Acetylation Blocks cGAS Activity and Inhibits Self-DNA-Induced Autoimmunity

Dai, Jiang; Huang, Yanhong; He, Xinhua; Zhao, Ming; Wang, Xinzheng; Liu, Zhao-Shan; Xue, Wei; Cai, Hong; Zhan, Xiaoyan; Huang, Shao-Yi; He, Kun; Wang, Hongxia; Wang, Na; Sang, Zhihong; Li, Tingting; Han, Qin; Mao, Jie; Diao, Xinping; Song, Nan; Chen, Yuan; Li, Weihua; Man, Jianghong; Li, Ailing; Zhou, Tao; Liu, Zheng-gang; Zhang, Xuemin; Li, Tao

doi:10.1016/j.cell.2019.01.016

Cited by 258 publications

(288 citation statements)

References 63 publications

Supporting

Mentioning

268

Contrasting

Unclassified

Order By: Relevance

“…In addition, novel small molecules such as RU320521 or G150 can occupy the enzymatic pocket of species-specific cGAS to abrogate cGAMP synthesis (272,273). Recently, a study found that aspirin can acetylate cGAS at three lysine residues and block cGAS activity (274). With regard to STING, the cyclopeptide Astin C can block IRF3 recruitment onto the STING signalosome (275).…”

Section: Targeting the Cgas-sting Pathway For Treatmentmentioning

confidence: 99%

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

2020

View full text Add to dashboard Cite

Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immunesurveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. cGAS-STING pathway interplays with other innate immune pathways, by which it participates in regulating infection, inflammatory disease, and cancer. The therapeutic approaches targeting this pathway show promise for future translation into clinical applications. Here, we present a review of the important previous works and recent advances regarding the cGAS-STING pathway, and provide a comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states.

show abstract

Section: Targeting the Cgas-sting Pathway For Treatmentmentioning

confidence: 99%

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

2020

View full text Add to dashboard Cite

show abstract

“…The cGAS N-terminal tail has been implicated in DNA interactions, protein stability, localization, and higher-order complex formation, suggesting that these extensions are important to regulate enzyme activation [10,39 ,41-43]. In addition to oligomerization, CD-NTase function is further regulated by intrinsic species-specific substitutions that fine-tune enzyme activation [29 ,44], additional domains like tandem arrays of the CD-NTase module or fusion to ubiquitin-like proteins in some OAS homologs [45], and post-translational modifications [46][47][48].…”

Section: Structural Anatomy Of Cd-ntase Enzymesmentioning

confidence: 99%

cGAS and CD-NTase enzymes: structure, mechanism, and evolution

Kranzusch

2019

Current Opinion in Structural Biology

View full text Add to dashboard Cite

Cyclic GMP-AMP synthase (cGAS) is a signaling enzyme in human cells that controls immune-sensing of cytosolic DNA. The recent discoveries of diverse structural homologs of cGAS in animals and bacteria reveal that cGAS-like signaling is surprisingly ancient and widespread in biology. Together with the Vibrio cholerae protein dinucleotide cyclase in Vibrio (DncV), cGAS and DncV homologs comprise a family of cGAS/ DncV-like nucleotidyltransferase (CD-NTase) enzymes that synthesize noncanonical RNA signals including cyclic dinucleotides, cyclic trinucleotides, and linear oligonucleotides. Structural and biochemical breakthroughs provide a framework to understand how CD-NTase signaling allows cells to respond to changing environmental conditions. The CD-NTase family also includes uncharacterized human genes like MB21D2 and Mab21L1, highlighting emerging functions of cGAS-like signaling beyond innate immunity.

show abstract

“…Knockout studies have shown that Trex1 null mice, which have elevated interferon levels, return to WT levels of interferon upon knockout of cGAS 38,39 , STING 40,41 , or IRF3 40 . These studies further validate the importance of cGAS and its role in regulating immunity, and it has become a prime candidate for the development of small molecules that activate or inhibit its immunopotent activity 42,43,44,45 . Identifying an effective cGAS inhibitor could serve as a tool to help assess the contribution of the cGAS-STING signaling axis in various immune responses, and could ultimately serve as a chemical scaffold towards the development of clinical compounds for the treatment of associated autoimmune diseases.…”

Section: Introductionmentioning

confidence: 65%

“…Given the importance of the cGAS pathway to stimulating the innate immune system, a number of agonists and antagonists have been generated in attempts to probe the molecular underpinnings and to manipulate activity for therapeutic intervention 53,43,54,45,44 . While in vitro studies have difficulties in showing that RU.521 can inhibit recombinant human cGAS 47,44 , our data here indicate that RU.521 does inhibit human cGAS activity in cells.…”

Section: Discussionmentioning

confidence: 99%

Small molecule inhibition of human cGAS reduces total cGAMP output and cytokine expression in cells

Wiser

Kim

Vincent

et al. 2020

Preprint

View full text Add to dashboard Cite

ABSTRACTThe cGAS-STING pathway is a major mechanism that mammalian cells utilize to detect cytoplasmic dsDNA from incoming viruses, bacteria, or self. CYCLIC GMP-AMP SYNTHASE (cGAS) is the sensor protein that directly binds dsDNAs. cGAS synthesizes cyclic GMP-AMP (cGAMP), which binds to the adaptor STIMULATOR OF INTERFERON GENES (STING), activating an INTERFERON REGULATORY FACTOR 3 (IRF3)-mediated immune response. Constitutive activation can result in interferonopathies such as Aicardi-Goutieres Syndrome (AGS) or other lupus-like autoimmune disorders. While inhibitors targeting mouse or human cGAS have been reported, the identification of a small molecule that targets both homologs of cGAS has been challenging. Here, we show that RU.521 is capable of potently and selectively inhibiting mouse and human cGAS in cell lines and human primary cells. This inhibitory activity requires the presence of cGAS, but it cannot suppress an immune response in cells activated by RNA, Toll-like receptor ligands, cGAMP, or recombinant interferon. Importantly, when RU.521 is applied to cells, the production of dsDNA-induced intracellular cGAMP is suppressed in a dose-dependent manner. Our work validates the use of RU.521 for probing DNA-induced innate immune responses and underscores its potential as an ideal scaffold towards pre-clinical development, given its potency against human and mouse cGAS.

show abstract

Acetylation Blocks cGAS Activity and Inhibits Self-DNA-Induced Autoimmunity

Abstract: Highlights d Acetylation suppresses cGAS activity d Aspirin directly acetylates cGAS d Aspirin inhibits cGAS-mediated interferon production d Aspirin alleviates DNA-induced autoimmunity in AGS mouse models and patient cells

Cited by 258 publications

References 63 publications

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

cGAS and CD-NTase enzymes: structure, mechanism, and evolution

Small molecule inhibition of human cGAS reduces total cGAMP output and cytokine expression in cells

Contact Info

Product

Resources

About