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cGAS Sting

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https://www.readbyqxmd.com/read/29156566/cgas-sting-pathway-in-cancer-jekyll-and-hyde-story-of-cancer-immune-response
#1
REVIEW
Debojit Bose
The last two decades have witnessed enormous growth in the field of cancer immunity. Mechanistic insights of cancer immunoediting have not only enhanced our understanding but also paved the way to target and/or harness the innate immune system to combat cancer, called cancer immunotherapy. Cyclic GMP-AMP synthase (cGAS)/Stimulator of interferon genes(STING) pathway has recently emerged as nodal player in cancer immunity and is currently being explored as potential therapeutic target. Although therapeutic activation of this pathway has shown promising anti-tumor effects in vivo, evidence also indicates the role of this pathway in inflammation mediated carcinogenesis...
November 18, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29142107/is-inflammatory-micronucleation-the-key-to-a-successful-anti-mitotic-cancer-drug
#2
REVIEW
T J Mitchison, J Pineda, J Shi, S Florian
Paclitaxel is a successful anti-cancer drug that kills cancer cells in two-dimensional culture through perturbation of mitosis, but whether it causes tumour regression by anti-mitotic actions is controversial. Drug candidates that specifically target mitosis, including inhibitors of kinesin-5, AurkA, AurkB and Plk1, disappointed in the clinic. Current explanations for this discrepancy include pharmacokinetic differences and hypothetical interphase actions of paclitaxel. Here, we discuss post-mitotic micronucleation as a special activity of taxanes that might explain their higher activity in solid tumours...
November 2017: Open Biology
https://www.readbyqxmd.com/read/29106411/extrachromosomal-telomere-repeat-dna-is-linked-to-alt-development-via-cgas-sting-dna-sensing-pathway
#3
Yi-An Chen, Yi-Ling Shen, Hsuan-Yu Hsia, Yee-Peng Tiang, Tzu-Ling Sung, Liuh-Yow Chen
Extrachromosomal telomere repeat (ECTR) DNA is unique to cancer cells that maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, but the role of ECTRs in ALT development remains elusive. We found that induction of ECTRs in normal human fibroblasts activated the cGAS-STING-TBK1-IRF3 signaling axis to trigger IFNβ production and a type I interferon response, resulting in cell-proliferation defects. In contrast, ALT cancer cells are commonly defective in sensing cytosolic DNA. We found that STING expression was inhibited in ALT cancer cell lines and transformed ALT cells...
November 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29106401/irf3-and-type-i-interferons-fuel-a-fatal-response-to-myocardial-infarction
#4
Kevin R King, Aaron D Aguirre, Yu-Xiang Ye, Yuan Sun, Jason D Roh, Richard P Ng, Rainer H Kohler, Sean P Arlauckas, Yoshiko Iwamoto, Andrej Savol, Ruslan I Sadreyev, Mark Kelly, Timothy P Fitzgibbons, Katherine A Fitzgerald, Timothy Mitchison, Peter Libby, Matthias Nahrendorf, Ralph Weissleder
Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections and cancer, but excessive IRF3 activation and type I IFN production cause autoinflammatory conditions such as Aicardi-Goutières syndrome and STING-associated vasculopathy of infancy (SAVI). Myocardial infarction (MI) elicits inflammation, but the dominant molecular drivers of MI-associated inflammation remain unclear. Here we show that ischemic cell death and uptake of cell debris by macrophages in the heart fuel a fatal response to MI by activating IRF3 and type I IFN production...
November 6, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29097162/innate-sensing-and-cell-autonomous-resistance-pathways-in-legionella-pneumophila-infection
#5
REVIEW
Jan Naujoks, Juliane Lippmann, Norbert Suttorp, Bastian Opitz
Legionella pneumophila is a facultative intracellular bacterium which can cause a severe pneumonia called Legionnaires' disease after inhalation of contaminated water droplets and replication in alveolar macrophages. The innate immune system is generally able to sense and -in most cases- control L. pneumophila infection. Comorbidities and genetic risk factors, however, can compromise the immune system and high infection doses might overwhelm its capacity, thereby enabling L. pneumophila to grow and disseminate inside the lung...
