Department of Cell & Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.
Department of Cell & Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.
Cytokine Growth Factor Rev. 2020 Oct;55:1-14. doi: 10.1016/j.cytogfr.2020.06.004. Epub 2020 Jun 6.
Rapid detection of microbes is crucial for eliciting an effective immune response. Innate immune receptors survey the intracellular and extracellular environment for signs of a microbial infection. When they detect a pathogen-associated molecular pattern (PAMP), such as viral DNA, they alarm the cell about the ongoing infection. The central signaling hub in sensing of viral DNA is the stimulator of interferon genes (STING). Upon activation, STING induces downstream signaling events that ultimately result in the production of type I interferons (IFN I), important cytokines in antimicrobial defense, in particular towards viruses. In this review, we describe the molecular features of STING, including its upstream sensors and ligands, its sequence and structural conservation, common polymorphisms, and its localization. We further highlight how STING activation requires a careful balance: its activity is essential for antiviral defense, but unwanted activation through mutations or accidental recognition of self-derived DNA causes autoinflammatory diseases. Several mechanisms, such as post-translational modifications, ensure this balance by fine-tuning STING activation. Finally, we discuss how viruses evade detection of their genomes by either exploiting cells that lack a functional DNA sensing pathway as a niche or by interfering with STING activation through viral evasion molecules. Insight into STING's exact mechanisms in health and disease will guide the development of novel clinical interventions for microbial infections, autoinflammatory diseases, and beyond.
快速检测微生物对于引发有效的免疫反应至关重要。先天免疫受体检测细胞内和细胞外环境中是否存在微生物感染的迹象。当它们检测到病原体相关分子模式（PAMP），如病毒 DNA 时，它们会向细胞发出正在发生感染的警报。在检测病毒 DNA 方面，中央信号枢纽是干扰素基因刺激物（STING）。STING 被激活后，会诱导下游信号事件，最终导致 I 型干扰素（IFN I）的产生，这是抗菌防御中重要的细胞因子，特别是针对病毒。在这篇综述中，我们描述了 STING 的分子特征，包括其上游传感器和配体、序列和结构保守性、常见的多态性以及其定位。我们进一步强调了 STING 激活需要精细的平衡：它的活性对于抗病毒防御至关重要，但通过突变或意外识别自身衍生的 DNA 导致的不受控制的激活会引起自身炎症性疾病。几种机制，如翻译后修饰，通过微调 STING 激活来确保这种平衡。最后，我们讨论了病毒如何通过利用缺乏功能性 DNA 感应途径的细胞作为小生境，或通过病毒逃逸分子干扰 STING 激活来逃避其基因组的检测。深入了解 STING 在健康和疾病中的确切机制将指导针对微生物感染、自身炎症性疾病等的新型临床干预措施的开发。
