Second messenger 2′3′-cyclic GMP–AMP (2′3′-cGAMP): Synthesis, transmission, and degradation

Su, Mincun; Zheng, Jianpei; Gan, Linchuan; Zhao, Yuxiang; Fu, Yajuan; Chen, Qi

doi:10.1016/j.bcp.2022.114934

Cited by 12 publications

(10 citation statements)

References 122 publications

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“…In addition, the unique 2′-5′- phosphodiester linkage might be a defense mechanism of eukaryotic cells that allows them to avoid subversion of the innate immune response by bacteria because bacterial cells might not be able to degrade 2′-5′ phosphodiester linkages ( 22 ). As seen with other CDNs, 2′,3′-cGAMP also has potential applications as an adjuvant ( 28 ). All CDNs can bind and stimulate the STING signaling pathway in eukaryotic cells, but 2′,3′-cGAMP binds to mammalian sting with a much greater affinity than bacterial CDNs because of their different phosphodiester linkage positions ( 27 , 29 ).…”

Section: Introductionmentioning

confidence: 86%

Intranasal Immunization With a c-di-GMP-Adjuvanted Acellular Pertussis Vaccine Provides Superior Immunity Against Bordetella pertussis in a Mouse Model

Jiang

Wang

et al. 2022

Front. Immunol.

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Pertussis, caused by the gram-negative bacterium Bordetella pertussis, is a highly contagious respiratory disease. Intranasal vaccination is an ideal strategy to prevent pertussis, as the nasal mucosa represents the first-line barrier to B. pertussis infection. The current intramuscular acellular pertussis (aP) vaccines elicit strong antibody and Th2-biased responses but not necessary cellular and mucosal immunity. Here, we formulated two cyclic dinucleotide (CDN)-adjuvanted aP subunit vaccines, a mammalian 2’,3’-cGAMP-adjuvanted aP vaccine and a bacterial-derived c-di-GMP-adjuvanted aP vaccine, and evaluated their immunogenicity in a mouse model. We found that the aP vaccine alone delivered intranasally (IN) induced moderate systemic and mucosal humoral immunity but weak cellular immunity, whereas the alum-adjuvanted aP vaccine administered intraperitoneally elicited higher Th2 and systemic humoral immune responses but weaker Th1 and Th17 and mucosal immune responses. In contrast, both CDN-adjuvanted aP vaccines administered via the IN route induced robust humoral and cellular immunity systemically and mucosally. Furthermore, the c-di-GMP-adjuvanted aP vaccine generated better antibody production and stronger Th1 and Th17 responses than the 2′,3′-cGAMP-adjuvanted aP vaccine. In addition, following B. pertussis challenge, the group of mice that received IN immunization with the c-di-GMP-adjuvanted aP vaccine showed better protection than all other groups of vaccinated mice, with decreased inflammatory cell infiltration in the lung and reduced bacterial burden in both the upper and lower respiratory tracts. In summary, the c-di-GMP-adjuvanted aP vaccine can elicit a multifaceted potent immune response resulting in robust bacterial clearance in the respiratory tract, which indicates that c-di-GMP can serve as a potential mucosal adjuvant for the pertussis vaccine.

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Section: Introductionmentioning

confidence: 86%

Intranasal Immunization With a c-di-GMP-Adjuvanted Acellular Pertussis Vaccine Provides Superior Immunity Against Bordetella pertussis in a Mouse Model

Jiang

Wang

et al. 2022

Front. Immunol.

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“…Furthermore, c-di-GMP-activated STING demonstrates promising immunotherapeutic efficacy in breast cancer ( Chandra et al, 2014 ), whereas c-di-GMP-loaded peptide nanotubes enhance immunotherapy for melanoma ( Zhang et al, 2022c ). As an endogenous member of the cGAS-STING signalling pathway, cGAMP exhibits significant potential as a STING agonist in anti-tumour therapy, as CAR-T cells generated using cGAMP display enhanced anti-tumour capacity in breast cancer ( Xu et al, 2021 ; Su et al, 2022 ). Similarly, cGAMP enhances the anti-tumour activity of CAR-NK cells in pancreatic cancer ( Da et al, 2022 ).…”

Section: Anti-cancer Effects Of Sting Agonistsmentioning

confidence: 99%

Targeting the stimulator of interferon genes (STING) in breast cancer

et al. 2023

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Breast cancer has a high occurrence rate globally and its treatment has demonstrated clinical efficacy with the use of systemic chemotherapy and immune checkpoint blockade. Insufficient cytotoxic T lymphocyte infiltration and the accumulation of immunosuppressive cells within tumours are the primary factors responsible for the inadequate clinical effectiveness of breast cancer treatment. The stimulator of interferon genes (STING) represents a pivotal protein in the innate immune response. Upon activation, STING triggers the activation and enhancement of innate and adaptive immune functions, resulting in therapeutic benefits for malignant tumours. The STING signalling pathway in breast cancer is influenced by various factors such as deoxyribonucleic acid damage response, tumour immune microenvironment, and mitochondrial function. The use of STING agonists is gaining momentum in breast cancer research. This review provides a comprehensive overview of the cyclic guanosine monophosphate-adenosine monophosphate synthase-STING pathway, its agonists, and the latest findings related to their application in breast cancer.

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“…In both in vitro cell-based infection and in mice infected with Herpes simplex virus 2 (HSV-2), local and systemic delivery of 2′3′ cGAMP induced strong IFN-I and ISG production. Of note, 2′3′ cGAMP showed stronger antiviral effect with respect to TLR agonists [ 119 , 120 , 121 ]. However, despite their strong IFN induction, CDNs are not suitable for drug therapy because of their poor membrane permeability and metabolic instability [ 29 , 122 ].…”

Section: Sting Agonists As Broad-spectrum Antiviralsmentioning

confidence: 99%

Unlocking STING as a Therapeutic Antiviral Strategy

Paulis

Tramontano

2023

IJMS

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Invading pathogens have developed weapons that subvert physiological conditions to weaken the host and permit the spread of infection. Cells, on their side, have thus developed countermeasures to maintain cellular physiology and counteract pathogenesis. The cyclic GMP-AMP (cGAMP) synthase (cGAS) is a pattern recognition receptor that recognizes viral DNA present in the cytosol, activating the stimulator of interferon genes (STING) protein and leading to the production of type I interferons (IFN-I). Given its role in innate immunity activation, STING is considered an interesting and innovative target for the development of broad-spectrum antivirals. In this review, we discuss the function of STING; its modulation by the cellular stimuli; the molecular mechanisms developed by viruses, through which they escape this defense system; and the therapeutical strategies that have been developed to date to inhibit viral replication restoring STING functionality.

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Second messenger 2′3′-cyclic GMP–AMP (2′3′-cGAMP): Synthesis, transmission, and degradation

Cited by 12 publications

References 122 publications

Intranasal Immunization With a c-di-GMP-Adjuvanted Acellular Pertussis Vaccine Provides Superior Immunity Against Bordetella pertussis in a Mouse Model

Intranasal Immunization With a c-di-GMP-Adjuvanted Acellular Pertussis Vaccine Provides Superior Immunity Against Bordetella pertussis in a Mouse Model

Targeting the stimulator of interferon genes (STING) in breast cancer

Unlocking STING as a Therapeutic Antiviral Strategy

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