Structural basis of nucleosome-dependent cGAS inhibition

Boyer, Joshua A.; Spangler, Cathy J; Strauss, J; Cesmat, Andrew P.; Liu, Pengda; McGinty, Robert K.; Zhang, Qi

doi:10.1126/science.abd0609

Cited by 168 publications

(130 citation statements)

References 45 publications

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“…In parallel with this study, five other groups also reported on the cryo-EM structures of human and mouse cGAS-nucleosome complexes. [11][12][13][14][15] We note that the 2:2 and higher-order assemblies mediated by cGAS site C are observed in all three human cGAS-NCP structures 9,12,15 but not in their mouse counterparts. 11,13,14 Consistent with this distinction, site C has been shown to be an evolutionarily strengthened DNA-binding interface when proceeding from mouse to humans.…”

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confidence: 65%

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Keeping innate immune response in check: when cGAS meets the nucleosome

Xie

Patel

2020

Cell Res

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Cao et al. report on cryo-EM structures of human cyclic GMP-AMP synthase (cGAS) sensor bound to the nucleosome core particle, thereby defining the molecular mechanism of how cGAS avoids activation by chromatinized self-DNA. Notably, disruption of cGAS dimer formation and prevention of dsDNA recognition by the sensor at the nucleosome level impede cGAS activation. Cyclic GMP-AMP synthase (cGAS) was first identified as a dsDNA sensor in the cytoplasm, 1 providing a surveillance mechanism for monitoring pathogenic DNA invasion, in which the cGAS-STING pathway triggers production of type I interferons and proinflammatory cytokines associated with the innate immune response and stimulates inflammatory signaling, autophagy and apoptosis. Given that cGAS exhibits a dsDNA length-dependent mode of activation, several groups have undertaken structure determination of a series of mouse and human cGAS-dsDNA complexes with increasing complexity, 2-6 which in turn have revealed three distinct DNA binding surfaces on cGAS (labeled sites A, B and C) that contribute to dsDNA sensing by cGAS. 2-6 cGAS, which adopts a dimeric topology, 6 undergoes a conformational change upon binding of naked dsDNA, and forms complexes with dsDNA through targeting separate dsDNAs by cGAS sites A and B, thereby triggering formation of the cGAS activation loop and a catalytically competent pocket for cyclic dinucleotide second messenger 2′,3′-cGAMP synthesis. 2,7 Furthermore, human cGAS has an additional site C interface to further promote dsDNA-induced enzymatic activation and liquid phase condensation 5 (Fig. 1a). A critical feature of the cGAS regulatory mechanism requires avoidance of cGAS activation by self-DNA under normal conditions since aberrant activation of cGAS causes autoimmune diseases. It has been established in the nucleus that reconstituted nucleosomes could directly bind cGAS more tightly than corresponding naked dsDNA but cannot stimulate second messenger cGAMP synthesis. 8 In the paper published in Cell Research, Cao et al. provide a structural explanation of nucleosome-mediated suppression of cGAS activity based on cryo-EM structures of human cGAS-nucleosome complexes. 9 They reconstituted the cGAS-nucleosome complex using the catalytic domain dimer of human cGAS and nucleosome core particles (NCPs) and determined the cryo-EM structures of cGAS-NCP complexes with 1:1 and 2:2 stoichiometries. The structures of both complexes showed that bound cGAS interacts with the nucleosome as a monomer, implying that nucleosome can competitively

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confidence: 65%

“…The studies discussed here 9,[11][12][13][14][15] provide compelling evidence of cGAS sequestration and inhibition by the nucleosome, with such nuclear tethering trapping cGAS in an inactive conformation. Fig.…”

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confidence: 73%

Keeping innate immune response in check: when cGAS meets the nucleosome

Xie

Patel

2020

Cell Res

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“…Another structure by Boyer et al reported the structure of cGAS bound to a single nucleosome. This binding sterically abrogates cGAS oligomerization required to yield functionally active 2:2 cGAS-dsDNA complex (112). These recent findings have provided important information that how cGAS is maintained in an inhibited state in the nucleus.…”

Section: Cgas-sting Pathwaymentioning

confidence: 88%

Molecular and Structural Basis of DNA Sensors in Antiviral Innate Immunity

Zahid

Ismail

et al. 2020

Front. Immunol.