October 27, 2017: International Journal of Medical Microbiology: IJMM
https://www.readbyqxmd.com/read/29074428/identification-and-function-analysis-of-canine-stimulator-of-interferon-gene-sting
#6
Yuxiang Zhang, Mengyan Zhu, Gairu Li, Jie Liu, Xiaofeng Zhai, Ruyi Wang, Junyan Zhang, Gang Xing, Jinyan Gu, Liping Yan, Jing Lei, Haifeng Sun, Zhiyu Shi, Fei Liu, Boli Hu, Shuo Su, Jiyong Zhou
Stimulator of interferon gene (STING) plays an important role in the cyclic GMP-AMP synthase (cGAS)-mediated activation of type I IFN responses. In this study, we identified and cloned canine STING gene. Full-length STING encodes a 375 amino acid product that shares the highest similarity with feline STING. Highest levels of mRNA of canine STING were detected in the spleen and lungs while the lowest levels in the heart and muscle. Analysis of its cellular localization showed that STING is localizes to the endoplasmic reticulum...
October 24, 2017: Microbial Pathogenesis
https://www.readbyqxmd.com/read/29054471/innate-immunity-and-tolerance-toward-mitochondria
#7
REVIEW
Anthony Rongvaux
Mitochondria are intracellular organelles that originate from a bacterial symbiont, and they retain multiple features of this bacterial ancestry. The immune system evolved to detect the presence of invading pathogens, including bacteria, to eliminate them by a diversity of antimicrobial mechanisms and to mount long-term protective immunity. Due to their bacterial ancestry, mitochondria are sensed by the innate immune system, and trigger inflammatory responses comparable to those induced by pathogenic bacteria...
October 17, 2017: Mitochondrion
https://www.readbyqxmd.com/read/29033128/the-dna-inflammasome-in-human-myeloid-cells-is-initiated-by-a-sting-cell-death-program-upstream-of-nlrp3
#8
Moritz M Gaidt, Thomas S Ebert, Dhruv Chauhan, Katharina Ramshorn, Francesca Pinci, Sarah Zuber, Fionan O'Duill, Jonathan L Schmid-Burgk, Florian Hoss, Raymund Buhmann, Georg Wittmann, Eicke Latz, Marion Subklewe, Veit Hornung
Detection of cytosolic DNA constitutes a central event in the context of numerous infectious and sterile inflammatory conditions. Recent studies have uncovered a bipartite mode of cytosolic DNA recognition, in which the cGAS-STING axis triggers antiviral immunity, whereas AIM2 triggers inflammasome activation. Here, we show that AIM2 is dispensable for DNA-mediated inflammasome activation in human myeloid cells. Instead, detection of cytosolic DNA by the cGAS-STING axis induces a cell death program initiating potassium efflux upstream of NLRP3...
November 16, 2017: Cell
https://www.readbyqxmd.com/read/29030458/a-noncanonical-function-of-cgamp-in-inflammasome-priming-and-activation
#9
Karen V Swanson, Robert D Junkins, Cathryn J Kurkjian, Elizabeth Holley-Guthrie, Avani A Pendse, Rachid El Morabiti, Alex Petrucelli, Glen N Barber, Chris A Benedict, Jenny P-Y Ting
Recognition of pathogen-associated molecular patterns and danger-associated molecular patterns by host cells is an important step in innate immune activation. The DNA sensor cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) binds to DNA and produces cGAMP, which in turn binds to stimulator of interferon genes (STING) to activate IFN-I. Here we show that cGAMP has a noncanonical function in inflammasome activation in human and mouse cells. Inflammasome activation requires two signals, both of which are activated by cGAMP...
October 13, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28982551/a-cell-based-high-throughput-screening-assay-for-the-discovery-of-cgas-sting-pathway-agonists
#10
Bowei Liu, Liudi Tang, Xiaohui Zhang, Julia Ma, Mohit Sehgal, Junjun Cheng, Xuexiang Zhang, Yan Zhou, Yanming Du, John Kulp, Ju-Tao Guo, Jinhong Chang
Stimulator of interferon genes (STING) is an endoplasmic reticulum transmembrane protein that serves as a molecular hub for activation of interferon and inflammatory cytokine response by multiple cellular DNA sensors. Not surprisingly, STING has been demonstrated to play an important role in host defense against microorganisms and pharmacologic activation of STING is considered as an attractive strategy to treat viral diseases and boost antitumor immunity. In light of this we established a HepAD38-derived reporter cell line that expresses firefly luciferase in response to the activation of cyclic GMP-AMP synthase (cGAS)-STING pathway for high throughput screening (HTS) of small molecular human STING agonists...
