STING binds c-di-GMP

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Reaction [omitted]
Homo sapiens
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Cyclic di-GMP (c-di-GMP) and cyclic-di-AMP (c-di-AMP) are ubiquitous secondary messengers secreted by bacteria, but not by eukarya. UV cross-linking experiment with radiolabeled c-di-GMP in lysates of human embryonic kidney 293T (HEK293T) cells expressing mouse Sting showed that STING recognizes and directly binds to c-di-GMP [Burdette DL et al 2011]. STING was reported to contain multiple trans-membrane regions at its N-terminus while its C-terminal domain (CTD) is cytosolic. Mutational analysis showed that the CTD is responsible for the binding to c-di-GMP and this binding enhances the recruitment of TBK1 by STING [Ouyang S et al 2012]. Furthermore, a C-terminal tail (CTT) within the CTD interacts with and activates TBK1 and IRF3 [Tanaka Y and Chen ZJ 2012]. Impotantly, Sting is required for both c-di-GMP and c-di-AMP induced type I IFN production in mouse cultured macrophages infected with intracellular pathogens in vitro [Jin L et al 2011; Sauer JD et al 2011]. Low levels of STING protein expressed in human embryonic kidney (HEK293T) cells were sufficient to reconstitute the responsiveness of the cells to both c-di-GMP and c-di-AMP [Burdette DL et al 2011]. However, structural studies of STING revealed, that STING prefers c-di-GMP over c-di-AMP [Ouyang S et al 2012].

Several studies have demonstrated that human STING functions as a dimer and STING dimerization was essential for the induction of IFN response [Sun W et al 2009; Burdette DL et al 2011; Jin L et al 2011; Ouyang S et al 2012]. Mouse Sting/Myps has been also reported to exist as a dimer constitutively [Jin L et al 2008]. Moreover, STING can function as a ROS sensor, which forms a disulfide-linked homodimer under conditions of oxidative stress in HEK293T cells [Jin L et al 2010]. Structure analysis of the C-terminal domain in complex with c-di-GMP revealed that two STING molecules associate with one molecule of c-di-GMP [Ouyang S et al 2012; Yin Q et al 2012; Scu C et al 2012]. The STING dimer is thought to have a V-shaped structure, and the c-di-GMP binding site is located at the bottom of the V of the dimer interface [Scu C et al 2012]. Isothermal titration calorimetry (ITC) experiments confirmed the stoichiometry of STING to c-di-GMP as 2:1 with a binding dissociation constant (Kd) of ~2.4 microM [Yin Q et al 2012; Scu C et al 2012]. The data are consistent with a previous measurement of mouse STING CTD binding affinity to c-di-GMP using equilibrium dialysis [Burdette DL et al 2011]. Although STING is considered as a direct sensor of bacterial c-di-GMP, it is noteworthy, that the binding affinity of c-di-GMP to mammalian STING is much weaker than to bacterial sensors. For example, E.coli protein YcgR binds to c-di-GMP with a Kd of ~0.84 microM [Ryjenkov DA et al 2006]. Also taking into account that, the normal concentration of c-di-GMP in bacteria varies from 0.1~10 microM, it remains to be determined whether STING binds to c-di-GMP under physiological conditions.

Literature References
PubMed ID Title Journal Year
21947006 STING is a direct innate immune sensor of cyclic di-GMP

Burdette, DL, Eckert, B, Vance, RE, Hayakawa, Y, Iwig, JS, Sotelo-Troha, K, Hyodo, M, Monroe, KM

Nature 2011
16920715 The PilZ domain is a receptor for the second messenger c-di-GMP: the PilZ domain protein YcgR controls motility in enterobacteria

Ryjenkov, DA, Römling, U, Simm, R, Gomelsky, M

J. Biol. Chem. 2006
22728658 Structure of STING bound to cyclic di-GMP reveals the mechanism of cyclic dinucleotide recognition by the immune system

Kao, CC, Li, P, Watts, T, Yi, G, Shu, C

Nat. Struct. Mol. Biol. 2012
21098106 The N-ethyl-N-nitrosourea-induced Goldenticket mouse mutant reveals an essential function of Sting in the in vivo interferon response to Listeria monocytogenes and cyclic dinucleotides

Vance, RE, Brubaker, SW, Sauer, JD, Hayakawa, Y, Rae, CS, Sotelo-Troha, K, Hyodo, M, Monroe, KM, Portnoy, DA, von Moltke, J, Woodward, JJ

Infect. Immun. 2011
22705373 Cyclic di-GMP Sensing via the Innate Immune Signaling Protein STING

Yin, Q, Chen, ZJ, Wu, H, Tu, D, Eck, MJ, Tian, Y, Jiang, X, Kabaleeswaran, V

Mol. Cell 2012
19433799 ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization

Chen, D, Chen, H, Zhou, X, Zhou, Y, Zhai, Z, Jiang, Z, Chen, L, You, F, Li, Y, Sun, W

Proc. Natl. Acad. Sci. U.S.A. 2009
21170271 Cellular reactive oxygen species inhibit MPYS induction of IFN?

Lenz, LL, Jin, L, Cambier, JC

PLoS ONE 2010
22579474 Structural Analysis of the STING Adaptor Protein Reveals a Hydrophobic Dimer Interface and Mode of Cyclic di-GMP Binding

Parvatiyar, K, Cheng, G, Niu, F, Qiu, W, Zhu, Y, Shaw, N, Ru, H, Liu, ZJ, Wang, Y, Ouyang, S, Song, X, Zhang, R, Li, Y, Jiang, Y

Immunity 2012
22394562 STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway

Tanaka, Y, Chen, ZJ

Sci Signal 2012
18559423 MPYS, a novel membrane tetraspanner, is associated with major histocompatibility complex class II and mediates transduction of apoptotic signals

Jonscher, KR, Waterman, PM, Short, CM, Jin, L, Reisdorph, NA, Cambier, JC

Mol. Cell. Biol. 2008
21813776 MPYS is required for IFN response factor 3 activation and type I IFN production in the response of cultured phagocytes to bacterial second messengers cyclic-di-AMP and cyclic-di-GMP

Mogan, J, Knowles, H, Lenz, LL, Hill, KK, Filak, H, Zhang, B, Jin, L, Cambier, JC, Perraud, AL

J. Immunol. 2011
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