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DNA viruses are a source of great morbidity and mortality throughout the world by causing many diseases; thus, we need substantial knowledge regarding viral pathogenesis and the host’s antiviral immune responses to devise better preventive and therapeutic strategies. The innate immune system utilizes numerous germ-line encoded receptors called pattern-recognition receptors (PRRs) to detect various pathogen-associated molecular patterns (PAMPs) such as viral nucleic acids, ultimately resulting in antiviral immune responses in the form of proinflammatory cytokines and type I interferons. The immune-stimulatory role of DNA is known for a long time; however, DNA sensing ability of the innate immune system was unraveled only recently. At present, multiple DNA sensors have been proposed, and most of them use STING as a key adaptor protein to exert antiviral immune responses. In this review, we aim to provide molecular and structural underpinnings on endosomal DNA sensor Toll-like receptor 9 (TLR9) and multiple cytosolic DNA sensors including cyclic GMP-AMP synthase (cGAS), interferon-gamma inducible 16 (IFI16), absent in melanoma 2 (AIM2), and DNA-dependent activator of IRFs (DAI) to provide new insights on their signaling mechanisms and physiological relevance. We have also addressed less well-understood DNA sensors such as DEAD-box helicase DDX41, RNA polymerase III (RNA pol III), DNA-dependent protein kinase (DNA-PK), and meiotic recombination 11 homolog A (MRE11). By comprehensive understanding of molecular and structural aspects of DNA-sensing antiviral innate immune signaling pathways, potential new targets for viral and autoimmune diseases can be identified.

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“…6A, Figure S3D). It was reported that cisplatin induced dsDNA fragments through accumulation of DNA damage and inhibiting DNA homologous complementary repair pathway 16 . We observed the signi cant increase of DNA damage marker γ-H2A.X in T24 and TCCSUP cell lines treated with cisplatin (Fig.…”

Section: Cisplatin Induced Dsdna May Function As An Important Role Inmentioning

confidence: 99%

“…For instance, translocation of cGAS from cytoplasm to cell membrane helps THP-1 and HeLa cells to recognize the exogenous virus DNA 37 . And nuclear translocation of cGAS can affect its functions by suppressing homologous recombination mediated repair 16 . But we found that cGAS was mainly located in nucleus in T24 and TCCSUP cell lines, and this subcellular distribution was not changed after cisplatin treatment.…”

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confidence: 99%

Cisplatin Inhibits Bladder Cancer Proliferation Through cGAS-STING Pathway.

Chen

et al. 2020

Preprint

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Background Cisplatin is a commonly used adjuvant chemotherapy for advanced bladder cancer, but its immune related mechanism is still unclear. Exploration the immune effects of cisplatin in bladder cancer would complement the comprehensive mechanism of cisplatin and provide the basis for combination therapy of cisplatin and immunotherapy in bladder cancer. Methods We confirmed the immune effects of cisplatin on T24 and TCCSUP bladder cancer cell lines in vitro and exploration the important function of these immune effects in bladder cancer microenvironment in mice tumor model. Results We found cisplatin induced immune response in bladder cancer by RNA sequencing, and validated cGAS-STING signal was deeply involved in this response. Cisplatin induced cGAS-STING signal inhibited the proliferation of bladder cancer and increased the infiltration percentages of CD8 + T cells and dendritic cells in transplantation mice tumor model. Accumulation of dsDNA and the release of chromatin bound cGAS are important to activate downstream STING. Conclusion Our findings indicated a cisplatin related immune effects in bladder cancer, cisplatin combined with immunotherapy might have a synergistic effect for bladder cancer therapy.

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Structural basis of nucleosome-dependent cGAS inhibition

Cited by 168 publications

References 45 publications

Keeping innate immune response in check: when cGAS meets the nucleosome

Keeping innate immune response in check: when cGAS meets the nucleosome

Molecular and Structural Basis of DNA Sensors in Antiviral Innate Immunity

Cisplatin Inhibits Bladder Cancer Proliferation Through cGAS-STING Pathway.

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