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IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP

Author

Listed:
  • K. L. Jønsson

    (Aarhus University
    Aarhus Research Centre of Innate Immunology, Aarhus University)

  • A. Laustsen

    (Aarhus University
    Aarhus Research Centre of Innate Immunology, Aarhus University)

  • C. Krapp

    (Aarhus University
    Ulm University Medical Center, Institute of Molecular Virology)

  • K. A. Skipper

    (Aarhus University
    Aarhus Research Centre of Innate Immunology, Aarhus University)

  • K. Thavachelvam

    (Aarhus University
    Aarhus Research Centre of Innate Immunology, Aarhus University)

  • D. Hotter

    (Ulm University Medical Center, Institute of Molecular Virology)

  • J. H. Egedal

    (Aarhus University
    Aarhus Research Centre of Innate Immunology, Aarhus University)

  • M. Kjolby

    (Aarhus University
    The Danish Diabetes Academy supported by the Novo Nordisk Foundation, Aarhus University)

  • P. Mohammadi

    (New York Genome Center
    Columbia University)

  • T. Prabakaran

    (Aarhus University
    Aarhus Research Centre of Innate Immunology, Aarhus University)

  • L. K. Sørensen

    (Aarhus University Hospital)

  • C. Sun

    (Aarhus University
    Aarhus Research Centre of Innate Immunology, Aarhus University)

  • S. B. Jensen

    (Aarhus University
    Aarhus Research Centre of Innate Immunology, Aarhus University)

  • C. K. Holm

    (Aarhus University
    Aarhus Research Centre of Innate Immunology, Aarhus University)

  • R. J. Lebbink

    (University Medical Center Utrecht)

  • M. Johannsen

    (Aarhus University Hospital)

  • M. Nyegaard

    (Aarhus University)

  • J. G. Mikkelsen

    (Aarhus University
    Aarhus Research Centre of Innate Immunology, Aarhus University)

  • F. Kirchhoff

    (Ulm University Medical Center, Institute of Molecular Virology)

  • S. R. Paludan

    (Aarhus University
    Aarhus Research Centre of Innate Immunology, Aarhus University)

  • M. R. Jakobsen

    (Aarhus University
    Aarhus Research Centre of Innate Immunology, Aarhus University)

Abstract

Innate immune activation by macrophages is an essential part of host defence against infection. Cytosolic recognition of microbial DNA in macrophages leads to induction of interferons and cytokines through activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Other host factors, including interferon-gamma inducible factor 16 (IFI16), have been proposed to contribute to immune activation by DNA. However, their relation to the cGAS-STING pathway is not clear. Here, we show that IFI16 functions in the cGAS-STING pathway on two distinct levels. Depletion of IFI16 in macrophages impairs cGAMP production on DNA stimulation, whereas overexpression of IFI16 amplifies the function of cGAS. Furthermore, IFI16 is vital for the downstream signalling stimulated by cGAMP, facilitating recruitment and activation of TANK-binding kinase 1 in STING complex. Collectively, our results suggest that IFI16 is essential for efficient sensing and signalling upon DNA challenge in macrophages to promote interferons and antiviral responses.

Suggested Citation

  • K. L. Jønsson & A. Laustsen & C. Krapp & K. A. Skipper & K. Thavachelvam & D. Hotter & J. H. Egedal & M. Kjolby & P. Mohammadi & T. Prabakaran & L. K. Sørensen & C. Sun & S. B. Jensen & C. K. Holm & R, 2017. "IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP," Nature Communications, Nature, vol. 8(1), pages 1-17, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14391
    DOI: 10.1038/ncomms14391
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    Cited by:

    1. Friederike L. Pennemann & Assel Mussabekova & Christian Urban & Alexey Stukalov & Line Lykke Andersen & Vincent Grass & Teresa Maria Lavacca & Cathleen Holze & Lila Oubraham & Yasmine Benamrouche & En, 2021. "Cross-species analysis of viral nucleic acid interacting proteins identifies TAOKs as innate immune regulators," Nature Communications, Nature, vol. 12(1), pages 1-22, December.

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