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https://www.readbyqxmd.com/read/28224203/nucleic-acid-sensing-pattern-recognition-receptors-in-the-development-of-colorectal-cancer-and-colitis
#1
REVIEW
Liangmei He, Yayun Chen, Yuanbing Wu, Ying Xu, Zixiang Zhang, Zhiping Liu
Colorectal cancer (CRC) is a leading cause of cancer-related deaths that is often associated with inflammation initiated by activation of pattern recognition receptors (PRRs). Nucleic acid sensing PRRs are one of the major subsets of PRRs that sense nucleic acid (DNA and RNA), mainly including some members of Toll-like receptors (TLR3, 7, 8, 9), AIM2-like receptors (AIM2, IFI16), STING, cGAS, RNA polymerase III, and DExD/H box nucleic acid helicases (such as RIG-I like receptors (RIG-I, MDA5, LPG2), DDX1, 3, 5, 7, 17, 21, 41, 60, and DHX9, 36)...
February 21, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28202760/restriction-of-hcmv-replication-by-isg15-a-host-effector-regulated-by-cgas-sting-dsdna-sensing
#2
Christopher Bianco, Ian Mohr
Accumulation of the interferon-stimulated gene (ISG) 15 protein product, which is reversibly conjugated to numerous polypeptide targets, impacts the proteome and physiology of uninfected and infected cells. While many viruses, including human cytomegalovirus (HCMV) blunt host antiviral defenses by limiting ISG expression, the overall abundance of ISG15 monomer and protein conjugates rises in HCMV-infected cells. However, the molecular signals underlying ISG15 accumulation and whether the ISG15 polypeptide itself influences HCMV infection biology remain unknown...
February 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28194029/ifi16-and-cgas-cooperate-in-the-activation-of-sting-during-dna-sensing-in-human-keratinocytes
#3
Jessica F Almine, Craig A J O'Hare, Gillian Dunphy, Ismar R Haga, Rangeetha J Naik, Abdelmadjid Atrih, Dympna J Connolly, Jordan Taylor, Ian R Kelsall, Andrew G Bowie, Philippa M Beard, Leonie Unterholzner
Many human cells can sense the presence of exogenous DNA during infection though the cytosolic DNA receptor cyclic GMP-AMP synthase (cGAS), which produces the second messenger cyclic GMP-AMP (cGAMP). Other putative DNA receptors have been described, but whether their functions are redundant, tissue-specific or integrated in the cGAS-cGAMP pathway is unclear. Here we show that interferon-γ inducible protein 16 (IFI16) cooperates with cGAS during DNA sensing in human keratinocytes, as both cGAS and IFI16 are required for the full activation of an innate immune response to exogenous DNA and DNA viruses...
February 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/28186168/ifi16-is-required-for-dna-sensing-in-human-macrophages-by-promoting-production-and-function-of-cgamp
#4
K L Jønsson, A Laustsen, C Krapp, K A Skipper, K Thavachelvam, D Hotter, J H Egedal, M Kjolby, P Mohammadi, T Prabakaran, L K Sørensen, C Sun, S B Jensen, C K Holm, R J Lebbink, M Johannsen, M Nyegaard, J G Mikkelsen, F Kirchhoff, S R Paludan, M R Jakobsen
Innate immune activation by macrophages is an essential part of host defence against infection. Cytosolic recognition of microbial DNA in macrophages leads to induction of interferons and cytokines through activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Other host factors, including interferon-gamma inducible factor 16 (IFI16), have been proposed to contribute to immune activation by DNA. However, their relation to the cGAS-STING pathway is not clear. Here, we show that IFI16 functions in the cGAS-STING pathway on two distinct levels...
February 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/28181006/cyclic-dinucleotides-in-the-scope-of-the-mammalian-immune-system
#5
Arun K Mankan, Martina Müller, Gregor Witte, Veit Hornung
First discovered in prokaryotes and more recently in eukaryotes, cyclic dinucleotides (CDNs) constitute a unique branch of second messenger signaling systems. Within prokaryotes CDNs regulate a wide array of different biological processes, whereas in the vertebrate system CDN signaling is largely dedicated to activation of the innate immune system. In this book chapter we summarize the occurrence and signaling pathways of these small-molecule second messengers, most importantly in the scope of the mammalian immune system...
