Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Jan 18;44(1):183-218.
doi: 10.24272/j.issn.2095-8137.2022.464.

Current understanding of the cGAS-STING signaling pathway: Structure, regulatory mechanisms, and related diseases

Jing Pan  1   2   3 , Chen-Jie Fei  1   2   3 , Yang Hu  1   2   3 , Xiang-Yu Wu  1   2   3 , Li Nie  1   2   4 , Jiong Chen  1   2   5
Affiliations
Review

Current understanding of the cGAS-STING signaling pathway: Structure, regulatory mechanisms, and related diseases

Jing Pan et al. Zool Res. .

Abstract
in English, Chinese

The innate immune system protects the host from external pathogens and internal damage in various ways. The cGAS-STING signaling pathway, comprised of cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and downstream signaling adaptors, plays an essential role in protective immune defense against microbial DNA and internal damaged-associated DNA and is responsible for various immune-related diseases. After binding with DNA, cytosolic cGAS undergoes conformational change and DNA-linked liquid-liquid phase separation to produce 2'3'-cGAMP for the activation of endoplasmic reticulum (ER)-localized STING. However, further studies revealed that cGAS is predominantly expressed in the nucleus and strictly tethered to chromatin to prevent binding with nuclear DNA, and functions differently from cytosolic-localized cGAS. Detailed delineation of this pathway, including its structure, signaling, and regulatory mechanisms, is of great significance to fully understand the diversity of cGAS-STING activation and signaling and will be of benefit for the treatment of inflammatory diseases and cancer. Here, we review recent progress on the above-mentioned perspectives of the cGAS-STING signaling pathway and discuss new avenues for further study.

先天免疫系统是宿主免疫防御的第一道防线，其通过多种机制保护宿主抵御外源病原入侵及内源损伤。cGAS-STING信号通路是先天免疫的重要通路之一，其由环磷酸鸟苷-磷酸腺苷酸合成酶（cyclic GMP-AMP synthase, cGAS）、干扰素基因刺激物（stimulator of interferon gene，STING）和一系列下游信号转导接头分子及效应分子共同组成。cGAS是一种DNA感受器，在与DNA结合后，细胞质中的cGAS发生构象变化并由DNA介导聚集形成液-液相分离。随后，cGAS催化ATP和GTP合成第二信使2'3'-cGAMP，以激活定位于内质网（endoplasmic reticulum, ER）的STING，诱导STING转运并介导下游I型干扰素的产生。近年来研究发现，除了定位于细胞质发挥DNA识别受体的功能外，cGAS更主要在细胞核中表达，并被束缚于染色质以防止其与核DNA的结合，避免自身免疫疾病的发生。在功能上，核定位的cGAS与细胞质cGAS也具有较大差异。此外，cGAS-STING信号通路的异常也与多种疾病的发生密切相关。因此，对于cGAS-STING的结构，信号转导和调控机制方面的系统性探究，将更有助于我们深入了解该信号通路的活化和信号传递机制，并将为免疫相关疾病和肿瘤的治疗提供新的方向。基于此，该文详细综述了cGAS-STING信号通路目前的研究进展，并对其将来的研究方向提出展望。.

Keywords: Diseases; Post-translational modification; STING; Signaling; Structure; cGAS.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Structural basis of cGAS-STING-mediated DNA recognition and signal transduction
Figure 2
Figure 2
Domain composition of STING isoforms in different species
Figure 3
Figure 3
Cytoplasmic cGAS-STING signaling and nuclear cGAS function
Figure 4
Figure 4
Post-translational modifications of cGAS and STING
Figure 5
Figure 5
Autophagic processes involving cGAS-STING, adapted from Gui et al. (2019) with some modifications
Figure 6
Figure 6
cGAS-STING and related diseases
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Aarreberg LD, Esser-Nobis K, Driscoll C, Shuvarikov A, Roby JA, Gale M Jr Interleukin-1β induces mtDNA release to activate innate immune signaling via cGAS-STING. Molecular Cell. 2019;74(4):801–815.e6. doi: 10.1016/j.molcel.2019.02.038. - DOI - PMC - PubMed
    1. Abe T, Barber GN Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NF-κB activation through TBK1. Journal of Virology. 2014;88(10):5328–5341. doi: 10.1128/JVI.00037-14. - DOI - PMC - PubMed
    1. Ablasser A ReGLUation of cGAS. Nature Immunology. 2016;17(4):347–349. doi: 10.1038/ni.3397. - DOI - PubMed
    1. Aden K, Tran F, Ito G, Sheibani-Tezerji R, Lipinski S, Kuiper JW, et al ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS-STING. Journal of Experimental Medicine. 2018;215(11):2868–2886. doi: 10.1084/jem.20171029. - DOI - PMC - PubMed
    1. Ahn J, Barber GN Self-DNA, STING-dependent signaling and the origins of autoinflammatory disease. Current Opinion in Immunology. 2014;31:121–126. doi: 10.1016/j.coi.2014.10.009. - DOI - PubMed

Grants and funding

This work was supported by the Natural Science Foundation of Zhejiang Province (LY23C190002), National Natural Science Foundation of China (32173004), and Natural Science Foundation of Ningbo City (202003N4011)