RNA editing enzyme adenosine deaminase is a restriction factor for controlling measles virus replication that also is required for embryogenesis. Proc Natl Acad Sci USA

Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2011; 108(1):331-6. DOI: 10.1073/pnas.1017241108
Source: PubMed


Measles virus (MV), a member of the family Paramyxoviridae and an exclusively human pathogen, is among the most infectious viruses. A progressive fatal neurodegenerative complication, subacute sclerosing panencephalitis (SSPE), occurs during persistent MV infection of the CNS and is associated with biased hypermutations of the viral genome. The observed hypermutations of A-to-G are consistent with conversions catalyzed by the adenosine deaminase acting on RNA (ADAR1). To evaluate the role of ADAR1 in MV infection, we selectively disrupted expression of the IFN-inducible p150 ADAR1 isoform and found it caused embryonic lethality at embryo day (E) 11-E12. We therefore generated p150-deficient and WT mouse embryo fibroblast (MEF) cells stably expressing the MV receptor signaling lymphocyte activation molecule (SLAM or CD150). The p150(-/-) but not WT MEF cells displayed extensive syncytium formation and cytopathic effect (CPE) following infection with MV, consistent with an anti-MV role of the p150 isoform of ADAR1. MV titers were 3 to 4 log higher in p150(-/-) cells compared with WT cells at 21 h postinfection, and restoration of ADAR1 in p150(-/-) cells prevented MV cytopathology. In contrast to infection with MV, p150 disruption had no effect on vesicular stomatitis virus, reovirus, or lymphocytic choriomeningitis virus replication but protected against CPE resulting from infection with Newcastle disease virus, Sendai virus, canine distemper virus, and influenza A virus. Thus, ADAR1 is a restriction factor in the replication of paramyxoviruses and orthomyxoviruses.

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Available from: Megan Welch, Jan 16, 2014
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    • "The Adar +/À mice resulting from the B6.129S4- Meox2 tm1(cre)Sor cross were subsequently bred to Tmem173 À/À (Sting À/À ) mice (Ishikawa et al., 2009), Mavs À/À mice (Gall et al., 2012), Ddx58 À/À (Rigi À/À ) mice (Kato et al., 2005), or Ifih1 À/À (Mda5 À/À ) mice (Gitlin et al., 2006). Adar p150 +/À gametes were generously provided by Dr. M.B.A. Oldstone (Ward et al., 2011). Sentinel mice (Crl:CD1[ICR]; Charles River) were tested quarterly for endo-and ectoparasites, mouse hepatitis virus, mouse parvovirus, and rotavirus and tested annually for Mycoplasma pulmonis, pneumonia virus of mice, reovirus 3, Sendai virus, and Theiler murine encephalomyelitis virus. "
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    ABSTRACT: Mutations in ADAR, which encodes the ADAR1 RNA-editing enzyme, cause Aicardi-Goutières syndrome (AGS), a severe autoimmune disease associated with an aberrant type I interferon response. How ADAR1 prevents autoimmunity remains incompletely defined. Here, we demonstrate that ADAR1 is a specific and essential negative regulator of the MDA5-MAVS RNA sensing pathway. Moreover, we uncovered a MDA5-MAVS-independent function for ADAR1 in the development of multiple organs. We showed that the p150 isoform of ADAR1 uniquely regulated the MDA5 pathway, whereas both the p150 and p110 isoforms contributed to development. Abrupt deletion of ADAR1 in adult mice revealed that both of these functions were required throughout life. Our findings delineate genetically separable roles for both ADAR1 isoforms in vivo, with implications for the human diseases caused by ADAR mutations.
    Full-text · Article · Nov 2015 · Immunity
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    • "Thus, ADAR1 acts as a suppressor of interferon signaling and potentially protects the organism from interferon-induced damage. Interestingly, specific deletion of only the ADAR1-p150 isoform is sufficient to cause embryonic lethality and increased interferon signaling (Ward et al. 2011). Vitali and Scadden could show that double-stranded RNA containing I-U base pairs suppresses the induction of interferon-stimulated genes (Vitali and Scadden 2010). "
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    ABSTRACT: Adenosine to inosine editing (A to I editing) is a cotranscriptional process that contributes to transcriptome complexity by deamination of adenosines to inosines. Initially, the impact of A to I editing has been described for coding targets in the nervous system. Here, A to I editing leads to recoding and changes of single amino acids since inosine is normally interpreted as guanosine by cellular machines. However, more recently, new roles for A to I editing have emerged: Editing was shown to influence splicing and is found massively in Alu elements. Moreover, A to I editing is required to modulate innate immunity. We summarize the multiple ways in which A to I editing generates transcriptome variability and highlight recent findings in the field.
    Full-text · Article · Jul 2015 · Chromosoma
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    • "of ADAR1 p150 on measles virus propagation, illustrating the importance of whole-animal studies (Ward et al., 2011). Hepatitis C virus encodes a protease that cleaves MAVS, and it would be interesting to determine whether this virus or protease rescue aspects of Adar1 mutant phenotypes. "
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    ABSTRACT: The ADAR RNA-editing enzymes deaminate adenosine bases to inosines in cellular RNAs. Aberrant interferon expression occurs in patients in whom ADAR1 mutations cause Aicardi-Goutières syndrome (AGS) or dystonia arising from striatal neurodegeneration. Adar1 mutant mouse embryos show aberrant interferon induction and die by embryonic day E12.5. We demonstrate that Adar1 embryonic lethality is rescued to live birth in Adar1; Mavs double mutants in which the antiviral interferon induction response to cytoplasmic double-stranded RNA (dsRNA) is prevented. Aberrant immune responses in Adar1 mutant mouse embryo fibroblasts are dramatically reduced by restoring the expression of editing-active cytoplasmic ADARs. We propose that inosine in cellular RNA inhibits antiviral inflammatory and interferon responses by altering RLR interactions. Transfecting dsRNA oligonucleotides containing inosine-uracil base pairs into Adar1 mutant mouse embryo fibroblasts reduces the aberrant innate immune response. ADAR1 mutations causing AGS affect the activity of the interferon-inducible cytoplasmic isoform more severely than the nuclear isoform.
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