February 9, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28137885/cgas-is-essential-for-the-antitumor-effect-of-immune-checkpoint-blockade
#6
Hua Wang, Shuiqing Hu, Xiang Chen, Heping Shi, Chuo Chen, Lijun Sun, Zhijian J Chen
cGMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates innate immune responses. cGAS catalyzes the synthesis of cGAMP, which functions as a second messenger that binds and activates the adaptor protein STING to induce type I interferons (IFNs) and other immune modulatory molecules. Here we show that cGAS is indispensable for the antitumor effect of immune checkpoint blockade in mice. Wild-type, but not cGAS-deficient, mice exhibited slower growth of B16 melanomas in response to a PD-L1 antibody treatment...
January 30, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28132838/human-cytomegalovirus-tegument-protein-ul82-inhibits-sting-mediated-signaling-to-evade-antiviral-immunity
#7
Yu-Zhi Fu, Shan Su, Yi-Qun Gao, Pei-Pei Wang, Zhe-Fu Huang, Ming-Ming Hu, Wei-Wei Luo, Shu Li, Min-Hua Luo, Yan-Yi Wang, Hong-Bing Shu
Recognition of human cytomegalovirus (HCMV) DNA by the cytosolic sensor cGAS initiates STING-dependent innate antiviral responses. HCMV can antagonize host immune responses to promote latency infection. However, it is unknown whether and how HCMV targets the cGAS-STING axis for immune evasion. Here we identified the HCMV tegument protein UL82 as a negative regulator of STING-dependent antiviral responses. UL82 interacted with STING and impaired STING-mediated signaling via two mechanisms. UL82 inhibited the translocation of STING from the ER to perinuclear microsomes by disrupting the STING-iRhom2-TRAPβ translocation complex...
February 8, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28100608/herpes-simplex-virus-type-1-ul24-abrogates-dna-sensing-signal-pathway-by-inhibiting-nf-%C3%AE%C2%BAb-activation
#8
Haiyan Xu, Chenhe Su, Angela Pearson, Christopher H Mody, Chunfu Zheng
: Cyclic GMP-AMP synthase (cGAS) is a newly identified DNA sensor that recognizes foreign DNA, including the genome of herpes simplex virus 1 (HSV-1). Upon binding of viral DNA, cGAS produces cyclic GMP-AMP, which interacts with and activates stimulator of interferon genes (STING) to trigger the transcription of anti-viral genes such as type I interferons and production of inflammatory cytokines. HSV-1 UL24 is widely conserved among the herpesviruses family and is essential for efficient viral replication...
January 18, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28095500/senp7-potentiates-cgas-activation-by-relieving-sumo-mediated-inhibition-of-cytosolic-dna-sensing
#9
Ye Cui, Huansha Yu, Xin Zheng, Rui Peng, Qiang Wang, Yi Zhou, Rui Wang, Jiehua Wang, Bo Qu, Nan Shen, Qiang Guo, Xing Liu, Chen Wang
Cyclic GMP-AMP (cGAMP) synthase (cGAS, a.k.a. MB21D1), a cytosolic DNA sensor, catalyzes formation of the second messenger 2'3'-cGAMP that activates the stimulator of interferon genes (STING) signaling. How the cGAS activity is modulated remains largely unknown. Here, we demonstrate that sentrin/SUMO-specific protease 7 (SENP7) interacted with and potentiated cGAS activation. The small ubiquitin-like modifier (SUMO) was conjugated onto the lysine residues 335, 372 and 382 of cGAS, which suppressed its DNA-binding, oligomerization and nucleotidyl-transferase activities...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28077645/herpes-simplex-virus-1-abrogates-cgas-sting-mediated-cytosolic-dna-sensing-pathway-via-its-virion-host-shutoff-protein-ul41
#10
Chenhe Su, Chunfu Zheng
: Cyclic GMP-AMP synthase (cGAS) is a key DNA sensor capable of detecting microbial DNA and activating the adaptor protein stimulator of interferon genes (STING), leading to interferon (IFN) production and host antiviral responses. Cells exhibited reduced type I IFN production in response to cytosolic DNA in the absence of cGAS. Although cGAS/STING-mediated DNA-sensing signal is crucial for host defense against many viruses, especial for DNA viruses, few viral components have been identified to specifically target this signaling pathway...
