AbstractThe cyclic GMP-AMP synthase-stimulator of the interferon gene (cGAS-STING) signaling pathway is considered an essential pattern recognition and effector pathway in the natural immune system and is mainly responsible for recognizing DNA molecules present in the cytoplasm and activating downstream signaling pathways to generate type I interferons (IFN-I) and other inflammatory factors.

摘要干扰素基因的环状GMP-AMP合酶刺激因子（cGAS-STING）信号通路被认为是天然免疫系统中必不可少的模式识别和效应通路，主要负责识别细胞质中存在的DNA分子并激活下游信号通路以产生I型干扰素（IFN-I）和其他炎症因子。

STING, a crucial junction protein in the innate immune system, exerts an essential role in host resistance to external pathogen invasion. The DNA introduced by pathogens or tumors is recognized by the cytoplasmic nucleic acid receptor cGAS, and a second messenger, cGAMP, is generated using intracellular guanosine triphosphate (GTP) and adenosine triphosphate (ATP).

STING是先天免疫系统中的关键连接蛋白，在宿主抵抗外部病原体入侵中发挥重要作用。病原体或肿瘤引入的DNA被细胞质核酸受体cGAS识别，第二信使cGAMP使用细胞内三磷酸鸟苷（GTP）和三磷酸腺苷（ATP）产生。

Furthermore, cellular and extracellular cGAMP concentrations are also controlled by ENPP1, an enzyme that breaks down cGAMP to AMP and GMP. Therefore, the role of the cGAS-STING signaling pathway has generated great interest in inflammatory and cancer research. To advance our understanding of innate immune system and in particular the STING pathway, we have developed a homogeneous, bioluminescent cGAMP detection assay that is very sensitive and highly selective against other nucleotides, cyclic nucleotides, and dicyclic nucleotides.

此外，细胞和细胞外cGAMP浓度也受ENPP1控制，ENPP1是一种将cGAMP分解为AMP和GMP的酶。因此，cGAS-STING信号通路的作用引起了炎症和癌症研究的极大兴趣。为了增进我们对先天免疫系统，特别是STING途径的理解，我们开发了一种均质的生物发光cGAMP检测方法，该方法对其他核苷酸，环核苷酸和双环核苷酸非常敏感且具有高度选择性。

The assay can be also used to monitor the activity of cGAS and ENPP1 to enable the development of inhibitors of both enzymes which might be used for therapeutic applications..

该测定法还可用于监测cGAS和ENPP1的活性，以开发可能用于治疗应用的两种酶的抑制剂。。

IntroductionThe discovery of the cGAS-STING pathway and its key messenger 2′,3′-cyclic GMP-AMP (cGAMP) has revolutionized our understanding of cellular defense mechanisms. cGAMP acts as a critical link between the detection of DNA in the cytoplasm and the activation of the STING (STimulator of INterferon Genes) pathway, leading to the production of type I interferons and other inflammatory cytokines1,2,3,4,5,6.

引言cGAS-STING途径及其关键信使2'，3'-环GMP-AMP（cGAMP）的发现彻底改变了我们对细胞防御机制的理解。cGAMP是细胞质中DNA检测与STING（干扰素基因刺激因子）途径激活之间的关键环节，导致产生I型干扰素和其他炎性细胞因子1,2,3,4,5,6。

This pathway is vital not only for antiviral defense but also has implications in autoinflammatory diseases, cancer biology, and vaccine development7,8,9,10,11,12,13,14.Recent studies have expanded our knowledge of cGAMP’s synthesis, structure, and mechanism of action. The elucidation of cGAMP’s structure has provided insights into its unique cyclic dinucleotide (CDN) scaffold, which is crucial for its binding and activation of STING.

该途径不仅对抗病毒防御至关重要，而且对自身炎症性疾病，癌症生物学和疫苗开发也有影响7,8,9,10,11,12,13,14。最近的研究扩展了我们对cGAMP合成，结构和作用机制的了解。cGAMP结构的阐明为其独特的环状二核苷酸（CDN）支架提供了见解，这对于其结合和激活STING至关重要。

Additionally, research has delved into the intricacies of how cGAMP is transported between cells, influencing immune signaling in a paracrine and autocrine manner15,16,17,18.A newly recognized function of STING is that it acts as an ion channel, where upon its activation and translocation to the Golgi apparatus, STING serves as a direct mediator for proton release into the cytosol.

