S6K-STING interaction regulates cytosolic DNA-mediated activation of the transcription factor IRF3.
S6K-STING interaction regulates cytosolic DNA-mediated activation of the transcription factor IRF3.
复制标题
S6K刺激相互作用调节胞质DNA介导的转录因子IRF3的激活。
DOI：
10.1038/ni.3433
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发表时间：
2016-05
影响因子：
30.5
通讯作者：
Lichty BD
中科院分区：
文献类型：
--
作者：
Wang F;Alain T;Szretter KJ;Stephenson K;Pol JG;Atherton MJ;Hoang HD;Fonseca BD;Zakaria C;Chen L;Rangwala Z;Hesch A;Chan ESY;Tuinman C;Suthar MS;Jiang Z;Ashkar AA;Thomas G;Kozma SC;Gale M Jr;Fitzgerald KA;Diamond MS;Mossman K;Sonenberg N;Wan Y;Lichty BD
细胞质 DNA 介导的转录因子 IRF3 激活是宿主抗病毒反应的关键事件。在这里，我们发现 DNA 病毒的感染以 cGAS（cGAMP 合酶）依赖性方式诱导 mTOR 下游效应器 S6K1（S6 激酶 1）和信号适配器 STING 的相互作用。我们进一步证明，S6K1-STING 相互作用需要激酶结构域，而不是 S6K1 的激酶功能，并且 TBK1 关键地促进了这一过程。 S6K1-STING-TBK1 三联复合物的形成是 IRF3 激活所必需的，而该信号轴的破坏会损害 IRF3 靶基因的早期表达以及 T 细胞反应和粘膜抗病毒免疫的诱导。因此，我们的结果揭示了细胞质 DNA 途径中 IRF3 激活的基本调节机制。
Cytosolic DNA-mediated activation of the transcription factor IRF3 is a key event in host antiviral responses. Here, we show that infection of DNA viruses induced the interaction of the mTOR downstream effector S6K1 (S6 kinase 1) and the signaling adaptor STING in a cGAS (cGAMP synthase)-dependent manner. We further demonstrate that the kinase domain, but not the kinase function of S6K1, was required for the S6K1-STING interaction and that the TBK1 critically promotes this process. The formation of a tripartite S6K1-STING-TBK1 complex was necessary for IRF3 activation and disruption of this signaling axis impaired the early-phase expression of IRF3 target genes and the induction of T cell responses and mucosal antiviral immunity. Thus, our results have uncovered a fundamental regulatory mechanism for IRF3 activation in the cytosolic DNA pathway.