The Cytosolic DNA Sensor cGAS Forms an Oligomeric Complex with DNA and Undergoes Switch-like Conformational Changes in the Activation Loop

Zhang, Xu; Wu, Jiaxi; Du, Fenghe; Xu, Hui; Sun, Lijun; Chen, Zhe; Brautigam, Chad A.; Zhang, Xuewu; Chen, Zhijian J.

doi:10.1016/j.celrep.2014.01.003

Cited by 396 publications

(417 citation statements)

References 26 publications

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“…cGAS binds DNA by interactions with the sugar-phosphate backbone of both DNA strands along a positively charged platform of the protein flanked by a helical spine and a zinc thumb (18)(19)(20). In addition, cGAS has a second positively charged surface interacting with DNA, and crystal structures have revealed that cGAS forms 2:2 complexes with DNA (21,22). AIM2 belongs to the family of PYHIN proteins, consisting of a pyrin domain and one or two may come into contact with DNA sensors in the endosome through uptake via endosomal or autophagy pathways.…”

Section: Recognition Of Dnamentioning

confidence: 99%

Activation and Regulation of DNA-Driven Immune Responses

Paludan

2015

Microbiol Mol Biol Rev

110

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SUMMARY The innate immune system provides early defense against infections and also plays a key role in monitoring alterations of homeostasis in the body. DNA is highly immunostimulatory, and recent advances in this field have led to the identification of the innate immune sensors responsible for the recognition of DNA as well as the downstream pathways that are activated. Moreover, information on how cells regulate DNA-driven immune responses to avoid excessive inflammation is now emerging. Finally, several reports have demonstrated how defects in DNA sensing, signaling, and regulation are associated with susceptibility to infections or inflammatory diseases in humans and model organisms. In this review, the current literature on DNA-stimulated innate immune activation is discussed, and important new questions facing this field are proposed.

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Section: Recognition Of Dnamentioning

confidence: 99%

Activation and Regulation of DNA-Driven Immune Responses

Paludan

2015

Microbiol Mol Biol Rev

110

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“…After binding to cytosolic DNA, cGAS enzymatically generates cyclic dinucleotides (2′3′ cyclic GMP-AMP) that signal via the adaptor molecule stimulator of interferon genes (STING), with the signaling cascade thought to culminate primarily in the production of type I IFN (7,8,14). While cGAS has been demonstrated to affect T cell-independent B cell responses (15), the role of cGAS in driving the humoral response during infection is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

“…cGAS is a PRR that senses the presence of cytosolic DNA (7)(8)(9); it is important for initiating the host immune response to intracellular bacteria (10)(11)(12) and DNA viruses (13). After binding to cytosolic DNA, cGAS enzymatically generates cyclic dinucleotides (2′3′ cyclic GMP-AMP) that signal via the adaptor molecule stimulator of interferon genes (STING), with the signaling cascade thought to culminate primarily in the production of type I IFN (7,8,14).…”

Section: Introductionmentioning

confidence: 99%

cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

Hahn¹,

Butler²,

Lindner³

et al. 2018

JCI Insight

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“…Notably, 3′3′-cGAMP has been found to be produced by certain bacteria (13,14), whereas 2′2′-cGAMP and 3′2′-cGAMP have yet to be found in nature. Recent studies have revealed the molecular basis for the selective formation of the mixed 2′3′-phosphodiester linkages by cGAS (10,(14)(15)(16)(17)(18). However, the function of this linkage isomerism remained unclear and crystallographic studies of the STING/cGAMP complexes provided no insight (9,19).…”

mentioning

confidence: 99%

Molecular basis for the specific recognition of the metazoan cyclic GMP-AMP by the innate immune adaptor protein STING

Shi

Chen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cyclic GMP-AMP containing a unique combination of mixed phosphodiester linkages (2′3′-cGAMP) is an endogenous second messenger molecule that activates the type-I IFN pathway upon binding to the homodimer of the adaptor protein STING on the surface of endoplasmic reticulum membrane. However, the preferential binding of the asymmetric ligand 2′3′-cGAMP to the symmetric dimer of STING represents a physicochemical enigma. Here we show that 2′3′-cGAMP, but not its linkage isomers, adopts an organized free-ligand conformation that resembles the STING-bound conformation and pays low entropy and enthalpy costs in converting into the active conformation. Our results demonstrate that analyses of free-ligand conformations can be as important as analyses of protein conformations in understanding protein-ligand interactions.T he presence of cytosolic DNA in mammalian cells is a danger signal that triggers the production of second messenger cGAMP by the DNA sensor protein cyclic GMP-AMP synthase (cGAS) (1, 2). cGAMP then activates the adaptor protein stimulator of IFN genes (STING, also known as TMEM173, MITA, ERIS, or MPYS) and induces the translocation of STING from the endoplasmic reticulum membrane to the Golgi, where it then recruits IκB kinase and TANK-binding kinase 1 (3, 4). The transcription factors nuclear factor κB and IFN regulatory factor 3 are subsequently activated, leading to the production of antiviral and proinflammatory cytokines, including type I interferons (IFNs). This cGAMP-mediated immune response is a fundamental defense mechanism against viral infection (5-7), making cGAMP and its structural derivatives potential vaccine adjuvants and immunotherapeutic agents against cancer (6,8).cGAMP is a hybrid cyclic dinucleotide that contains a guanosine unit and an adenosine unit joined by two phosphates in a macrocycle (Fig. 1). In contrast with the well-known bacterial signaling molecules cyclic di-GMP (c-di-GMP) and cyclic di-AMP (c-di-AMP) that contain a pair of (3′→5′)-phosphodiester linkages, the endogenous cGAMP molecule in mammalian cells contains unprecedented mixed phosphodiester linkages (9-12). Its two phosphate groups connect the two nucleosides from the 2′-and 5′ positions of guanosine and the 3′-and 5′ positions of adenosine. Denoted as 2′3′-cGAMP, this asymmetric ligand binds to the symmetric dimer of STING with an affinity significantly higher than its linkage isomers 2′2′-cGAMP, 3′2′-cGAMP, and 3′3′-cGAMP (SI Appendix, Table S1) (9). Notably, 3′3′-cGAMP has been found to be produced by certain bacteria (13, 14), whereas 2′2′-cGAMP and 3′2′-cGAMP have yet to be found in nature. Recent studies have revealed the molecular basis for the selective formation of the mixed 2′3′-phosphodiester linkages by cGAS (10, 14-18). However, the function of this linkage isomerism remained unclear and crystallographic studies of the STING/cGAMP complexes provided no insight (9, 19). Here we show that the preferred binding of 2′3′-cGAMP originates from its favorable free-ligand instead of protein-bound conformatio...

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The Cytosolic DNA Sensor cGAS Forms an Oligomeric Complex with DNA and Undergoes Switch-like Conformational Changes in the Activation Loop

Cited by 396 publications

References 26 publications

Activation and Regulation of DNA-Driven Immune Responses

Activation and Regulation of DNA-Driven Immune Responses

cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

Molecular basis for the specific recognition of the metazoan cyclic GMP-AMP by the innate immune adaptor protein STING

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