January 11, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28073693/crosstalk-between-cytoplasmic-rig-i-and-sting-sensing-pathways
#11
REVIEW
Alessandra Zevini, David Olagnier, John Hiscott
Detection of evolutionarily conserved molecules on microbial pathogens by host immune sensors represents the initial trigger of the immune response against infection. Cytosolic receptors sense viral and intracellular bacterial genomes, as well as nucleic acids produced during replication. Once activated, these sensors trigger multiple signaling cascades, converging on the production of type I interferons and proinflammatory cytokines. Although distinct classes of receptors are responsible for the RNA and DNA sensing, the downstream signaling components are physically and functionally interconnected...
January 7, 2017: Trends in Immunology
https://www.readbyqxmd.com/read/28069950/chronic-innate-immune-activation-of-tbk1-suppresses-mtorc1-activity-and-dysregulates-cellular-metabolism
#12
Maroof Hasan, Vijay K Gonugunta, Nicole Dobbs, Aktar Ali, Guillermo Palchik, Maria A Calvaruso, Ralph J DeBerardinis, Nan Yan
Three-prime repair exonuclease 1 knockout (Trex1(-/-)) mice suffer from systemic inflammation caused largely by chronic activation of the cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) signaling pathway. We showed previously that Trex1-deficient cells have reduced mammalian target of rapamycin complex 1 (mTORC1) activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1(-/-) mice and cells that revealed both cellular and systemic metabolic defects, including reduced mitochondrial respiration and increased glycolysis, energy expenditure, and fat metabolism...
January 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28041929/the-chlamydia-trachomatis-inclusion-membrane-protein-cpos-counteracts-sting-mediated-cellular-surveillance-and-suicide-programs
#13
Barbara S Sixt, Robert J Bastidas, Ryan Finethy, Ryan M Baxter, Victoria K Carpenter, Guido Kroemer, Jörn Coers, Raphael H Valdivia
Evading cell death is critical for Chlamydia to maintain a replicative niche, but the underlying mechanisms are unknown. We screened a library of Chlamydia mutants for modulators of cell death. Inactivation of the inclusion membrane protein CpoS (Chlamydia promoter of survival) induced rapid apoptotic and necrotic death in infected cells. The protection afforded by CpoS is limited to the inclusion in which it resides, indicating that it counteracts a spatially restricted pro-death signal. CpoS-deficient Chlamydia induced an exacerbated type I interferon response that required the host cGAS/STING/TBK1/IRF3 signaling pathway...
January 11, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28031360/herpes-simplex-virus-1-ubiquitin-specific-protease-ul36-abrogates-nf-%C3%AE%C2%BAb-activation-in-dna-sensing-signal-pathway
#14
Ruijie Ye, Chenhe Su, Haiyan Xu, Chunfu Zheng
The DNA sensing pathway triggers innate immune responses against DNA virus infection, and NF-κB signaling plays a critical role in establishing innate immunity. We report here that the herpes simplex virus 1 (HSV-1) ubiquitin-specific protease (UL36USP), which is a deubiquitinase (DUB), antagonizes NF-κB activation, depending on its DUB activity. In this study, ectopically expressed UL36USP blocked promoter activation of beta interferon (IFN-β) and NF-κB induced by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING)...
March 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28007901/a-rat-model-of-ataxia-telangiectasia-evidence-for-a-neurodegenerative-phenotype
#15
Hazel Quek, John Luff, KaGeen Cheung, Sergei Kozlov, Magtouf Gatei, C Soon Lee, Mark C Bellingham, Peter G Noakes, Yi Chieh Lim, Nigel L Barnett, Steven Dingwall, Ernst Wolvetang, Tomoji Mashimo, Tara L Roberts, Martin F Lavin
Ataxia-telangiectasia (A-T), an autosomal recessive disease caused by mutations in the ATM gene is characterised by cerebellar atrophy and progressive neurodegeneration which has been poorly recapitulated in Atm mutant mice. Consequently, pathways leading to neurodegeneration in A-T are poorly understood. We describe here the generation of an Atm knockout rat model that does not display cerebellar atrophy but instead paralysis and spinal cord atrophy, reminiscent of that seen in older patients and milder forms of the disorder...
