RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself

By Brian J. Liddicoat, Robert Piskol, A. Chalk, Gokul Ramaswami, M. Higuchi, Jochen C. Hartner, J. B. Li, P. Seeburg, Carl R Walkley. Science, 2015

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RNA editing helps identify cellular RNAs Adenosine bases in messenger RNA (mRNAs) can be enzymatically modified and changed into inosine bases. This RNA “editing” is mediated by adenosine deaminase acting on RNA (ADAR) enzymes. Liddicoat et al. show that the in vivo targets of the principal editing enzyme, ADAR1, are long double-stranded RNA (dsRNA) structures in noncoding portions of cellular mRNAs. ADAR1-directed editing of these cellular targets is critical to avoid activation of an immune response to dsRNA in the cytoplasm, because dsRNA is also a marker of viral infection. Science, this issue p. 1115 The principal RNA-editing enzyme modifies cellular RNAs to prevent their erroneous identification as foreign RNA. Adenosine-to-inosine (A-to-I) editing is a highly prevalent posttranscriptional modification of RNA, mediated by ADAR (adenosine deaminase acting on RNA) enzymes. In addition to RNA editing, additional functions have been proposed for ADAR1. To determine the specific role of RNA editing by ADAR1, we generated mice with an editing-deficient knock-in mutation (Adar1E861A, where E861A denotes Glu861→Ala861). Adar1E861A/E861A embryos died at ~E13.5 (embryonic day 13.5), with activated interferon and double-stranded RNA (dsRNA)–sensing pathways. Genome-wide analysis of the in vivo substrates of ADAR1 identified clustered hyperediting within long dsRNA stem loops within 3′ untranslated regions of endogenous transcripts. Finally, embryonic death and phenotypes of Adar1E861A/E861A were rescued by concurrent deletion of the cytosolic sensor of dsRNA, MDA5. A-to-I editing of endogenous dsRNA is the essential function of ADAR1, preventing the activation of the cytosolic dsRNA response by endogenous transcripts.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/26e7f0da2f0d586c60fc3a8bf8605d4b2a38ff78

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Citations in the corpus

ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA (2015, background): “On one hand, RNA editing (Liddicoat et al., 2015) and methylation (Schuberth-Wagner et al., 2015) modifies particular types of self-RNA that would otherwise form reasonable ligands for RIG-I or MDA5.”
Unified mechanisms for self-RNA recognition by RIG-I Singleton-Merten syndrome variants (2018, background): “ribonucleic acids for instance are shielded from RLRs by introducing 2’O-methylations or by destabilizing double-stranded parts through A-to-I editing (Chung et al., 2018; Devarkar et al., 2016; Liddicoat et al., 2015; Schuberth-Wagner et al., 2015).”
Sequential action of a tRNA base editor in conversion of cytidine to pseudouridine (2022, background): “Furthermore, A-to-I editing alters mRNA secondary structure, preventing innate immune responses triggered by mRNAs’ rigid double-stranded structures (Liddicoat et al., 2015).”
DUSP11-mediated control of 5′-triphosphate RNA regulates RIG-I sensitivity (2020, background): “…can be sensed by host PRRs and trigger inflammation (Tarallo et al. 2012; Boelens et al. 2014; White et al. 2014; Chiappinelli et al. 2015; Liddicoat et al. 2015; Roulois et al. 2015; Nabet et al. 2017; Chiang et al. 2018; Chung et al. 2018; Dhir et al. 2018; Zhao et al. 2018; Rehwinkel…”