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The RNA helicase DDX46 inhibits innate immunity by entrapping m6A-demethylated antiviral transcripts in the nucleus

Nature Immunology volume 18, pages 10941103 (2017) | Download Citation

  • A Corrigendum to this article was published on 16 November 2017

This article has been updated

Abstract

DEAD-box (DDX) helicases are vital for the recognition of RNA and metabolism and are critical for the initiation of antiviral innate immunity. Modification of RNA is involved in many biological processes; however, its role in antiviral innate immunity has remained unclear. Here we found that nuclear DDX member DDX46 inhibited the production of type I interferons after viral infection. DDX46 bound Mavs, Traf3 and Traf6 transcripts (which encode signaling molecules involved in antiviral responses) via their conserved CCGGUU element. After viral infection, DDX46 recruited ALKBH5, an 'eraser' of the RNA modification N6-methyladenosine (m6A), via DDX46's DEAD helicase domain to demethylate those m6A-modified antiviral transcripts. It consequently enforced their retention in the nucleus and therefore prevented their translation and inhibited interferon production. DDX46 also suppressed antiviral innate immunity in vivo. Thus, DDX46 inhibits antiviral innate responses by entrapping selected antiviral transcripts in the nucleus by erasing their m6A modification, a modification normally required for export from the nucleus and translation.

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Change history

  • 20 September 2017

    In the version of this article initially published, the label 'siDDX46' in the key to Figure 5g is incorrect. That label should read 'siALKBH5'. The error has been corrected in the HTML and PDF versions of this article.

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Acknowledgements

We thank T. Fang, M. Jin and Y. Li for technical assistance; X. Liu, C. Han, S. Xu, Y. Han and T. Chen for discussions; and the SIDANSAI Biotechnology Company (Shanghai, China) for helping to generate Ddx46+/− mice. Supported by the National Key Basic Research Program of China (2013CB530503 and 2012CB518900), the National Natural Science Foundation of China (31390431, 81422037 and 81671564) and the CAMS Innovation Fund for Medical Sciences (2016-12M-1-003).

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Author notes

    • Qingliang Zheng
    •  & Jin Hou

    These authors contributed equally to this work.

Affiliations

  1. Department of Immunology & Center for Immunotherapy, CAMS-Oxford University International Center for Translational Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.

    • Qingliang Zheng
    •  & Xuetao Cao
  2. National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China.

    • Jin Hou
    • , Ye Zhou
    • , Zhenyang Li
    •  & Xuetao Cao

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Contributions

Q.Z., J.H., Y.Z., and Z.L. performed the experiments; Q.Z., J.H. and X.C. analyzed data and wrote the paper; and X.C. designed and supervised the research.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Xuetao Cao.

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https://doi.org/10.1038/ni.3830

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