The innate immune DNA sensor cGAS produces a non-canonical cyclic-di-nucleotide that activates human STING

By Elie J. Diner, Dara L Burdette, Stephen C. Wilson, K. Monroe, C. A. Kellenberger, M. Hyodo, Y. Hayakawa, M. Hammond, R. Vance. Cell Reports, 2013

712 citations recorded by the source corpus.

SUMMARY The presence of foreign DNA in the cytosol of mammalian cells elicits a potent antiviral interferon response. Recently, cytosolic DNA was proposed to induce the synthesis of cyclic-GMP-AMP (cGAMP) upon binding to an enzyme called cGAMP synthase (cGAS). cGAMP activates an interferon response by binding to a downstream receptor called STING. Here we identify natural variants of human STING that are poorly responsive to cGAMP, yet unexpectedly, are normally responsive to DNA and cGAS signaling. We explain this paradox by demonstrating that the cGAS product is actually a non-canonical cyclic-di-nucleotide, cyclic[G(2′ -5′)pA(3′ -5′)p], which contains a single 2′ -5′ phosphodiester bond. Cyclic[G(2′ -5′)pA(3′ -5′)p] potently activates diverse human STING receptors and may therefore be a useful adjuvant or immunotherapeutic. Our results indicate that human STING variants have evolved that can distinguish conventional (3′ -5′) cyclic-di-nucleotides, known only to be produced by bacteria, from the non-canonical cyclic-di-nucleotide produced by mammalian cGAS.

Subfields: Immunology, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/82f552bdc2437c4c7e829c2e2ebb67b690f7af45

How researchers see this paper

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In Immunology

1. Zhijian J. Chen
2. A. Ablasser
3. Y. Chiu
4. Xin Cai
5. J. Rehwinkel
6. T. Gajewski
7. M. F. Gulen
8. G. Barber

In Infectious Diseases

1. A. Ablasser
2. Xin Cai
3. Zhijian J. Chen

Citations in the corpus

• Cyclic GMP-AMP Synthase is Activated by Double-stranded DNA-Induced Oligomerization (2013, background): “Consistent with this observation, others have shown that the product of cGAS is 20,50 cGAMP instead of 30,50 cGAMP (Ablasser et al., 2013; Diner et al., 2013; Gao et al., 2013a).”
• Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity (2015, background): “Cells expressing hSTINGREF responded poorly to stimulation with the bacterial CDN compounds cGAMP, CDA, and CDG but were responsive to the endogenously produced cGAS product, ML cGAMP (Diner et al., 2013).”
• The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. (2014, background): “Subsequent biophysical, structural, and cell-based analyses revealed that cGAS generated a unique cGAMP distinguishable from all other known CDNs (Ablasser et al., 2013a; Diner et al., 2013; Gao et al., 2013b; Zhang et al., 2013).”