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

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IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP. / 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, Robert Jan; Johannsen, M; Nyegaard, M; Mikkelsen, J G; Kirchhoff, F; Paludan, S R; Jakobsen, M R.

In: Nature Communications, Vol. 8, 14391, 10.02.2017.

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@article{b287c9cf627d42af9adc12246d663f71,
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, {Robert Jan} and M Johannsen and M Nyegaard and Mikkelsen, {J G} and F Kirchhoff and Paludan, {S R} and Jakobsen, {M R}",
year = "2017",
month = "2",
day = "10",
doi = "10.1038/ncomms14391",
language = "English",
volume = "8",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

RIS

TY - JOUR

T1 - IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP

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, Robert Jan

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.

U2 - 10.1038/ncomms14391

DO - 10.1038/ncomms14391

M3 - Journal article

C2 - 28186168

VL - 8

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 14391

ER -