STING is a direct innate immune sensor of cyclic di-GMP.
STING is a direct innate immune sensor of cyclic di-GMP.
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DOI：
10.1038/nature10429
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发表时间：
2011-09-25
期刊：
影响因子：
64.8
通讯作者：
Vance, Russell E.
中科院分区：
文献类型：
--
作者：
Burdette, Dara L.;Monroe, Kathryn M.;Sotelo-Troha, Katia;Iwig, Jeff S.;Eckert, Barbara;Hyodo, Mamoru;Hayakawa, Yoshihiro;Vance, Russell E.
先天免疫系统通过使用对保守微生物分子特异性的种系编码受体来检测感染。对微生物配体的识别导致细胞因子的产生，如I型干扰素（IFN），这是成功消除病原体所必需的。病原体来源DNA的细胞质检测是IFN诱导的主要机制之一，需要通过Tank Binding Kinase 1 （TBK1）及其下游转录因子干扰素调节因子3 （IRF3）发出信号。此外，一种名为STING（干扰素基因刺激因子，也称为MITA、ERIS、MPYS、TMEM173）的跨膜蛋白作为一种必要的信号适配器，将细胞内DNA检测与TBK1/IRF3信号轴连接起来。最近，被称为环二核苷酸的独特核酸，作为细菌中的保守信号分子，也被证明可以诱导sting依赖的I型干扰素反应。然而，哺乳动物的环二核苷酸传感器尚未被确定。在这里，我们报告证据表明STING本身是环二核苷酸的先天免疫传感器。我们证明了STING直接与放射性标记的环二胍酸单磷酸（c-di-GMP）结合，并且这种结合与未标记的环二核苷酸竞争，而不是与其他核苷酸或核酸竞争。此外，我们确定了选择性影响环状二核苷酸反应的STING突变，而不影响对DNA的反应。因此，除了在干扰素对细胞质DNA的反应中作为信号转接器的既定作用外，STING似乎还可以作为环二核苷酸的直接传感器。环二核苷酸作为新型疫苗佐剂和免疫疗法已显示出前景。我们的研究结果为先天免疫系统感知环二核苷酸的机制提供了深入的见解。
The innate immune system detects infection by employing germline-encoded receptors specific for conserved microbial molecules. Recognition of microbial ligands leads to the production of cytokines, such as type I interferons (IFN), that are essential for successful pathogen elimination. Cytosolic detection of pathogen-derived DNA is one major mechanism of IFN induction, and requires signaling via Tank Binding Kinase 1 (TBK1), and its downstream transcription factor, Interferon Regulatory Factor 3 (IRF3). In addition, a transmembrane protein called STING (STimulator of INterferon Genes; also called MITA, ERIS, MPYS, TMEM173) functions as an essential signaling adaptor linking cytosolic detection of DNA to the TBK1/IRF3 signaling axis. Recently, unique nucleic acids called cyclic dinucleotides, which function as conserved signaling molecules in bacteria, were also shown to induce a STING-dependent type I interferon response. However, a mammalian sensor of cyclic dinucleotides has not been identified. Here we report evidence that STING itself is an innate immune sensor of cyclic dinucleotides. We demonstrate that STING binds directly to radiolabelled cyclic diguanylate monophosphate (c-di-GMP) and that this binding is competed by unlabelled cyclic dinucleotides but not by other nucleotides or nucleic acids. Furthermore, we identify mutations in STING that selectively affect the response to cyclic dinucleotides without affecting the response to DNA. Thus, STING appears to function as a direct sensor of cyclic dinucleotides, in addition to its established role as a signaling adaptor in the interferon response to cytosolic DNA. Cyclic dinucleotides have shown promise as novel vaccine adjuvants and immunotherapeutics. Our results provide insight into the mechanism by which cyclic dinucleotides are sensed by the innate immune system.
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DOI：
10.1084/jem.20082874
发表时间：
2009-08-31
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
McWhirter SM;Barbalat R;Monroe KM;Fontana MF;Hyodo M;Joncker NT;Ishii KJ;Akira S;Colonna M;Chen ZJ;Fitzgerald KA;Hayakawa Y;Vance RE
通讯作者：
Vance RE
影响因子：
3.2
作者：
Simm, Roger;Remminghorst, Uwe;Romling, Ute
通讯作者：
Romling, Ute
影响因子：
4
作者：
Hyodo, M;Hayakawa, Y
通讯作者：
Hayakawa, Y
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
9.8
作者：
De N;Pirruccello M;Krasteva PV;Bae N;Raghavan RV;Sondermann H
通讯作者：
Sondermann H