IFI16 and cGAS cooperate in the activation of STING during DNA sensing in human keratinocytes

Jessica F. Almine; Craig A. J. O'Hare; Gillian Dunphy; Ismar R. Haga; Rangeetha J. Naik; Abdelmadjid Atrih; Dympna J. Connolly; Jordan Taylor; Ian R. Kelsall; Andrew G. Bowie; Philippa M. Beard; Leonie Unterholzner

doi:10.1038/ncomms14392

IFI16 and cGAS cooperate in the activation of STING during DNA sensing in human keratinocytes

Jessica F. Almine, Craig A. J. O'Hare, Gillian Dunphy, Ismar R. Haga, Rangeetha J. Naik, Abdelmadjid Atrih, Dympna J. Connolly, Jordan Taylor, Ian R. Kelsall, Andrew G. Bowie, Philippa M. Beard, Leonie Unterholzner (Lead / Corresponding author)

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Abstract

Many human cells can sense the presence of exogenous DNA during infection though the cytosolic DNA receptor cyclic GMP-AMP synthase (cGAS), which produces the second messenger cyclic GMP-AMP (cGAMP). Other putative DNA receptors have been described, but whether their functions are redundant, tissue-specific or integrated in the cGAS-cGAMP pathway is unclear. Here we show that interferon-γ inducible protein 16 (IFI16) cooperates with cGAS during DNA sensing in human keratinocytes, as both cGAS and IFI16 are required for the full activation of an innate immune response to exogenous DNA and DNA viruses. IFI16 is also required for the cGAMP-induced activation of STING, and interacts with STING to promote STING phosphorylation and translocation. We propose that the two DNA sensors IFI16 and cGAS cooperate to prevent the spurious activation of the type I interferon response.

Original language	English
Article number	14392
Pages (from-to)	1-15
Number of pages	15
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14392
Publication status	Published - 13 Feb 2017

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Final published version, 2.48 MBLicence: CC BY

Elucidating the Molecular Mechanism of Intracellular DNA Recognition by the Innate Immune Sensor IFI16 (Career Development Fellowship)
Unterholzner, L. (Investigator) & Watts, C. (Investigator)
Medical Research Council
1/02/13 → 31/01/18
Project: Research

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title = "IFI16 and cGAS cooperate in the activation of STING during DNA sensing in human keratinocytes",

abstract = "Many human cells can sense the presence of exogenous DNA during infection though the cytosolic DNA receptor cyclic GMP-AMP synthase (cGAS), which produces the second messenger cyclic GMP-AMP (cGAMP). Other putative DNA receptors have been described, but whether their functions are redundant, tissue-specific or integrated in the cGAS-cGAMP pathway is unclear. Here we show that interferon-γ inducible protein 16 (IFI16) cooperates with cGAS during DNA sensing in human keratinocytes, as both cGAS and IFI16 are required for the full activation of an innate immune response to exogenous DNA and DNA viruses. IFI16 is also required for the cGAMP-induced activation of STING, and interacts with STING to promote STING phosphorylation and translocation. We propose that the two DNA sensors IFI16 and cGAS cooperate to prevent the spurious activation of the type I interferon response.",

author = "Almine, {Jessica F.} and O'Hare, {Craig A. J.} and Gillian Dunphy and Haga, {Ismar R.} and Naik, {Rangeetha J.} and Abdelmadjid Atrih and Connolly, {Dympna J.} and Jordan Taylor and Kelsall, {Ian R.} and Bowie, {Andrew G.} and Beard, {Philippa M.} and Leonie Unterholzner",

note = "The work was supported by the Medical Research Council (Career Development Award to L.U., MR/K00655X/1), the British Skin Foundation (Innovative Project Grant, 6057i), Tenovus Scotland (Ref. T14/14), the Biotechnology and Biological Sciences Research Council (BB/J004324/1), the National Institutes of Health (AI093752) and Science Foundation Ireland (11/PI/1056). C.A.J.O.H. and G.D. were supported through a Wellcome Trust ISSF grant and the MRC doctoral training program at the University of Dundee.",

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AU - Almine, Jessica F.

AU - O'Hare, Craig A. J.

AU - Dunphy, Gillian

AU - Haga, Ismar R.

AU - Naik, Rangeetha J.

AU - Atrih, Abdelmadjid

AU - Connolly, Dympna J.

AU - Taylor, Jordan

AU - Kelsall, Ian R.

AU - Bowie, Andrew G.

AU - Beard, Philippa M.

AU - Unterholzner, Leonie

N1 - The work was supported by the Medical Research Council (Career Development Award to L.U., MR/K00655X/1), the British Skin Foundation (Innovative Project Grant, 6057i), Tenovus Scotland (Ref. T14/14), the Biotechnology and Biological Sciences Research Council (BB/J004324/1), the National Institutes of Health (AI093752) and Science Foundation Ireland (11/PI/1056). C.A.J.O.H. and G.D. were supported through a Wellcome Trust ISSF grant and the MRC doctoral training program at the University of Dundee.

PY - 2017/2/13

Y1 - 2017/2/13

N2 - Many human cells can sense the presence of exogenous DNA during infection though the cytosolic DNA receptor cyclic GMP-AMP synthase (cGAS), which produces the second messenger cyclic GMP-AMP (cGAMP). Other putative DNA receptors have been described, but whether their functions are redundant, tissue-specific or integrated in the cGAS-cGAMP pathway is unclear. Here we show that interferon-γ inducible protein 16 (IFI16) cooperates with cGAS during DNA sensing in human keratinocytes, as both cGAS and IFI16 are required for the full activation of an innate immune response to exogenous DNA and DNA viruses. IFI16 is also required for the cGAMP-induced activation of STING, and interacts with STING to promote STING phosphorylation and translocation. We propose that the two DNA sensors IFI16 and cGAS cooperate to prevent the spurious activation of the type I interferon response.

AB - Many human cells can sense the presence of exogenous DNA during infection though the cytosolic DNA receptor cyclic GMP-AMP synthase (cGAS), which produces the second messenger cyclic GMP-AMP (cGAMP). Other putative DNA receptors have been described, but whether their functions are redundant, tissue-specific or integrated in the cGAS-cGAMP pathway is unclear. Here we show that interferon-γ inducible protein 16 (IFI16) cooperates with cGAS during DNA sensing in human keratinocytes, as both cGAS and IFI16 are required for the full activation of an innate immune response to exogenous DNA and DNA viruses. IFI16 is also required for the cGAMP-induced activation of STING, and interacts with STING to promote STING phosphorylation and translocation. We propose that the two DNA sensors IFI16 and cGAS cooperate to prevent the spurious activation of the type I interferon response.

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DO - 10.1038/ncomms14392

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IFI16 and cGAS cooperate in the activation of STING during DNA sensing in human keratinocytes

Abstract

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Elucidating the Molecular Mechanism of Intracellular DNA Recognition by the Innate Immune Sensor IFI16 (Career Development Fellowship)

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