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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    • "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.
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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.
    Cell Reports 11/2014; 9(4-4):1482-1494. DOI:10.1016/j.celrep.2014.10.041 · 8.36 Impact Factor
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    • "PKR activation correlates with reduced virus yield (Toth et al., 2009a), enhanced IFN induction (McAllister et al., 2010), formation of stress granules (Okonski and Samuel, 2013), and increased cytotoxicity and apoptosis (Toth et al., 2009b). ADAR1 deficiency leads to increased PKR activation (Toth et al., 2009b), enhanced IRF3 activation and increased IFN induction (Li et al., 2012; Ward et al., 2011), increased cytotoxicity (Toth et al., 2009b; Ward et al., 2011), and increased stress granule formation (Okonski and Samuel, 2013) in MV-infected cells. In contrast, ADAR1 sufficiency or overexpression leads to increased virus yields (Gelinas et al., 2011; Toth et al., 2009b), suppression of stress granule formation, PKR activation and IFN induction (Li et al., 2012; Okonski and Samuel, 2013) and suppression of apoptosis (Toth et al., 2009b). "
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    ABSTRACT: Measles virus (MV) deficient in C protein (Cko) expression efficiently induces both stress granules (SG) and interferon (IFNβ), whereas isogenic wild-type (WT) and V mutant (Vko) viruses do not. We therefore examined the effect of IFNβ pretreatment on SG formation, and the roles played by the IFN-inducible double-stranded (ds) RNA-dependent protein kinase (PKR) and dsRNA adenosine deaminase (ADAR1). SG formation in ADAR1-sufficient cells infected with WT or Vko mutant virus was enhanced by IFN treatment and was PKR-dependent. SG formation in Cko virus-infected cells was already high without IFN treatment and was not further enhanced by IFN. IFN treatment alone, in the absence of infection, induced SG formation in ADAR1-deficient but not ADAR1-sufficient cells. Type I IFN-induced enhancement in SG formation occurred by a canonical IFN signaling response dependent upon STAT1 and STAT2. These results further establish ADAR1 as a suppressor of the interferon and SG innate immune responses.
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