此外，研究已经深入研究了cGAMP如何在细胞之间运输的复杂性，以旁分泌和自分泌的方式影响免疫信号传导[15,16,17,18]。STING的一个新发现的功能是它作为离子通道，在激活和易位到高尔基体时，STING作为质子释放到细胞质中的直接介质。

This unique function allows STING to translate danger signals into ion flow within the cell. STING is the first human immune sensor known to have this ion channel activity19. The proton leakage from the Golgi body is associated with non-canonical LC3B lipidation and NLRP3 inflammasome activation. Hence, it has generated interest in exploring how this ion channel activity affects immune responses and cellular processes.

这种独特的功能允许STING将危险信号转化为细胞内的离子流。。高尔基体的质子泄漏与非经典LC3B脂化和NLRP3炎性体激活有关。因此，人们对探索这种离子通道活性如何影响免疫反应和细胞过程产生了兴趣。

Thus, STING’s dual role as an immune sensor and ion channel adds complexity to our understanding of innate immunity. This finding warrants.

因此，STING作为免疫传感器和离子通道的双重作用增加了我们对先天免疫的理解的复杂性。这一发现值得肯定。

Data availability

数据可用性

The authors will make data available upon reasonable request and my contact information is “said.goueli@promega.com”.

作者将在合理要求下提供数据，我的联系信息是“said.goueli@promega.com“。

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Download referencesAcknowledgementsThe authors acknowledge the financial support by Promega Corp. The authors acknowledge the generous gift of cGAMP antibodies provided by Takeda Pharmaceuticals to develop cGAMP Lumit assay.Author informationAuthors and AffiliationsPromega Corporation, 2800 Woods Hollow Road, Madison, WI, 53711, USAKevin Hsiao, Nathan H.

下载参考文献致谢作者感谢Promega Corp.的财务支持。作者感谢武田制药提供的cGAMP抗体的慷慨礼物，用于开发cGAMP-Lumit分析。作者信息作者和附属机构罗米加公司，美国威斯康星州麦迪逊伍兹空心路2800号，53711 Kevin Hsiao，Nathan H。

Murray, Dareen Mikheil & Said A. GoueliPromega Corporation, 277 Granada Drive, San Luis Obispo, CA, 93401, USAMatthew A. Larsen, Hui Wang & Tim UgoAuthorsKevin HsiaoView author publicationsYou can also search for this author in.

Murray，Dareen Mikheil＆Said A.GoueliPromega Corporation，277 Granada Drive，San Luis Obispo，CA，93401，USAMATHEW A.Larsen，Hui Wang＆Tim UgoAuthorsKevin HsiaoView作者出版物您也可以在中搜索这位作者。

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PubMed Google ScholarContributionsKH performed experiments and prepared the figures, ML, HW, and TU developed the tracers and verified their chemical sytucture. NM and DM also verified the validity of the recombinant antibodies used in these studies. SG initiated this project and provided guidance for implementation of the experiments proposed in this project.

。NM和DM还验证了这些研究中使用的重组抗体的有效性。SG启动了该项目，并为该项目中提出的实验的实施提供了指导。

All authors were involved in editing and proofreading the manuscript before submission.Corresponding authorCorrespondence to.

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Reprints and permissionsAbout this articleCite this articleHsiao, K., Murray, N.H., Mikheil, D. et al. Homogeneous and bioluminescent biochemical and cellular assay for monitoring cGAMP and enzymes that generate and degrade cGAMP.

转载和许可本文引用本文Hsiao，K.，Murray，N.H.，Mikheil，D。等人。用于监测cGAMP和产生和降解cGAMP的酶的均相和生物发光生化和细胞测定。

Sci Rep 14, 31165 (2024). https://doi.org/10.1038/s41598-024-82525-1Download citationReceived: 11 October 2024Accepted: 05 December 2024Published: 28 December 2024DOI: https://doi.org/10.1038/s41598-024-82525-1Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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KeywordscGAMPSTINGcGASENPP1HomogeneousBioluminescence

关键词cgampstingcgasenpp1均质或生物发光