Group B Streptococcus Degrades Cyclic-di-AMP to Modulate STING-Dependent Type I Interferon Production.
Group B Streptococcus Degrades Cyclic-di-AMP to Modulate STING-Dependent Type I Interferon Production.
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DOI：
10.1016/j.chom.2016.06.003
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发表时间：
2016-07-13
影响因子：
30.3
通讯作者：
Kaminski PA
中科院分区：
文献类型：
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作者：
Andrade WA;Firon A;Schmidt T;Hornung V;Fitzgerald KA;Kurt-Jones EA;Trieu-Cuot P;Golenbock DT;Kaminski PA
响应于微生物病原体的I型干扰素的诱导依赖于保守的cGAS-STING信号传导途径。细胞质中DNA的存在激活cGAS，而STING被cGAS或细菌来源产生的环状二核苷酸（cdN）激活。在这里，我们表明，B族链球菌（GBS）诱导IFN-β的生产几乎完全通过cGAS-STING依赖性识别细菌DNA。然而，我们发现GBS表达外核苷酸酶CdnP，其水解细胞外细菌环二AMP。CdnP的失活导致c-di-AMP在细菌外积累并增加IFN-β的产生。体内较高的IFN-β水平增加宿主对GBS的杀伤。在不存在CdnP的情况下观察到的IFN-β过量产生是由于cGAS的DNA传感和c-di-AMP的STING依赖性传感的累积效应。这些发现描述了细菌c-di-AMP外核苷酸酶的重要性，并提出了抑制cGAS-STING轴激活的直接细菌机制。I型IFN的诱导对于控制B族链球菌（GBS）感染是重要的。Andrade等人表明，GBS感染引起的I型干扰素诱导依赖于cGAS/STING途径。GBS表达外核苷酸酶，其降解由GBS产生的c-di-AMP并减少细胞外c-di-AMP，从而抑制I型IFN应答。
Induction of type I interferon in response to microbial pathogens depends on a conserved cGAS-STING signaling pathway. The presence of DNA in the cytoplasm activates cGAS, while STING is activated by cyclic dinucleotides (cdNs) produced by cGAS or from bacterial origins. Here, we show that Group B Streptococcus (GBS) induces IFN-β production almost exclusively through cGAS-STING-dependent recognition of bacterial DNA. However, we find that GBS expresses an ectonucleotidase, CdnP, which hydrolyzes extracellular bacterial cyclic-di-AMP. Inactivation of CdnP leads to c-di-AMP accumulation outside the bacteria and increased IFN-β production. Higher IFN-β levels in vivo increase GBS killing by the host. The IFN-β overproduction observed in the absence of CdnP is due to the cumulative effect of DNA sensing by cGAS and STING-dependent sensing of c-di-AMP. These findings describe the importance of a bacterial c-di-AMP ectonucleotidase and suggest a direct bacterial mechanism that dampens activation of the cGAS-STING axis. Type I IFN induction is important to control Group B Streptococcus (GBS) infection. Andrade et al. show that type I interferon induction by GBS infection depends on the cGAS/STING pathway. GBS expresses an ectonucleotidase that degrades c-di-AMP produced by GBS and reduces extracellular c-di-AMP, thus dampening type I IFN responses.