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

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. J. Lebbink; M. Johannsen; M. Nyegaard; J. G. Mikkelsen; F. Kirchhoff; S. R. Paludan; M. R. Jakobsen

doi:10.1038/ncomms14391

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

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. J. Lebbink, M. Johannsen, M. Nyegaard, J. G. Mikkelsen, F. Kirchhoff, S. R. PaludanM. R. Jakobsen

Research output: Contribution to journal › Article › peer-review

206 Scopus citations

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.

Original language	English (US)
Article number	14391
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14391
State	Published - Feb 10 2017
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Jønsson, K. L., Laustsen, A., Krapp, C., Skipper, K. A., Thavachelvam, K., Hotter, D., Egedal, J. H., Kjolby, M., Mohammadi, P., Prabakaran, T., Sørensen, L. K., Sun, C., Jensen, S. B., Holm, C. K., Lebbink, R. J., Johannsen, M., Nyegaard, M., Mikkelsen, J. G., Kirchhoff, F., ... Jakobsen, M. R. (2017). IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP. Nature communications, 8, Article 14391. https://doi.org/10.1038/ncomms14391

Jønsson, KL, Laustsen, A, Krapp, C, Skipper, KA, Thavachelvam, K, Hotter, D, Egedal, JH, Kjolby, M, Mohammadi, P, Prabakaran, T, Sørensen, LK, Sun, C, Jensen, SB, Holm, CK, Lebbink, RJ, Johannsen, M, Nyegaard, M, Mikkelsen, JG, Kirchhoff, F, Paludan, SR & Jakobsen, MR 2017, 'IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP', Nature communications, vol. 8, 14391. https://doi.org/10.1038/ncomms14391

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

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.",

author = "J{\o}nsson, {K. L.} and A. Laustsen and C. Krapp and Skipper, {K. A.} and K. Thavachelvam and D. Hotter and Egedal, {J. H.} and M. Kjolby and P. Mohammadi and T. Prabakaran and S{\o}rensen, {L. K.} and C. Sun and Jensen, {S. B.} and Holm, {C. K.} and Lebbink, {R. J.} and M. Johannsen and M. Nyegaard and Mikkelsen, {J. G.} and F. Kirchhoff and Paludan, {S. R.} and Jakobsen, {M. R.}",

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doi = "10.1038/ncomms14391",

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AU - Jønsson, K. L.

AU - Laustsen, A.

AU - Krapp, C.

AU - Skipper, K. A.

AU - Thavachelvam, K.

AU - Hotter, D.

AU - Egedal, J. H.

AU - Kjolby, M.

AU - Mohammadi, P.

AU - Prabakaran, T.

AU - Sørensen, L. K.

AU - Sun, C.

AU - Jensen, S. B.

AU - Holm, C. K.

AU - Lebbink, R. J.

AU - Johannsen, M.

AU - Nyegaard, M.

AU - Mikkelsen, J. G.

AU - Kirchhoff, F.

AU - Paludan, S. R.

AU - Jakobsen, M. R.

PY - 2017/2/10

Y1 - 2017/2/10

N2 - 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.

AB - 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.

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

Abstract

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