IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP.
IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP.
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DOI：
10.1038/ncomms14391
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发表时间：
2017-02-10
影响因子：
16.6
通讯作者：
Jakobsen MR
中科院分区：
文献类型：
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作者：
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
巨噬细胞的天然免疫激活是宿主防御感染的重要组成部分。巨噬细胞中微生物DNA的胞质识别导致通过激活环GMP-AMP合酶（cGAS）和干扰素基因的刺激物（STING）诱导干扰素和细胞因子。其他宿主因子，包括干扰素-γ诱导因子16（IFI 16），已被认为有助于DNA的免疫激活。然而，它们与cGAS-STING通路的关系尚不清楚。在这里，我们表明IFI 16在两个不同的水平上在cGAS-STING通路中发挥作用。巨噬细胞中IFI 16的缺失会损害DNA刺激下cGAMP的产生，而IFI 16的过表达会增强cGAS的功能。此外，IFI 16对于cGAMP刺激的下游信号传导至关重要，促进STING复合物中TANK结合激酶1的募集和活化。总的来说，我们的研究结果表明，IFI 16是必不可少的有效传感和信号后，DNA的挑战，在巨噬细胞，以促进干扰素和抗病毒反应。IFI 16作为DNA传感器的作用是非常有争议的。在来自Almine等人的Nature Communications背靠背出版物的支持下，作者在这里提供了IFI 16通过人类巨噬细胞中的cGAS-STING途径进行DNA传感所需的功能证据。
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. The role of IFI16 as a DNA sensor is highly controversial. With support from a Nature Communications back-to-back publication from Almine et al. the authors here provide functional evidence that IFI16 is required for DNA sensing via the cGAS-STING pathway in human macrophages.