Molecular mechanisms and cellular functions of cGAS-STING signalling
- PMID: 32424334
- DOI: 10.1038/s41580-020-0244-x
Molecular mechanisms and cellular functions of cGAS-STING signalling
Abstract
The cGAS-STING signalling axis, comprising the synthase for the second messenger cyclic GMP-AMP (cGAS) and the cyclic GMP-AMP receptor stimulator of interferon genes (STING), detects pathogenic DNA to trigger an innate immune reaction involving a strong type I interferon response against microbial infections. Notably however, besides sensing microbial DNA, the DNA sensor cGAS can also be activated by endogenous DNA, including extranuclear chromatin resulting from genotoxic stress and DNA released from mitochondria, placing cGAS-STING as an important axis in autoimmunity, sterile inflammatory responses and cellular senescence. Initial models assumed that co-localization of cGAS and DNA in the cytosol defines the specificity of the pathway for non-self, but recent work revealed that cGAS is also present in the nucleus and at the plasma membrane, and such subcellular compartmentalization was linked to signalling specificity of cGAS. Further confounding the simple view of cGAS-STING signalling as a response mechanism to infectious agents, both cGAS and STING were shown to have additional functions, independent of interferon response. These involve non-catalytic roles of cGAS in regulating DNA repair and signalling via STING to NF-κB and MAPK as well as STING-mediated induction of autophagy and lysosome-dependent cell death. We have also learnt that cGAS dimers can multimerize and undergo liquid-liquid phase separation to form biomolecular condensates that could importantly regulate cGAS activation. Here, we review the molecular mechanisms and cellular functions underlying cGAS-STING activation and signalling, particularly highlighting the newly emerging diversity of this signalling pathway and discussing how the specificity towards normal, damage-induced and infection-associated DNA could be achieved.
Similar articles
-
cGAS-mediated autophagy protects the liver from ischemia-reperfusion injury independently of STING.Am J Physiol Gastrointest Liver Physiol. 2018 Jun 1;314(6):G655-G667. doi: 10.1152/ajpgi.00326.2017. Epub 2018 Feb 15. Am J Physiol Gastrointest Liver Physiol. 2018. PMID: 29446653 Free PMC article.
-
Human plasmacytoid dentritic cells elicit a Type I Interferon response by sensing DNA via the cGAS-STING signaling pathway.Eur J Immunol. 2016 Jul;46(7):1615-21. doi: 10.1002/eji.201546113. Epub 2016 May 27. Eur J Immunol. 2016. PMID: 27125983 Free PMC article.
-
The cGAS-STING pathway: The role of self-DNA sensing in inflammatory lung disease.FASEB J. 2020 Oct;34(10):13156-13170. doi: 10.1096/fj.202001607R. Epub 2020 Aug 28. FASEB J. 2020. PMID: 32860267 Free PMC article. Review.
-
Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing.Nat Immunol. 2016 Sep 20;17(10):1142-9. doi: 10.1038/ni.3558. Nat Immunol. 2016. PMID: 27648547 Review.
-
Regulation of cGAS and STING signaling during inflammation and infection.J Biol Chem. 2023 Jul;299(7):104866. doi: 10.1016/j.jbc.2023.104866. Epub 2023 May 27. J Biol Chem. 2023. PMID: 37247757 Free PMC article. Review.
Cited by
-
Targeted Delivery of STING Agonist via Albumin Nanoreactor Boosts Immunotherapeutic Efficacy against Aggressive Cancers.Pharmaceutics. 2024 Sep 17;16(9):1216. doi: 10.3390/pharmaceutics16091216. Pharmaceutics. 2024. PMID: 39339252 Free PMC article.
-
Pentagalloylglucose alleviates acetaminophen-induced acute liver injury by modulating inflammation via cGAS-STING pathway.Mol Med. 2024 Sep 27;30(1):160. doi: 10.1186/s10020-024-00924-6. Mol Med. 2024. PMID: 39333876 Free PMC article.
-
Increasing intracellular dNTP levels improves prime editing efficiency.Nat Biotechnol. 2024 Sep 25. doi: 10.1038/s41587-024-02405-x. Online ahead of print. Nat Biotechnol. 2024. PMID: 39322763
-
Genomic investigation of innate sensing pathways in the tumor microenvironment.BMC Cancer. 2024 Sep 18;24(1):1157. doi: 10.1186/s12885-024-12944-w. BMC Cancer. 2024. PMID: 39289651 Free PMC article.
-
Multifaceted activation of STING axis upon Nipah and measles virus-induced syncytia formation.PLoS Pathog. 2024 Sep 16;20(9):e1012569. doi: 10.1371/journal.ppat.1012569. eCollection 2024 Sep. PLoS Pathog. 2024. PMID: 39283943 Free PMC article.
References
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials