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cGAS Sting

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https://www.readbyqxmd.com/read/28422568/cgas-sting-tbk1-irf3-7-induced-interferon-%C3%AE-contributes-to-the-clearing-of-non-tuberculous-mycobacterial-infection-in-mice
#1
Nanthapon Ruangkiattikul, Andreas Nerlich, Ketema Abdissa, Stefan Lienenklaus, Abdulhadi Suwandi, Nina Janze, Kristin Laarmann, Julia Spanier, Ulrich Kalinke, Siegfried Weiss, Ralph Goethe
Type I interferons (IFN-I), such as IFN-α and IFN-β are important messengers in the host response against bacterial infections. Knowledge about the role of IFN-I in infections by nontuberculous mycobacteria (NTM) is limited. Here we show that macrophages infected with pathogens of the Mycobacterium avium complex produced significantly lower amounts of IFN-β than macrophages infected with the opportunistic pathogen M. smegmatis. To dissect the molecular mechanisms of this phenomenon, we focussed on the obligate pathogen Mycobacterium avium ssp...
April 19, 2017: Virulence
https://www.readbyqxmd.com/read/28416447/evolutionary-origins-of-cgas-sting-signaling
#2
REVIEW
Shally R Margolis, Stephen C Wilson, Russell E Vance
Detection of foreign nucleic acids is an important strategy for innate immune recognition of pathogens. In vertebrates, pathogen-derived DNA is sensed in the cytosol by cGAS, which produces the cyclic dinucleotide (CDN) second messenger cGAMP to activate the signaling adaptor STING. While induction of antiviral type I interferons (IFNs) is the major outcome of STING activation in vertebrates, it has recently become clear that core components of the cGAS-STING pathway evolved more than 600 million years ago, predating the evolution of type I IFNs...
April 14, 2017: Trends in Immunology
https://www.readbyqxmd.com/read/28412547/intracellular-dna-sensing-pathway-of-cgas-cgamp-is-decreased-in-human-newborns-and-young-children
#3
Zhan-Sheng Wang, Yu-Lu Liu, Nan Mi, Dao-Yun Duan
Newborns are highly susceptible to DNA virus infections, which may result from the characteristics of neonatal innate immune systems. Here we analyzed for the first time the development of innate immune sensing and signaling of intracellular DNA virus infection in human newborns and young children. Both mRNA and protein expression of cGAS, an intracellular DNA sensor, were shown to be significantly reduced in neonatal peripheral blood mononuclear cells (PBMCs). In addition, cGAS expression in neonatal PBMCs could be induced upon herpes simplex virus type 1 (HSV-1) or interferon-α (IFNα) stimulation...
April 13, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28399655/cyclic-gmp-amp-as-an-endogenous-second-messenger-in-innate-immune-signaling-by-cytosolic-dna
#4
Kazuki Kato, Hiroki Omura, Ryuichiro Ishitani, Osamu Nureki
The innate immune system functions as the first line of defense against invading bacteria and viruses. In this context, the cGAS/STING [cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase/ STING] signaling axis perceives the nonself DNA associated with bacterial and viral infections, as well as the leakage of self DNA by cellular dysfunction and stresses, to elicit the host's immune responses. In this pathway, the noncanonical cyclic dinucleotide 2',3'-cyclicGMP-AMP(2',3'-cGAMP) functions as a second messenger for signal transduction: 2',3'-cGAMP is produced by the enzyme cGAS upon its recognition of double-stranded DNA, and then the 2',3'-cGAMP is recognized by the receptor STING to induce the phosphorylation of downstream factors, including TBK1 (TANK binding kinase 1) and IRF3 (interferon regulatory factor 3)...
April 7, 2017: Annual Review of Biochemistry
https://www.readbyqxmd.com/read/28377530/topoisomerase-ii-inhibitors-induce-dna-damage-dependent-interferon-responses-circumventing-ebola-virus-immune-evasion
#5
Priya Luthra, Sebastian Aguirre, Benjamin C Yen, Colette A Pietzsch, Maria T Sanchez-Aparicio, Bersabeh Tigabu, Lorraine K Morlock, Adolfo García-Sastre, Daisy W Leung, Noelle S Williams, Ana Fernandez-Sesma, Alexander Bukreyev, Christopher F Basler
Ebola virus (EBOV) protein VP35 inhibits production of interferon alpha/beta (IFN) by blocking RIG-I-like receptor signaling pathways, thereby promoting virus replication and pathogenesis. A high-throughput screening assay, developed to identify compounds that either inhibit or bypass VP35 IFN-antagonist function, identified five DNA intercalators as reproducible hits from a library of bioactive compounds. Four, including doxorubicin and daunorubicin, are anthracycline antibiotics that inhibit topoisomerase II and are used clinically as chemotherapeutic drugs...
April 4, 2017: MBio
https://www.readbyqxmd.com/read/28363908/nonspecific-dna-binding-of-cgas-n-terminus-promotes-cgas-activation
#6
Jianli Tao, Xiao-Wei Zhang, Jianshi Jin, Xiao-Xia Du, Tengfei Lian, Jing Yang, Xiang Zhou, Zhengfan Jiang, Xiao-Dong Su
The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) mediates innate immune responses against invading pathogens, or against self-dsDNA, which causes autoimmune disorders. Upon nonspecific binding of cytosolic B-form DNA, cGAS synthesizes the second messenger 2'3'-cGAMP and triggers STING-dependent signaling to produce type I IFNs. The cGAS comprises less-conserved N-terminal residues and highly conserved nucleotidyltransferase/Mab21 domains. The function and structure of the well-conserved domains have been extensively studied, whereas the physiological function of the N-terminal domain of cGAS is largely uncharacterized...
