Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
Institut de Recherche en Infectiologie de Montpellier (IRIM) - CNRS UMR 9004, Université de Montpellier, Montpellier, France.
Front Immunol. 2023 May 23;14:1150705. doi: 10.3389/fimmu.2023.1150705. eCollection 2023.
2'3'-cGAMP is a key molecule in the cGAS-STING pathway. This cyclic dinucleotide is produced by the cytosolic DNA sensor cGAS in response to the presence of aberrant dsDNA in the cytoplasm which is associated with microbial invasion or cellular damage. 2'3'-cGAMP acts as a second messenger and activates STING, the central hub of DNA sensing, to induce type-I interferons and pro-inflammatory cytokines necessary for responses against infection, cancer or cellular stress. Classically, detection of pathogens or danger by pattern recognition receptors (PRR) was thought to signal and induce the production of interferon and pro-inflammatory cytokines in the cell where sensing occurred. These interferon and cytokines then signal in both an autocrine and paracrine manner to induce responses in neighboring cells. Deviating from this dogma, recent studies have identified multiple mechanisms by which 2'3'-cGAMP can travel to neighboring cells where it activates STING independent of DNA sensing by cGAS. This observation is of great importance, as the cGAS-STING pathway is involved in immune responses against microbial invaders and cancer while its dysregulation drives the pathology of a wide range of inflammatory diseases to which antagonists have been elusive. In this review, we describe the fast-paced discoveries of the mechanisms by which 2'3'-cGAMP can be transported. We further highlight the diseases where they are important and detail how this change in perspective can be applied to vaccine design, cancer immunotherapies and treatment of cGAS-STING associated disease.
2'3'-cGAMP 是 cGAS-STING 通路中的关键分子。这种环二核苷酸是由细胞质中的细胞质 DNA 传感器 cGAS 产生的，以响应细胞质中存在的异常双链 DNA，这与微生物入侵或细胞损伤有关。2'3'-cGAMP 作为第二信使激活 STING，即 DNA 感应的中心枢纽，诱导产生 I 型干扰素和促炎细胞因子，这些细胞因子对于对抗感染、癌症或细胞应激是必要的。经典地，模式识别受体（PRR）对病原体或危险的检测被认为是信号，并诱导发生感应的细胞中干扰素和促炎细胞因子的产生。这些干扰素和细胞因子然后以自分泌和旁分泌的方式信号传递，以诱导相邻细胞的反应。与这一教条背离的是，最近的研究已经确定了多种机制，通过这些机制 2'3'-cGAMP 可以转移到相邻的细胞中，在这些细胞中，cGAS 独立于 DNA 感应激活 STING。这一观察结果非常重要，因为 cGAS-STING 途径参与了对微生物入侵者和癌症的免疫反应，而其失调会导致广泛的炎症性疾病的病理，针对这些疾病的拮抗剂一直难以捉摸。在这篇综述中，我们描述了 2'3'-cGAMP 可以被转运的机制的快速发现。我们进一步强调了它们在重要疾病中的作用，并详细说明了这种观点的转变如何应用于疫苗设计、癌症免疫疗法和 cGAS-STING 相关疾病的治疗。
