Cyclic GMP-AMP Synthase Is an Innate Immune DNA Sensor for Mycobacterium tuberculosis

Collins, Angela C.; Cai, Haocheng; Li, Tuo; Franco, Luis H.; Li, Xiao Dong; Nair, Vidhya R.; Scharn, Caitlyn R.; Stamm, Chelsea E.; Levine, Beth; Chen, Zhijian J.; Shiloh, Michael U.

doi:10.1016/j.chom.2015.05.005

Cited by 315 publications

(311 citation statements)

References 41 publications

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“…STIN G gt/gt and cGAS −/− BMDMs were derived from corresponding knockout mice, and then cultured in M-CSF containing medium for 6-7days. THP-1 cells were purchased from ATCC and we established THP-1 cell lines stably expressing shRNA targeting hSTING and hcGAS as described before 38 . B16-OVA cells were kindly provided by Dr. Patrick Hwu at MD Anderson Cancer Center, TC-1 cells were kindly provided by Dr. T. C. Wu at John Hopkins University, MC38 cells were kindly provide by Dr. Yangxin Fu(UT Southwestern).…”

Section: Methodsmentioning

confidence: 99%

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A STING-activating nanovaccine for cancer immunotherapy

et al. 2017

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Generation of tumor-specific T cells is critically important for cancer immunotherapy1,2. A major challenge in achieving a robust T cell response is the spatio-temporal orchestration of antigen cross-presentation in antigen presenting cells (APCs) with innate stimulation. Here we report a minimalist nanovaccine by a simple physical mixture of an antigen with a synthetic polymeric nanoparticle, PC7A NP, which generated a strong cytotoxic T cell response with low systemic cytokine expression. Mechanistically, PC7A NP achieved efficient cytosolic delivery of tumor antigens to APCs in draining lymph nodes leading to increased surface presentation while simultaneously activating type I interferon-stimulated genes. This effect was dependent on STING but not Toll-like receptor or MAVS pathway. Nanovaccine produced potent tumor growth inhibition in melanoma, colon cancer, and human papilloma virus-E6/E7 tumor models. Combination of PC7A nanovaccine with an anti-PD-1 antibody showed great synergy with 100% survival over 60 days in a TC-1 tumor model. Rechallenging of these tumor-free animals with TC-1 cells led to complete inhibition of tumor growth, suggesting generation of long-term antitumor memory. The STING-activating nanovaccine offers a simple, safe and robust strategy in boosting anti-tumor immunity for cancer immunotherapy.

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Section: Methodsmentioning

confidence: 99%

“…Total RNAs were extracted by TRIzol (Invitrogen) from cells or tissues according to the manufacturer’s instructions. q-RT-PCR were performed as previously described 37,38 . Samples were run in triplicate.…”

Section: Methodsmentioning

confidence: 99%

A STING-activating nanovaccine for cancer immunotherapy

et al. 2017

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“…Although cGAS is the dominant DNA sensor responsible for activating the IFN pathways in response to infections by a variety of pathogens, including DNA viruses, retroviruses, and some bacteria such as Mycobacterium tuberculosis (13,(38)(39)(40)(41)(42)(43), the role of cGAS in autoimmune diseases has not been extensively investigated. Here we show that deletion of cGas in Trex1 −/− and DNaseII −/− mice rescued the lethal autoimmune phenotypes of these mice and prevented the accumulation of cGAMP and the expression of ISGs in the mutant animals.…”

Section: Significancementioning

confidence: 99%

Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases

Gao

et al. 2015

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

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TREX1 is an exonuclease that digests DNA in the cytoplasm. Loss-of-function mutations of TREX1 are linked to Aicardi–Goutieres Syndrome (AGS) and systemic lupus erythematosus (SLE) in humans. Trex1−/− mice exhibit autoimmune and inflammatory phenotypes that are associated with elevated expression of interferon (IFN)-induced genes (ISGs). Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates the IFN pathway. Upon binding to DNA, cGAS is activated to catalyze the synthesis of cGAMP, which functions as a second messenger that binds and activates the adaptor protein STING to induce IFNs and other cytokines. Here we show that genetic ablation of cGas in Trex1−/− mice eliminated all detectable pathological and molecular phenotypes, including ISG induction, autoantibody production, aberrant T-cell activation, and lethality. Even deletion of just one allele of cGas largely rescued the phenotypes of Trex1−/− mice. Similarly, deletion of cGas in mice lacking DNaseII, a lysosomal enzyme that digests DNA, rescued the lethal autoimmune phenotypes of the DNaseII−/− mice. Through quantitative mass spectrometry, we found that cGAMP accumulated in mouse tissues deficient in Trex1 or DNaseII and that this accumulation was dependent on cGAS. These results demonstrate that cGAS activation causes the autoimmune diseases in Trex1−/− and DNaseII−/− mice and suggest that inhibition of cGAS may lead to prevention and treatment of some human autoimmune diseases caused by self-DNA.

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“…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%