December 22, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27988520/dna-sensing-and-nuclease-gene-expressions-as-markers-for-colorectal-cancer-progression
#16
Chin-An Yang, Hsi-Yuan Huang, Ya-Sian Chang, Chia-Li Lin, I-Lu Lai, Jan-Gowth Chang
OBJECTIVE: Oncogene-driven stress-related DNA damage has been observed in lesions of colon cancer. Furthermore, DNA sensors and nucleases are stimulated during active DNA damage and replication. However, their changes and influences with respect to cancer remain largely unknown. METHODS: The gene expression levels of cGAS, IFI16, STING, TBK1, IFNB1, TREX1, SAMHD1, RNASEH2A, RNASEH2B, and RNASEH2C were examined in the paired colorectal cancer and adjacent normal part tissues of 53 patients...
2017: Oncology
https://www.readbyqxmd.com/read/27935834/viral-dna-sensors-ifi16-and-cyclic-gmp-amp-synthase-possess-distinct-functions-in-regulating-viral-gene-expression-immune-defenses-and-apoptotic-responses-during-herpesvirus-infection
#17
Benjamin A Diner, Krystal K Lum, Jared E Toettcher, Ileana M Cristea
: The human interferon-inducible protein IFI16 is an important antiviral factor that binds nuclear viral DNA and promotes antiviral responses. Here, we define IFI16 dynamics in space and time and its distinct functions from the DNA sensor cyclic dinucleotide GMP-AMP synthase (cGAS). Live-cell imaging reveals a multiphasic IFI16 redistribution, first to viral entry sites at the nuclear periphery and then to nucleoplasmic puncta upon herpes simplex virus 1 (HSV-1) and human cytomegalovirus (HCMV) infections...
November 15, 2016: MBio
https://www.readbyqxmd.com/read/27902332/inhibition-of-hepatitis-b-virus-replication-by-activation-of-the-cgas-sting-pathway
#18
Jing He, Ruidong Hao, Dan Liu, Xing Liu, Shaoshuai Wu, Shuting Guo, Yuan Wang, Po Tien, Deyin Guo
Cyclic GMP-AMP (cGAMP) synthase (cGAS) senses cytosolic DNA and catalyses synthesis of the second messenger cGAMP, which activates the downstream signalling adaptor protein STING, leading to the expression of type I interferons. Hepatitis B virus (HBV) is a small DNA virus, and the cGAS-STING pathway may inhibit HBV RNA synthesis and viral assembly in cell culture, but the exact roles of the cGAS pathway in the restriction of HBV replication in infection systems remain to be elucidated. In this study, replication of HBV was significantly inhibited both in cell culture and in vivo in a mouse model when the cGAS-STING pathway was activated by dsDNA or cGAMP...
December 2016: Journal of General Virology
https://www.readbyqxmd.com/read/27889408/an-rna-based-fluorescent-biosensor-for-high-throughput-analysis-of-the-cgas-cgamp-sting-pathway
#19
Debojit Bose, Yichi Su, Assaf Marcus, David H Raulet, Ming C Hammond
In mammalian cells, the second messenger (2'-5',3'-5') cyclic guanosine monophosphate-adenosine monophosphate (2',3'-cGAMP), is produced by the cytosolic DNA sensor cGAMP synthase (cGAS), and subsequently bound by the stimulator of interferon genes (STING) to trigger interferon response. Thus, the cGAS-cGAMP-STING pathway plays a critical role in pathogen detection, as well as pathophysiological conditions including cancer and autoimmune disorders. However, studying and targeting this immune signaling pathway has been challenging due to the absence of tools for high-throughput analysis...
December 22, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27830700/sensing-of-hsv-1-by-the-cgas-sting-pathway-in-microglia-orchestrates-antiviral-defence-in-the-cns
#20
Line S Reinert, Katarína Lopušná, Henriette Winther, Chenglong Sun, Martin K Thomsen, Ramya Nandakumar, Trine H Mogensen, Morten Meyer, Christian Vægter, Jens R Nyengaard, Katherine A Fitzgerald, Søren R Paludan
Herpes simplex encephalitis (HSE) is the most common form of acute viral encephalitis in industrialized countries. Type I interferon (IFN) is important for control of herpes simplex virus (HSV-1) in the central nervous system (CNS). Here we show that microglia are the main source of HSV-induced type I IFN expression in CNS cells and these cytokines are induced in a cGAS-STING-dependent manner. Consistently, mice defective in cGAS or STING are highly susceptible to acute HSE. Although STING is redundant for cell-autonomous antiviral resistance in astrocytes and neurons, viral replication is strongly increased in neurons in STING-deficient mice...
November 10, 2016: Nature Communications
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