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

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DOI

  • K L Jønsson
  • A Laustsen
  • C Krapp
  • K A Skipper
  • K Thavachelvam
  • D Hotter, Ulm University Medical Center, Institute of Molecular Virology, Meyerhofstr. 1, Ulm 89081, Germany.
  • ,
  • J H Egedal
  • M Kjolby
  • P Mohammadi, Department of Systems Biology, Columbia University, 1130 St Nicholas Avenue, New York City, New York 10032, USA.
  • ,
  • T Prabakaran
  • L K Sørensen
  • C Sun, Aarhus Research Centre of Innate Immunology, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.
  • ,
  • S B Jensen, Aarhus Research Centre of Innate Immunology, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.
  • ,
  • C K Holm
  • Robert Jan Lebbink, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584 CX, Netherlands.
  • ,
  • M Johannsen
  • M Nyegaard
  • J G Mikkelsen
  • F Kirchhoff, Ulm University Medical Center, Institute of Molecular Virology, Meyerhofstr. 1, Ulm 89081, Germany.
  • ,
  • S R Paludan
  • M R Jakobsen

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.

Original languageEnglish
Article number14391
JournalNature Communications
Volume8
ISSN2041-1723
DOIs
Publication statusPublished - 10 Feb 2017

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