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PMID: 25456137 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Cell reports ·Vol. 9 ·No. 4 ·2014-11-20 ·Pages 1482-94

Mannion NM, Greenwood SM, Young R, Cox S, Brindle J, Read D, Nellåker C, Vesely C, Ponting CP, McLaughlin PJ, Jantsch MF, Dorin J, Adams IR, Scadden AD, Ohman M, Keegan LP, O'Connell MA

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.

MeSH Terms
Adaptor Proteins, Signal Transducing/genetics Adenosine Deaminase/genetics,metabolism Animals Autoimmune Diseases of the Nervous System/genetics,immunology Crosses, Genetic Cytokines/metabolism Embryo Loss/pathology Embryo, Mammalian/pathology Female Fibroblasts/metabolism Humans Immunity, Innate Inflammation Mediators/metabolism Inosine/metabolism Liver/metabolism Male Mice, Inbred C57BL Mutation/genetics Nervous System Malformations/genetics,immunology Phenotype RNA Editing RNA, Double-Stranded/metabolism RNA-Binding Proteins/genetics,metabolism Receptors, Interferon/metabolism Survival Analysis Transcription, Genetic Tumor Suppressor Protein p53/metabolism Uracil/metabolism
Chemicals
Adaptor Proteins, Signal Transducing Cytokines IPS-1 protein, mouse Inflammation Mediators RNA, Double-Stranded RNA-Binding Proteins Receptors, Interferon Tumor Suppressor Protein p53 Uracil Inosine ADAR protein, human ADAR1 protein, mouse Adenosine Deaminase
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Mannion Niamh M
MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
Greenwood Sam M
MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
Young Robert
MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
Cox Sarah
MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
Brindle James
MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
Read David
MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
Nellåker Christoffer
MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.
Vesely Cornelia
Department of Chromosome Biology, Max F. Perutz Laboratories, University of Vienna, Dr. Bohr-Gasse 9/5, 1030 Vienna, Austria.
Ponting Chris P
MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.
McLaughlin Paul J
Institute of Structural and Molecular Biology, Michael Swann Building, School of Biological Sciences, Kings Buildings, West Mains Road, Edinburgh EH9 3JG, UK.
Jantsch Michael F
Department of Chromosome Biology, Max F. Perutz Laboratories, University of Vienna, Dr. Bohr-Gasse 9/5, 1030 Vienna, Austria.
Dorin Julia
MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
Adams Ian R
MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
Scadden A D J
Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
Ohman Marie
Department of Molecular Biosciences, Wenner Gren Institute, Stockholm University, 106 91 Stockholm, Sweden.
Keegan Liam P
MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK. Electronic address: [email protected].
O'Connell Mary A
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: [email protected].
Supplementary Concepts
Aicardi-Goutieres syndrome (Disease)
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Article Info
Journal
Cell reports
Abbr.
Cell Rep
ISSN
2211-1247
DOI
10.1016/j.celrep.2014.10.041
Email
[email protected]
[email protected]
Published
2014-11-20
Epub
2014-00-13
Pages
1482-94
Language
English
Region
United States
NLM ID
101573691
PMCID
PMC4542304
Subset
IM
Grants
Medical Research Council · MC_UU_12021/1 · United Kingdom
Medical Research Council · MC_PC_U127580973 · United Kingdom
Medical Research Council · MC_U137761446 · United Kingdom
Medical Research Council · MC_U127584490 · United Kingdom
Medical Research Council · MC_PC_U127597124 · United Kingdom
Medical Research Council · MC_PC_U127527201 · United Kingdom
Medical Research Council · MC_PC_U127584490 · United Kingdom
Databases
GEO
GSE62917
External Links
PubMed source DOI: 10.1016/j.celrep.2014.10.041 PMC Full Text View journal details
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