cGAS–STING signaling pathway in gastrointestinal inflammatory disease and cancers

Ke, Xinxin; Hu, Tao; Jiang, Mizu

doi:10.1096/fj.202101199r

Cited by 16 publications

(23 citation statements)

References 153 publications

(267 reference statements)

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“… 114 – 116 After binding to DNA, cGAS then exerts a catalytic role to promote the synthesis of the second messenger 2′3′-cyclic GMP–AMP (cGAMP). 117 , 118 Binding of 2′3′-cGAMP stimulates STING and promotes the translocation to the Golgi which acivates TANK-binding kinase 1 (TBK1). 115 , 119 , 120 TBK1 phosphorylates STING and promote the interferon regulatory factor 3 (IRF3) to translocate to the nucleus which triggers the expression of IFN-β gene.…”

Section: Rationale Of Irtmentioning

confidence: 99%

Radiotherapy combined with immunotherapy: the dawn of cancer treatment

Zhang

Liu

Chen

et al. 2022

Sig Transduct Target Ther

183

141

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Radiotherapy (RT) is delivered for purposes of local control, but can also exert systemic effect on remote and non-irradiated tumor deposits, which is called abscopal effect. The view of RT as a simple local treatment has dramatically changed in recent years, and it is now widely accepted that RT can provoke a systemic immune response which gives a strong rationale for the combination of RT and immunotherapy (iRT). Nevertheless, several points remain to be addressed such as the interaction of RT and immune system, the identification of the best schedules for combination with immunotherapy (IO), the expansion of abscopal effect and the mechanism to amplify iRT. To answer these crucial questions, we roundly summarize underlying rationale showing the whole immune landscape in RT and clinical trials to attempt to identify the best schedules of iRT. In consideration of the rarity of abscopal effect, we propose that the occurrence of abscopal effect induced by radiation can be promoted to 100% in view of molecular and genetic level. Furthermore, the “radscopal effect” which refers to using low-dose radiation to reprogram the tumor microenvironment may amplify the occurrence of abscopal effect and overcome the resistance of iRT. Taken together, RT could be regarded as a trigger of systemic antitumor immune response, and with the help of IO can be used as a radical and systemic treatment and be added into current standard regimen of patients with metastatic cancer.

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Section: Rationale Of Irtmentioning

confidence: 99%

Radiotherapy combined with immunotherapy: the dawn of cancer treatment

Zhang

Liu

Chen

et al. 2022

Sig Transduct Target Ther

183

141

View full text Add to dashboard Cite

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“…STING-dependent immunosurveillance plays a critical role in maintaining gastric mucosal homeostasis and regulating inflammatory responses with carcinogenic potential (Ke et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies demonstrate that in addition to detecting invading microbial threats, cGAS senses and responds to DNA damage and genomic instability (Cai et al, 2014;Ke et al, 2022).…”

Section: H Pylori Provokes Multiple Dna Surveillance Systems In a Cag...mentioning

confidence: 99%

“…Dysregulation of mucosal STING signaling can disrupt gut homeostasis and generate protumorigenic inflammatory microenvironments (Ke et al, 2022); however, the outcomes of STINGdependent immune surveillance within the context of gastric inflammation and infectionassociated carcinogenesis remain unresolved.…”

Section: Introductionmentioning

confidence: 99%

“…In turn, 2’3’-cGAMP stimulates the endoplasmic reticulum receptor STING ( st imulator of in terferon g enes) to elicit interferon (IFN) signaling and the production of multifarious inflammatory cytokines (Ishii et al, 2006; Ishikawa and Barber, 2008; Ishikawa et al, 2009; Stetson and Medzhitov, 2006; Sun et al, 2009; Zhong et al, 2008). Dysregulation of mucosal STING signaling can disrupt gut homeostasis and generate pro-tumorigenic inflammatory microenvironments (Ke et al, 2022); however, the outcomes of STING-dependent immune surveillance within the context of gastric inflammation and infection-associated carcinogenesis remain unresolved.…”

Section: Introductionmentioning

confidence: 99%

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Helicobacter pylori provokes STING immunosurveillance via trans-kingdom conjugation

Damke

Wood

Shaffer

2022

Preprint

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Recognition of foreign nucleic acids is an evolutionarily conserved mechanism by which the host detects microbial threats. Whereas some intracellular bacterial pathogens trigger DNA surveillance pathways following phagosomal membrane perturbation, mechanisms by which extracellular bacteria activate cytosolic nucleic acid reconnaissance systems remain unresolved. Here, we demonstrate that Helicobacter pylori exploits cag type IV secretion system (cag T4SS) activity to provoke STING signaling in gastric epithelial cells. We provide direct evidence that chromosomal fragments delivered to the host cell cytoplasm via trans-kingdom conjugation bind and activate the key DNA sensor cGMP-AMP synthase. To enable paracrine-like signal amplification, translocated H. pylori DNA is sorted into exosomes that stimulate DNA-sensing pathways in uninfected bystander cells. We show that DNA cargo is loaded into the cag T4SS apparatus in the absence of host cell contact to establish a ready-to-fire nanomachine and provide evidence that cag T4SS-dependent DNA translocation is mechanistically coupled to chromosomal replication and replichore decatenation. Collectively, these studies suggest that H. pylori evolved mechanisms to stimulate nucleic acid surveillance pathways that regulate both pro- and anti-inflammatory programs to facilitate chronic persistence in the gastric niche.

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Deletion of Cyclic GMP-AMP Synthase Aggravates Concanavalin A-Induced Acute Hepatic Injury by Facilitating Leukocyte Chemotaxis

Liu

et al. 2023

Inflammation

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Growing evidence demonstrates that cyclic GMP-AMP synthase (cGAS), as a cytosolic DNA sensor, is essential for activating innate immunity and regulating in ammatory response against cellular damage. However, its role in immune-mediated hepatitis remains unclear. Here by challenging the cGAS knockout (KO) and their littermate wide-type (WT) mice with intravenous ConA injection to induce acute immunemediated liver injury, we found that lack of cGAS drastically aggravated the ConA-induced liver damage, re ected by increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and ampli ed hepatic necrosis. The number of apoptotic hepatocytes was also signi cantly increased in the KO mice. RNA-sequencing analysis revealed that leukocyte chemotaxis and migration related genes were remarkably upregulated in the KO livers. Consistently, immuno uorescence assays illustrated that the in ltrating F4/80-positive macrophages, Ly6G-positive neutrophils, and CD3-positive T cells were all signi cantly increased in the KO liver sections. The hepatic expression of the pro-in ammatory genes was elevated as well. Supporting the in vivo ndings, knockdown of cGAS in cultured macrophages showed promoted migration potential and enhanced pro-in ammatory gene expression. These results collectively demonstrated that deletion of cGAS could accelerate ConA-induced acute liver injury, and its mechanism might be related to facilitating leukocyte chemotaxis and promoting liver in ammatory response.

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cGAS–STING signaling pathway in gastrointestinal inflammatory disease and cancers

Cited by 16 publications

References 153 publications

Radiotherapy combined with immunotherapy: the dawn of cancer treatment

Radiotherapy combined with immunotherapy: the dawn of cancer treatment

Helicobacter pylori provokes STING immunosurveillance via trans-kingdom conjugation

Deletion of Cyclic GMP-AMP Synthase Aggravates Concanavalin A-Induced Acute Hepatic Injury by Facilitating Leukocyte Chemotaxis

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