Cyclic GMP-AMP Containing Mixed Phosphodiester Linkages Is An Endogenous High Affinity Ligand for STING

By Xu Zhang, Heping Shi, Jiaxi Wu, Xuewu Zhang, Lijun Sun, Chuo Chen, Zhijian J. Chen. Molecules and Cells, 2013

999 citations recorded by the source corpus.

The presence of microbial or self DNA in the cytoplasm of mammalian cells is a danger signal detected by the DNA sensor cyclic-GMP-AMP (cGAMP) synthase (cGAS), which catalyzes the production of cGAMP that in turn serves as a second messenger to activate innate immune responses. Here we show that endogenous cGAMP in mammalian cells contains two distinct phosphodiester linkages, one between 2′-OH of GMP and 5′-phosphate of AMP, and the other between 3′-OH of AMP and 5′-phosphate of GMP. This molecule, termed 2′3′-cGAMP, is unique in that it binds to the adaptor protein STING with a much greater affinity than cGAMP molecules containing other combinations of phosphodiester linkages. The crystal structure of STING bound to 2′3′-cGAMP revealed the structural basis of this high-affinity binding and a ligand-induced conformational change in STING that may underlie its activation.

Subfields: Immunology, Infectious Diseases, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/a47a7c039b7291fa3fa63600069ccbe244293de5

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Zhijian J. Chen
2. S. Tait
3. Joel S. Riley
4. A. Ablasser
5. Y. Chiu
6. Xin Cai
7. yang-xin fu
8. R. Weichselbaum

In Infectious Diseases

1. S. Tait
2. Joel S. Riley
3. A. Ablasser
4. Xin Cai
5. P. Jat
6. R. Kumari
7. Zhijian J. Chen

In Public Health, Environmental and Occupational Health

1. Zhijian J. Chen

Citations in the corpus

• STING-dependent Cytosolic DNA Sensing Promotes Radiation-induced Type I interferon-dependent Antitumor Immunity in Immunogenic Tumors (2014, background): “…andRadiation Synergistically Amplify the Antitumor Immune Response It has been demonstrated that 2030-cGAMP (cyclic [G(20,50) pA(30,50)p]) is generated inmammalian cells by cGAS in response to double-stranded DNA in the cytoplasm (Gao et al., 2013a; Wu et al., 2013; Zhang et al., 2013).”
• The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. (2014, background): “Similarly, 2030-cGAMP binding induced a large conformational change of wild-type human STING (Figure 2B) (Gao et al., 2013c; Zhang et al., 2013).”
• Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity (2015, background): “IFN-b is the signature cytokine induced in response to activating STING, by either exogenous CDNs produced by bacterial infection or through binding of a structurally distinct endogenous CDN produced by a host cyclic GMPAMP synthetase (cGAS) in response to sensing cytosolic double-stranded DNA (dsDN”
• Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021, background): “Since SAHFs are not seen in all senescent cells, it seems that they are cell type and stimulus dependent (Kennedy et al., 2010; Di Micco et al., 2011; Aird and Zhang, 2013; Criscione et al., 2016; Zirkel et al., 2018).”
• Cyclic GMP-AMP Synthase is Activated by Double-stranded DNA-Induced Oligomerization (2013, background): “Even though two structures of 20,50 cGAMP bound to STING have been reported (Gao et al., 2013b; Zhang et al., 2013), the electron density observed in these studies corresponds to the average electron density of 20,50 cGAMP in two distinct orientations.”
• STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade (2015, background): “The noncanonical mixed linkage (ML) has been reported to increase the binding affinity for hSTING by at least 10-fold (34), resulting in a 20-Å ligand-induced conformational shift of the STING homodimer (35).”