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

Mannion, N. M. et al. (2014) The RNA-editing enzyme ADAR1 controls innate immune responses to RNA. Cell Reports, 9(4), pp. 1482-1494. (doi: 10.1016/j.celrep.2014.10.041) (PMID:25456137) (PMCID:PMC4542304)

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.

• Item Type: Articles
• Additional Information: This work was funded by the Medical Research Council.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Mannion, Dr Niamh and Young, Mr Robert
• Authors: Mannion, N. M., Greenwood, S. M., Young, R., Cox, S., Brindle, J., Read, D., Nellåker, C., Vesely, C., Ponting, C. P., McLaughlin, P. J., Jantsch, M. F., Dorin, J., Adams, I. R., Scadden, A.D.J., Ohman, M., Keegan, L. P., and O'Connell, M. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > MRC/CSO SPHSU
• Journal Name: Cell Reports
• Publisher: Elsevier (Cell Press)
• ISSN: 2211-1247
• ISSN (Online): 2211-1247
• Published Online: 13 November 2014
• Copyright Holders: Copyright © 2014 The Authors
• First Published: First published in Cell Reports 9(4): 1482-1494
• Publisher Policy: Reproduced under a Creative Commons License