PDF(Pubmed)
Abstract：
The cGAS/STING sensor system drives innate immune responses to intracellular microbial double-stranded DNA (dsDNA) and bacterial cyclic nucleotide second messengers (e.g., c-di-AMP). STING-dependent cell-intrinsic responses can increase resistance to microbial infection and speed pathogen clearance. Correspondingly, STING activation and signaling are known to be targeted for suppression by effectors from several bacterial pathogens. Whether STING responses are also positively regulated through sensing of specific bacterial effectors is less clear. We find that STING activation through dsDNA, by its canonical ligand 2\'-3\' cGAMP, or the small molecule DMXAA is potentiated following intracellular delivery of the AB5 toxin family member pertussis toxin from Bordetella pertussis or the B subunit of cholera toxin from Vibrio cholerae. Entry of pertussis toxin or cholera toxin B into mouse macrophages triggers markers of endoplasmic reticulum (ER) stress and enhances ligand-dependent STING responses at the level of STING receptor activation in a manner that is independent of toxin enzymatic activity. Our results provide an example in which STING responses integrate information about the presence of relevant ER-transiting bacterial toxins into the innate inflammatory response and may help to explain the in vivo adjuvant effects of catalytically inactive toxins.
摘要：
cGAS/STING传感器系统驱动对细胞内微生物双链DNA(dsDNA)和细菌环核苷酸第二信使(例如，c-di-AMP)。STING依赖性细胞内在反应可以增加对微生物感染的抗性并加速病原体清除。相应地,已知STING激活和信号传导是通过来自几种细菌病原体的效应子抑制的目标。STING应答是否也通过对特定细菌效应物的感知而被正调节尚不清楚。我们发现STING通过dsDNA激活，通过其典型配体2\'-3\'cGAMP，或小分子DMXAA在细胞内递送来自百日咳博德特氏菌的AB5毒素家族成员百日咳毒素或来自霍乱弧菌的霍乱毒素的B亚基后增强。百日咳毒素或霍乱毒素B进入小鼠巨噬细胞会触发内质网（ER）应激的标志物，并在STING受体激活水平上以独立于毒素酶活性的方式增强配体依赖性STING反应。我们的结果提供了一个例子，其中STING反应将有关相关ER转运细菌毒素的存在的信息整合到先天炎症反应中，并可能有助于解释无催化活性毒素的体内佐剂作用。