November 2017: Antiviral Research
https://www.readbyqxmd.com/read/28976970/cytoplasmic-chromatin-triggers-inflammation-in-senescence-and-cancer
#11
Zhixun Dou, Kanad Ghosh, Maria Grazia Vizioli, Jiajun Zhu, Payel Sen, Kirk J Wangensteen, Johayra Simithy, Yemin Lan, Yanping Lin, Zhuo Zhou, Brian C Capell, Caiyue Xu, Mingang Xu, Julia E Kieckhaefer, Tianying Jiang, Michal Shoshkes-Carmel, K M Ahasan Al Tanim, Glen N Barber, John T Seykora, Sarah E Millar, Klaus H Kaestner, Benjamin A Garcia, Peter D Adams, Shelley L Berger
Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence, a form of terminal cell-cycle arrest associated with pro-inflammatory responses. The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS-STING (cyclic GMP-AMP synthase linked to stimulator of interferon genes) pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer...
October 4, 2017: Nature
https://www.readbyqxmd.com/read/28968560/human-b-cells-fail-to-secrete-type-i-interferons-upon-cytoplasmic-dna-exposure
#12
Anna M Gram, Chenglong Sun, Sanne L Landman, Timo Oosenbrug, Hester J Koppejan, Mark J Kwakkenbos, Rob C Hoeben, Søren R Paludan, Maaike E Ressing
Most cells are believed to be capable of producing type I interferons (IFN I) as part of an innate immune response against, for instance, viral infections. In macrophages, IFN I is potently induced upon cytoplasmic exposure to foreign nucleic acids. Infection of these cells with herpesviruses leads to triggering of the DNA sensors interferon-inducible protein 16 (IFI16) and cyclic GMP-AMP (cGAMP) synthase (cGAS). Thereby, the stimulator of interferon genes (STING) and the downstream molecules TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) are sequentially activated culminating in IFN I secretion...
November 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28947539/priming-and-activation-of-inflammasome-by-canarypox-virus-vector-alvac-via-the-cgas-ifi16-sting-type-i-ifn-pathway-and-aim2-sensor
#13
Fengliang Liu, Qingli Niu, Xiuzhen Fan, Connie Liu, Jie Zhang, Zhi Wei, Wei Hou, Thirumala-Devi Kanneganti, Merlin L Robb, Jerome H Kim, Nelson L Michael, Jiaren Sun, Lynn Soong, Haitao Hu
Viral vectors derived from different virus families, including poxvirus (canarypox virus vector ALVAC) and adenovirus (human Ad5 vector), have been widely used in vaccine development for a range of human diseases including HIV/AIDS. Less is known about the mechanisms underlying the host innate response to these vectors. Increasing evidence from clinical vaccine trials testing different viral vectors has suggested the importance of understanding basic elements of host-viral vector interactions. In this study, we investigated the innate interactions of APCs with two commonly used HIV vaccine vectors, ALVAC and Ad5, and identified AIM2 as an innate sensor for ALVAC, triggering strong inflammasome activation in both human and mouse APCs...
November 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28939760/nemo-ikk%C3%AE-are-essential-for-irf3-and-nf-%C3%AE%C2%BAb-activation-in-the-cgas-sting-pathway
#14
Run Fang, Chenguang Wang, Qifei Jiang, Mengze Lv, Pengfei Gao, Xiaoyu Yu, Ping Mu, Rui Zhang, Sheng Bi, Ji-Ming Feng, Zhengfan Jiang
Cytosolic dsDNA activates the cyclic GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway to produce cytokines, including type I IFNs. The roles of many critical proteins, including NEMO, IKKβ, and TBK1, in this pathway are unclear because of the lack of an appropriate system to study. In this article, we report that lower FBS concentrations in culture medium conferred high sensitivities to dsDNA in otherwise unresponsive cells, whereas higher FBS levels abrogated this sensitivity. Based on this finding, we demonstrated genetically that NEMO was critically involved in the cGAS-STING pathway...
November 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28930687/the-rab2b-garil5-complex-promotes-cytosolic-dna-induced-innate-immune-responses
#15
Michihiro Takahama, Mitsunori Fukuda, Norihiko Ohbayashi, Tatsuya Kozaki, Takuma Misawa, Toru Okamoto, Yoshiharu Matsuura, Shizuo Akira, Tatsuya Saitoh
Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that induces the IFN antiviral response. However, the regulatory mechanisms that mediate cGAS-triggered signaling have not been fully explored. Here, we show the involvement of a small GTPase, RAB2B, and its effector protein, Golgi-associated RAB2B interactor-like 5 (GARIL5), in the cGAS-mediated IFN response. RAB2B-deficiency affects the IFN response induced by cytosolic DNA. Consistent with this, RAB2B deficiency enhances replication of vaccinia virus, a DNA virus...
September 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/28921470/cgas-sting-activation-in-the-tumor-microenvironment-and-its-role-in-cancer-immunity
#16
Geneviève Pépin, Michael P Gantier
Stimulator of interferon (IFN) genes (STING) is a key mediator in the immune response to cytoplasmic DNA sensed by cyclic GMP-AMP (cGAMP) synthase (cGAS). After synthesis by cGAS, cGAMP acts as a second messenger activating STING in the cell harboring cytoplasmic DNA but also in adjacent cells through gap junction transfer. While the role of the cGAS-STING pathway in pathogen detection is now well established, its importance in cancer immunity has only recently started to emerge. Nonetheless, STING appears to be an essential component in the recruitment of immune cells to the tumor microenvironment, which is paramount to immune clearance of the tumor...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28901270/reappraisal-of-antimalarials-in-interferonopathies-new-perspectives-for-old-drugs
#17
Elisa Piscianz, Eva Cuzzoni, Rajan Sharma, Alessandra Tesser, Pooja Sapra, Alberto Tommasini
The story of antimalarials as antinflammatory drugs dates back several centuries. Chinin, the extract of the Cinchona bark, has been exploited since the 18th century for its antimalarial and antifebrile properties. Later, during the Second World War, the broad use of antimalarials allowed arguing their antirheumatic effect on soldiers. Since then, these drugs have been broadly used to treat Systemic Lupus Erythematosus, but, only recently, have the molecular mechanisms of action been partly clarified. Inhibitory action on vacuole function and trafficking has been considered for decades the main mechanism of the action of antimalarials, affecting the activation of phagocytes and dendritic cells...
September 11, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28900038/socs1-is-an-inducible-negative-regulator-of-interferon-%C3%AE-ifn-%C3%AE-induced-gene-expression-in-vivo
#18
Tanja Blumer, Mairene Coto-Llerena, Francois H T Duong, Markus H Heim
Type I (α and β) and type III (λ) IFNs are induced upon viral infection through host sensory pathways that activate IFN regulatory factors (IRFs) and nuclear factor κB. Secreted IFNs induce autocrine and paracrine signaling through the JAK-STAT pathway, leading to the transcriptional induction of hundreds of IFN-stimulated genes, among them sensory pathway components such as cGAS, STING, RIG-I, MDA5, and the transcription factor IRF7, which enhance the induction of IFN-αs and IFN-λs. This positive feedback loop enables a very rapid and strong host response that, at some point, has to be controlled by negative regulators to maintain tissue homeostasis...
October 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28889286/detection-of-cyclic-dinucleotides-by-sting
#19
Xiao-Xia Du, Xiao-Dong Su
STING (stimulator of interferon genes) is an essential signaling adaptor protein mediating cytosolic DNA-induced innate immunity for both microbial invasion and self-DNA leakage. STING is also a direct receptor for cytosolic cyclic dinucleotides (CDNs), including the microbial secondary messengers c-di-GMP (3',3'-cyclic di-GMP), 3',3'cGAMP (3',3'-cyclic GMP-AMP), and mammalian endogenous 2',3'cGAMP (2',3'-cyclic GMP-AMP) synthesized by cGAS (cyclic GMP-AMP synthase). Upon CDN binding, STING undergoes a conformational change to enable signal transduction by phosphorylation and finally to active IRF3 (Interferon regulatory factor 3) for type I interferon production...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28874664/signalling-strength-determines-proapoptotic-functions-of-sting
#20
Muhammet F Gulen, Ute Koch, Simone M Haag, Fabian Schuler, Lionel Apetoh, Andreas Villunger, Freddy Radtke, Andrea Ablasser
Mammalian cells use cytosolic nucleic acid receptors to detect pathogens and other stress signals. In innate immune cells the presence of cytosolic DNA is sensed by the cGAS-STING signalling pathway, which initiates a gene expression programme linked to cellular activation and cytokine production. Whether the outcome of the STING response varies between distinct cell types remains largely unknown. Here we show that T cells exhibit an intensified STING response, which leads to the expression of a distinct set of genes and results in the induction of apoptosis...
September 5, 2017: Nature Communications
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