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The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells

Nature Immunology volume 12, pages 959–965 (2011)Cite this article

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A Corrigendum to this article was published on 19 January 2012

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Abstract

The recognition of pathogenic DNA is important to the initiation of antiviral responses. Here we report the identification of DDX41, a member of the DEXDc family of helicases, as an intracellular DNA sensor in myeloid dendritic cells (mDCs). Knockdown of DDX41 expression by short hairpin RNA blocked the ability of mDCs to mount type I interferon and cytokine responses to DNA and DNA viruses. Overexpression of both DDX41 and the membrane-associated adaptor STING together had a synergistic effect in promoting Ifnb promoter activity. DDX41 bound both DNA and STING and localized together with STING in the cytosol. Knockdown of DDX41 expression blocked activation of the mitogen-activated protein kinase TBK1 and the transcription factors NF-κB and IRF3 by B-form DNA. Our results suggest that DDX41 is an additional DNA sensor that depends on STING to sense pathogenic DNA.

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Figure 1: DDX41 senses cytosolic DNA in mDCs.
Figure 2: Knockdown of DDX41 or STING in BMDCs abolishes their cytokine responses to DNA alone and DNA viruses.
Figure 3: Knockdown of DDX41 or STING in THP-1 cells abolishes their cytokine responses to DNA or HSV-1.
Figure 4: DDX41 interacts with DNA but not with RNA.
Figure 5: Recombinant DDX41 can 'rescue' the defect in DNA-activated production of interferon caused by knockdown of DDX41 via siRNA.
Figure 6: Interaction of DDX41 with STING.
Figure 7: The Walker motifs in DDX41 are essential for sensing DNA.
Figure 8: STING is the key adaptor for DDX41 signaling.

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Change history

  • 17 November 2011

    In the version of this article initially published, the sensor DDX41 was suggested to recognize Z-form DNA in addition to conventional B-form DNA. Although GC-rich DNA has the potential to adopt a left-handed Z-DNA conformation under conditions of high salt or ethanol, whether the GC-rich oligonucleotides used the original study actually adopted the Z-DNA conformation remains uncertain. Therefore, the article has been corrected throughout to reflect whether poly(dA:dT) or poly(dG:dC) was used to stimulate cells. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank M. Wentz and S. Watowich for critical reading; T. Zal for technical support with confocal microscopy; G. Cheng and K. Parvatiyar for suggestions on the experiments; and all colleagues in our laboratory.

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Authors and Affiliations

  1. Department of Immunology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Zhiqiang Zhang, Bin Yuan, Musheng Bao, Ning Lu, Taeil Kim & Yong-Jun Liu

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  1. Zhiqiang Zhang
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  2. Bin Yuan
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  3. Musheng Bao
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  4. Ning Lu
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  5. Taeil Kim
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  6. Yong-Jun Liu
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Contributions

Z.Z. designed and did most of experiments; B.Y., M.B., N.L. and T.K. helped with experiments; and Y.-J.L. designed the research and supervised the project.

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Correspondence to Yong-Jun Liu.

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The authors declare no competing financial interests.

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Supplementary Figures 1–7, Table 1 and Methods (PDF 470 kb)

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Zhang, Z., Yuan, B., Bao, M. et al. The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat Immunol 12, 959–965 (2011). https://doi.org/10.1038/ni.2091

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