cGAS and cancer therapy: a double-edged sword

Du, Jiamin; Qian, Meijia; Yuan, Tao; Chen, Ruihan; He, Qiaojun; Yang, Bo; Ling, Qi; Zhu, Hong

doi:10.1038/s41401-021-00839-6

Cited by 21 publications

(17 citation statements)

References 103 publications

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“…cGAS is an unstructured, highly basic protein of approximately 160 amino acid amino-terminal (N-terminal) domain and a globular approximately 360 amino acid domain of 520 amino acid protein ( 4 , 27 , 28 ). The catalytic domain of cGAs consists of two structural lobes in which the active site is located ( 4 , 29 , 30 ).…”

Section: Biological Characteristics Of Cgas-sting Pathwaymentioning

confidence: 99%

Advances of MnO2 nanomaterials as novel agonists for the development of cGAS-STING-mediated therapeutics

Zhang

et al. 2023

Front. Immunol.

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As an essential micronutrient, manganese plays an important role in the physiological process and immune process. In recent decades, cGAS-STING pathway, which can congenitally recognize exogenous and endogenous DNA for activation, has been widely reported to play critical roles in the innate immunity against some important diseases, such as infections and tumor. Manganese ion (Mn2+) has been recently proved to specifically bind with cGAS and activate cGAS-STING pathway as a potential cGAS agonist, however, is significantly restricted by the low stability of Mn2+ for further medical application. As one of the most stable forms of manganese, manganese dioxide (MnO2) nanomaterials have been reported to show multiple promising functions, such as drug delivery, anti-tumor and anti-infection activities. More importantly, MnO2 nanomaterials are also found to be a potential candidate as cGAS agonist by transforming into Mn2+, which indicates their potential for cGAS-STING regulations in different diseased conditions. In this review, we introduced the methods for the preparation of MnO2 nanomaterials as well as their biological activities. Moreover, we emphatically introduced the cGAS-STING pathway and discussed the detailed mechanisms of MnO2 nanomaterials for cGAS activation by converting into Mn2+. And we also discussed the application of MnO2 nanomaterials for disease treatment by regulating cGAS-STING pathway, which might benefit the future development of novel cGAS-STING targeted treatments based on MnO2 nanoplatforms.

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Section: Biological Characteristics Of Cgas-sting Pathwaymentioning

confidence: 99%

Advances of MnO2 nanomaterials as novel agonists for the development of cGAS-STING-mediated therapeutics

Zhang

et al. 2023

Front. Immunol.

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Section: Intratumoral Activation Of Self-dna-reactive Cgas∆n Promotes...mentioning

confidence: 99%

“…There is an increasing interest in the cGAS-STING pathway for cancer therapeutics, yet this pathway has dichotomous roles in cancer (32). Although cGAS-STING signaling can promote tumor progression (5,(32)(33)(34), this pathway can also induce protective immunity (32,(35)(36)(37)(38)(39)(40). Our ability to engineer cells to express active cGAS alleles provided an opportunity to determine whether cGAS signaling in a single-cell type would affect tumor progression.…”

Section: Intratumoral Activation Of Self-dna-reactive Cgas∆n Promotes...mentioning

confidence: 99%

Species-specific self-DNA detection mechanisms by mammalian cyclic GMP-AMP synthases

et al. 2023

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The mechanisms by which innate immune receptors mediate self-nonself discrimination are unclear. In this study, we found species-specific molecular determinants of self-DNA reactivity by cyclic guanosine monophosphate–adenosine monophosphate (GMP–AMP) synthase (cGAS). Human cGAS contained a catalytic domain that was intrinsically self-DNA reactive and stimulated interferon responses in diverse cell types. This reactivity was prevented by an upstream amino (N)-terminal domain. The cGAS proteins from several nonhuman primate species exhibited a similar pattern of self-DNA reactivity in cells, but chimpanzee cGAS was inactive even when its amino-terminal domain was deleted. In contrast, the N terminus of mouse cGAS promoted self-DNA reactivity. When expressed within tumors, only self-DNA–reactive cGAS proteins protected mice from tumor-induced lethality. In vitro studies of DNA- or chromatin-induced cGAS activation did not reveal species-specific activities that correlate with self-DNA reactivity observed in macrophages. Cell biological analysis revealed that self-DNA reactivity by human cGAS, but not mouse cGAS, correlated with localization to mitochondria. We found that epitope tag positions affected self-DNA reactivity in cells and that DNA present in cell lysates undermines the reliability of cGAS biochemical fractionations. These studies reveal species-specific diversity of cGAS functions, even within the primate lineage, and highlight experimental considerations for the study of this innate immune receptor.

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“…Thus, the constitutive induction of beneficial (early) type I IFN response confers antiviral protection to the host cells [ 48 , 49 , 50 , 51 ]. Also, cGAS can be activated differentially during mitotic errors and later contributes to birth defects, aging, carcinogenesis, and cancer therapy [ 52 , 53 ]. While mitotic error occurs at a low frequency in normal cells, a much higher frequency occurs in conditions, such as chemotherapeutics which can lead to cGAS activation via forming micronuclei and chromatin bridges [ 54 , 55 ].…”

Section: Cgasmentioning

confidence: 99%

Regulation of cGAS Activity and Downstream Signaling

Joshi

Mehta

2022

Cells

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Cyclic GMP-AMP synthase (cGAS) is a predominant and ubiquitously expressed cytosolic onfirmedDNA sensor that activates innate immune responses by producing a second messenger, cyclic GMP-AMP (cGAMP), and the stimulator of interferon genes (STING). cGAS contains a highly disordered N-terminus, which can sense genomic/chromatin DNA, while the C terminal of cGAS binds dsDNA liberated from various sources, including mitochondria, pathogens, and dead cells. Furthermore, cGAS cellular localization dictates its response to foreign versus self-DNA. Recent evidence has also highlighted the importance of dsDNA-induced post-translational modifications of cGAS in modulating inflammatory responses. This review summarizes and analyzes cGAS activity regulation based on structure, sub-cellular localization, post-translational mechanisms, and Ca2+ signaling. We also discussed the role of cGAS activation in different diseases and clinical outcomes.

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cGAS and cancer therapy: a double-edged sword

Cited by 21 publications

References 103 publications

Advances of MnO2 nanomaterials as novel agonists for the development of cGAS-STING-mediated therapeutics

Advances of MnO2 nanomaterials as novel agonists for the development of cGAS-STING-mediated therapeutics

Species-specific self-DNA detection mechanisms by mammalian cyclic GMP-AMP synthases

Regulation of cGAS Activity and Downstream Signaling

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