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Double-stranded RNAs containing multiple IU pairs are sufficient to suppress interferon induction and apoptosis

Nature Structural & Molecular Biology volume 17, pages 1043–1050 (2010)Cite this article

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Abstract

Adenosine deaminases acting on RNA (ADARs) catalyze hyperediting of long double-stranded RNAs (dsRNAs), whereby up to 50% of adenosines are converted to inosine (I). Although hyperedited dsRNAs (IU-dsRNAs) have been implicated in various cellular functions, we now provide evidence for another role. We show that IU-dsRNA suppresses the induction of interferon-stimulated genes (ISGs) and apoptosis by poly(IC). Moreover, we show that IU-dsRNA inhibits the activation of interferon regulatory factor 3 (IRF3), which is essential for the induction of ISGs and apoptosis. Finally, we speculate that the inhibition of IRF3 results from specific binding of IU-dsRNA to MDA-5 or RIG-I, both of which are cytosolic sensors for poly(IC). Although our data are consistent with a previous study in which ADAR1 deletion resulted in increased expression of ISGs and apoptosis, we show that IU-dsRNA per se suppresses ISGs and apoptosis. We therefore propose that any IU-dsRNA generated by ADAR1 can inhibit both pathways.

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Figure 1: IU-dsRNA suppressed induction of ISGs.
Figure 2: IU-dsRNA suppressed induction of ISGs by poly(IC).
Figure 3: Genes involved in immunity and defense were enriched.
Figure 4: Microarray validation by RT-qPCR.
Figure 5: Poly(IC)-induced apoptosis is inhibited by C-IU dsRNA.
Figure 6: C-IU dsRNA inhibits IRF3 activation.
Figure 7: IU-dsRNA binds specifically to MDA-5 and RIG-I.

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Change history

  • 24 August 2010

    In the version of this article initially published online, there was a formatting error in the sequences shown in Table 1. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank C. Smith for helpful comments, J. Hiscott (McGill Univ.), J. De Miranda (Columbia Univ.) and S. Akira (Osaka Univ.) for reagents, R. Walker (Wellcome Trust Centre for Stem Cell Research) for FACS and E. Clemente and J. Bauer (Cambridge Genomic Services) for microarrays. This work was supported by the Wellcome Trust.

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  1. Department of Biochemistry, University of Cambridge, Cambridge, UK

    Patrice Vitali & A D J Scadden

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Contributions

A.D.J.S. designed the study; P.V. and A.D.J.S. performed the experiments and data analysis; A.D.J.S. prepared the manuscript.

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Correspondence to A D J Scadden.

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The authors declare no competing financial interests.

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Supplementary Figures 1–6, Supplementary Tables 1–4, Supplementary Methods (PDF 3546 kb)

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Vitali, P., Scadden, A. Double-stranded RNAs containing multiple IU pairs are sufficient to suppress interferon induction and apoptosis. Nat Struct Mol Biol 17, 1043–1050 (2010). https://doi.org/10.1038/nsmb.1864

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