Format

Send to

Choose Destination
Cell Rep. 2014 Nov 20;9(4):1482-94. doi: 10.1016/j.celrep.2014.10.041. Epub 2014 Nov 13.

The RNA-editing enzyme ADAR1 controls innate immune responses to RNA.

Author information

1
MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
2
MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.
3
Department of Chromosome Biology, Max F. Perutz Laboratories, University of Vienna, Dr. Bohr-Gasse 9/5, 1030 Vienna, Austria.
4
Institute of Structural and Molecular Biology, Michael Swann Building, School of Biological Sciences, Kings Buildings, West Mains Road, Edinburgh EH9 3JG, UK.
5
Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
6
Department of Molecular Biosciences, Wenner Gren Institute, Stockholm University, 106 91 Stockholm, Sweden.
7
MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK. Electronic address: liam.keegan@igmm.ed.ac.uk.
8
MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK; Department of Molecular Biosciences, Wenner Gren Institute, Stockholm University, 106 91 Stockholm, Sweden. Electronic address: mary.oconnell@igmm.ed.ac.uk.

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.

PMID:
25456137
PMCID:
PMC4542304
DOI:
10.1016/j.celrep.2014.10.041
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Supplementary concept, Secondary source ID, Grant support

Publication type

MeSH terms

Substances

Supplementary concept

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center