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The methyltransferase PRMT6 attenuates antiviral innate immunity by blocking TBK1–IRF3 signaling

Cellular & Molecular Immunology volume 16, pages 800–809 (2019)Cite this article

A Correction to this article was published on 27 November 2019

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Abstract

Protein arginine methyltransferases (PRMTs) play diverse biological roles and are specifically involved in immune cell development and inflammation. However, their role in antiviral innate immunity has not been elucidated. Viral infection triggers the TBK1–IRF3 signaling pathway to stimulate the production of type-I interferon, which mediates antiviral immunity. We performed a functional screen of the nine mammalian PRMTs for regulators of IFN-β expression and found that PRMT6 inhibits the antiviral innate immune response. Viral infection also upregulated PRMT6 protein levels. We generated PRMT6-deficient mice and found that they exhibited enhanced antiviral innate immunity. PRMT6 deficiency promoted the TBK1–IRF3 interaction and subsequently enhanced IRF3 activation and type-I interferon production. Mechanistically, viral infection enhanced the binding of PRMT6 to IRF3 and inhibited the interaction between IRF3 and TBK1; this mechanism was independent of PRMT6 methyltransferase activity. Thus, PRMT6 inhibits antiviral innate immunity by sequestering IRF3, thereby blocking TBK1-IRF3 signaling. Our work demonstrates a methyltransferase-independent role for PRMTs. It also identifies a negative regulator of the antiviral immune response, which may protect the host from the damaging effects of an overactive immune system and/or be exploited by viruses to escape immune detection.

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  • 27 November 2019

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

This work was supported by grants from the National Key R&D program of China (2018YFA0507401), National Natural Science Foundation of China (31390431, 31522019, 81471568, 80178104, and 31770945), and the CAMS Innovation Fund for Medical Sciences (2016-12M-1-003). We thank Ms. Xiaofei Li for technical assistance and Life Science Editors for editing assistance.

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  1. These authors contributed equally: Hua Zhang, Chaofeng Han.

Authors and Affiliations

  1. National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China

    Hua Zhang, Chaofeng Han, Tianliang Li, Nan Li & Xuetao Cao

  2. Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China

    Xuetao Cao

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  1. Hua Zhang
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X.C. designed and supervised the study. H.Z., C.H., T.L., and N.L. performed the experiments. H.Z., C.H., and X.C. analyzed the data and wrote the paper.

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Correspondence to Xuetao Cao.

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Zhang, H., Han, C., Li, T. et al. The methyltransferase PRMT6 attenuates antiviral innate immunity by blocking TBK1–IRF3 signaling. Cell Mol Immunol 16, 800–809 (2019). https://doi.org/10.1038/s41423-018-0057-4

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