Transcriptional regulation of human cyclic GMP-AMP synthase gene

Chen, Haiyan; Pang, Xiao‐Yu; Xu, Yanyan; Zhou, Guoping; Xu, Hua‐Guo

doi:10.1016/j.cellsig.2019.109355

Cited by 12 publications

(9 citation statements)

References 25 publications

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“…Furthermore, similarly, cGAS acetylation at either Lys414 or Lys394/384 impedes cGAS activity 73 . In addition, transcription factor Sp1 and cAMP response element-binding protein, CREB, positively regulate and maintain cGAS transcription activity 74 .…”

Section: Basic Structural Features Of Cgas and Stingmentioning

confidence: 99%

The cGAS–STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy

Oduro

Zheng

Wei

et al. 2022

Acta Pharmaceutica Sinica B

127

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The cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling exert essential regulatory function in microbial-and onco-immunology through the induction of cytokines, primarily type I interferons. Recently, the aberrant and deranged signaling of the cGAS–STING axis is closely implicated in multiple sterile inflammatory diseases, including heart failure, myocardial infarction, cardiac hypertrophy, nonalcoholic fatty liver diseases, aortic aneurysm and dissection, obesity, etc. This is because of the massive loads of damage-associated molecular patterns (mitochondrial DNA, DNA in extracellular vesicles) liberated from recurrent injury to metabolic cellular organelles and tissues, which are sensed by the pathway. Also, the cGAS–STING pathway crosstalk with essential intracellular homeostasis processes like apoptosis, autophagy, and regulate cellular metabolism. Targeting derailed STING signaling has become necessary for chronic inflammatory diseases. Meanwhile, excessive type I interferons signaling impact on cardiovascular and metabolic health remain entirely elusive. In this review, we summarize the intimate connection between the cGAS–STING pathway and cardiovascular and metabolic disorders. We also discuss some potential small molecule inhibitors for the pathway. This review provides insight to stimulate interest in and support future research into understanding this signaling axis in cardiovascular and metabolic tissues and diseases.

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Section: Basic Structural Features Of Cgas and Stingmentioning

confidence: 99%

The cGAS–STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy

Oduro

Zheng

Wei

et al. 2022

Acta Pharmaceutica Sinica B

127

View full text Add to dashboard Cite

show abstract

“…Finally, cGAS activity is also affected by transcriptional regulation and post-translational regulatory controls. The transcriptional factors Sp1 and CREB can bind to the promoter region of the cGAS gene to facilitate transcription [29]. The acetylation of cGAS at residues K384, K394, and K414 can render cGAS inactive, whereas stimulation with exogenous DNA causes cGAS deacetylation by the histone deacetylase HDAC3 prior to cGAS pathway activation [26].…”

Section: Endogenous Dna Activates the Cgas-sting Pathway Cgas Producementioning

confidence: 99%

cGAS-STING pathway in oncogenesis and cancer therapeutics

et al. 2020

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The host innate immunity offers the first line of defense against infection. However, recent evidence shows that the host innate immunity is also critical in sensing the presence of cytoplasmic DNA derived from genomic instability events, such as DNA damage and defective cell cycle progression. This is achieved through the cyclic GMP-AMP synthase (cGAS)/Stimulator of interferon (IFN) genes (STING) pathway. Here we discuss recent insights into the regulation of this pathway in cancer immunosurveillance, and the downstream signaling cascades that coordinate immune cell recruitment to the tumor microenvironment to destroy transformed cells through cellular senescence or cell death programs. Its central role in immunosurveillance positions the cGAS-STING pathway as an attractive anti-cancer immunotherapeutic drug target for chemical agonists or vaccine adjuvants and suggests a key node to be targeted in a synthetic lethal approach. We also discuss adaptive mechanisms used by cancer cells to circumvent cGAS-STING signaling and present evidence linking chronic cGAS-STING activation to inflammation-induced carcinogenesis, cautioning against the use of activating the cGAS-STING pathway as an anti-tumor immunotherapy. A deeper mechanistic understanding of the cGAS-STING pathway will aid in the identification of potentially efficacious anti-cancer therapeutic targets. www.oncotarget.com Jackson for editing and providing comments on the manuscript.

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“…While both viral proteins can induce DNA breaks, only E6 was shown to increase cGAS levels indicating that in addition to DNA damage, impairment of p53 is also required. cGAS transcription is regulated by factors such as Sp1 and CREB [ 57 ] and p53 could act through these factors or instead act directly on the promoter. cGAS has also been reported to be an ISG that is responsive to IFNs but addition of exogenous IFN-β failed to increase its expression in HPV positive cells.…”

Section: Discussionmentioning

confidence: 99%

Human papillomaviruses sensitize cells to DNA damage induced apoptosis by targeting the innate immune sensor cGAS

Gusho

Laimins

2022

PLoS Pathog

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The cyclic GMP-AMP synthase (cGAS) is a critical regulator of the innate immune response acting as a sensor of double-strand DNAs from pathogens or damaged host DNA. Upon activation, cGAS signals through the STING/TBK1/IRF3 pathway to induce interferon expression. Double stranded DNA viruses target the cGAS pathway to facilitate infection. In HPV positive cells that stably maintain viral episomes, the levels of cGAS were found to be significantly increased over those seen in normal human keratinocytes. Furthermore the downstream effectors of the cGAS pathway, STING and IRF3, were fully active in response to signaling from the secondary messenger cGAMP or poly (dA:dT). In HPV positive cells cGAS was detected in both cytoplasmic puncta as well as in DNA damage induced micronuclei. E6 was responsible for increased levels of cGAS that was dependent on inhibition of p53. CRISPR-Cas9 mediated knockout of cGAS prevented activation of STING and IRF3 but had a minimal effect on viral replication. A primary function of cGAS in HPV positive cells was in response to treatment with etoposide or cisplatin which lead to increased levels of H2AX phosphorylation and activation of caspase 3/7 cleavage while having only a minimal effect on activation of homologous recombination repair factors ATM, ATR or CHK2. In HPV positive cells cGAS was found to regulate the levels of the phosphorylated non-homologous end-joining kinase, DNA-PK, which may contribute to H2AX phosphorylation along with other factors. Importantly cGAS was also responsible for increased levels of DNA breaks along with enhanced apoptosis in HPV positive cells but not in HFKs. This study identifies an important and novel role for cGAS in mediating the response of HPV positive cells to chemotherapeutic drugs.

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Transcriptional regulation of human cyclic GMP-AMP synthase gene

Cited by 12 publications

References 25 publications

The cGAS–STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy

The cGAS–STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy

cGAS-STING pathway in oncogenesis and cancer therapeutics

Human papillomaviruses sensitize cells to DNA damage induced apoptosis by targeting the innate immune sensor cGAS

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