subtle amount of ADAR1 p150, is sufficient to prevents MDA5 activation, at least in the mouse brain.
Editor: United States: Public Library of Science
Idioma: Inglês

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RNA editing at a limited number of sites is sufficient to prevent MDA5 activation in the mouse brain

Kim, Jung In ; Nakahama, Taisuke ; Yamasaki, Ryuichiro ; Costa Cruz, Pedro Henrique ; Vongpipatana, Tuangtong ; Inoue, Maal ; Kanou, Nao ; Xing, Yanfang ; Todo, Hiroyuki ; Shibuya, Toshiharu ; Kato, Yuki ; Kawahara, Yukio Hunter, Kent

United States: Public Library of Science

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