March 31, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28351933/cytosolic-dna-sensor-initiated-innate-immune-responses-in-mouse-ovarian-granulosa-cells
#7
Keqin Yan, Dingqing Feng, Jing Liang, Qing Wang, Lin Deng, Xiao Zhang, Bin Ling, Daishu Han
Viral infections of the ovary may perturb ovarian functions. However, the mechanisms underlying innate immune responses in the ovary are poorly understood. The present study demonstrates that cytosolic viral DNA sensor signaling initiates the innate immune response in mouse ovarian granulosa cells and affects endocrine function. The cytosolic DNA sensors p204 and cGAS and their common signaling adaptor stimulator of interferon (IFN) genes (STING) were constitutively expressed in granulosa cells. Transfection with VACV70, a synthetic vaccinia virus (VACV) DNA analogue, induced the expression of type I interferons (IFNA/B) and major inflammatory cytokines (TNFA and IL6) through IRF3 and NF-κB activation, respectively...
March 28, 2017: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/28314590/inflammasome-activation-triggers-caspase-1-mediated-cleavage-of-cgas-to-regulate-responses-to-dna-virus-infection
#8
Yutao Wang, Xiaohan Ning, Pengfei Gao, Shuxian Wu, Mengyin Sha, Mengze Lv, Xiang Zhou, Juyi Gao, Run Fang, Guangxun Meng, Xiaodong Su, Zhengfan Jiang
Viral infection triggers host innate immune responses that result in the production of various cytokines including type I interferons (IFN), activation of inflammasomes, and programmed cell death of the infected cells. Tight control of inflammatory cytokine production is crucial for the triggering of an effective immune response that can resolve the infection without causing host pathology. In examining the inflammatory response of Asc(-/-) and Casp1(-/-) macrophages, we found that deficiency in these molecules resulted in increased IFN production upon DNA virus infection, but not RNA virus challenge...
March 21, 2017: Immunity
https://www.readbyqxmd.com/read/28297677/recombinant-bcg-expressing-esx-1-of-mycobacterium-marinum-combines-low-virulence-with-cytosolic-immune-signaling-and-improved-tb-protection
#9
Matthias I Gröschel, Fadel Sayes, Sung Jae Shin, Wafa Frigui, Alexandre Pawlik, Mickael Orgeur, Robin Canetti, Nadine Honoré, Roxane Simeone, Tjip S van der Werf, Wilbert Bitter, Sang-Nae Cho, Laleh Majlessi, Roland Brosch
Recent insights into the mechanisms by which Mycobacterium tuberculosis, the etiologic agent of human tuberculosis, is recognized by cytosolic nucleotide sensors have opened new avenues for rational vaccine design. The only licensed anti-tuberculosis vaccine, Mycobacterium bovis BCG, provides limited protection. A feature of BCG is the partial deletion of the ESX-1 type VII secretion system, which governs phagosomal rupture and cytosolic pattern recognition, key intracellular phenotypes linked to increased immune signaling...
March 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/28273161/the-e3-ubiquitin-ligase-rnf185-facilitates-the-cgas-mediated-innate-immune-response
#10
Qiang Wang, Liyuan Huang, Ze Hong, Zhongshi Lv, Zhaomin Mao, Yijun Tang, Xiufang Kong, Senlin Li, Ye Cui, Heng Liu, Lele Zhang, Xiaojie Zhang, Lindi Jiang, Chen Wang, Qin Zhou
The cyclic GMP-AMP synthase (cGAS), upon cytosolic DNA stimulation, catalyzes the formation of the second messenger 2'3'-cGAMP, which then binds to stimulator of interferon genes (STING) and activates downstream signaling. It remains to be elucidated how the cGAS enzymatic activity is modulated dynamically. Here, we reported that the ER ubiquitin ligase RNF185 interacted with cGAS during HSV-1 infection. Ectopic-expression or knockdown of RNF185 respectively enhanced or impaired the IRF3-responsive gene expression...
March 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28224203/nucleic-acid-sensing-pattern-recognition-receptors-in-the-development-of-colorectal-cancer-and-colitis
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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...
February 14, 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
#17
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-1-ul24-abrogates-the-dna-sensing-signal-pathway-by-inhibiting-nf-%C3%AE%C2%BAb-activation
#18
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 antiviral genes such as type I interferons (IFNs), and the production of inflammatory cytokines. HSV-1 UL24 is widely conserved among members of the herpesviruses family and is essential for efficient viral replication...
April 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28095500/senp7-potentiates-cgas-activation-by-relieving-sumo-mediated-inhibition-of-cytosolic-dna-sensing
#19
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-the-cgas-sting-mediated-cytosolic-dna-sensing-pathway-via-its-virion-host-shutoff-protein-ul41
#20
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 the cGAS/STING-mediated DNA-sensing signal is crucial for host defense against many viruses, especially for DNA viruses, few viral components have been identified to specifically target this signaling pathway...
March 15, 2017: Journal of Virology
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