Cell‐autonomous sensing of nucleic acids is essential for host defence against invading pathogens by inducing antiviral and inflammatory cytokines. cGAS has emerged in recent years as a non‐redundant DNA sensor important for detection of many viruses and bacteria. Upon binding to DNA, cGAS synthesises the cyclic dinucleotide 2′3′‐cGAMP that binds to the adaptor protein STING and thereby triggers IRF3‐ and NFκB‐dependent transcription. In addition to infection, the pathophysiology of an ever‐increasing number of sterile inflammatory conditions in humans involves the recognition of DNA through cGAS. Consequently, the cGAS/STING signalling axis has emerged as an attractive target for pharmacological modulation. However, the development of cGAS and STING inhibitors has just begun and a need for specific and effective compounds persists. In this review, we focus on cGAS and explore how its activation by immunostimulatory DNA is regulated by cellular mechanisms, viral immune modulators and small molecules. We further use our knowledge of cGAS modulation by cells and viruses to conceptualise potential new ways of pharmacological cGAS targeting.

中文翻译：

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DNA 传感器 cGAS 的调节和抑制


核酸的细胞自主传感对于宿主通过诱导抗病毒和炎症细胞因子防御入侵病原体至关重要。近年来，cGAS 成为一种非冗余 DNA 传感器，对于检测许多病毒和细菌非常重要。与 DNA 结合后，cGAS 合成环状二核苷酸 2'3'-cGAMP，该二核苷酸与接头蛋白 STING 结合，从而触发 IRF3 和 NFκB 依赖性转录。除了感染之外，人类中越来越多的无菌炎症状况的病理生理学涉及通过 cGAS 识别 DNA。因此，cGAS/STING 信号轴已成为药理学调节的一个有吸引力的目标。然而，cGAS 和 STING 抑制剂的开发才刚刚开始，仍然需要特定且有效的化合物。在这篇综述中，我们重点关注 cGAS，并探讨细胞机制、病毒免疫调节剂和小分子如何调节免疫刺激 DNA 对其的激活。我们进一步利用细胞和病毒对 cGAS 调节的知识来概念化药理学 cGAS 靶向的潜在新方法。