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cGAS Sting

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https://www.readbyqxmd.com/read/29322423/assessing-the-cgas-cgamp-sting-activity-of-cancer-cells
#1
Geneviève Pépin, Michael P Gantier
DNA sensing by the STING pathway is emerging to be a crucial component of the antitumor immune response. Although it plays a key role in the activation of tumor immune cells, exactly how STING is activated by tumor cells is not fully understood. Recent evidence suggests that cGAS can be directly engaged and produces 2'3'-cyclic-GMP-AMP (cGAMP) within certain tumor cells upon stimulation with DNA damaging agents. Because cGAMP can transfer between adjacent cells, the capacity of tumor cells to produce cGAMP may activate tumor immune cells, even in the absence of functional STING signaling within the tumor...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29298342/the-common-haq-sting-variant-impairs-cgas-dependent-antibacterial-responses-and-is-associated-with-susceptibility-to-legionnaires-disease-in-humans
#2
Juan S Ruiz-Moreno, Lutz Hamann, Javeed A Shah, Annelies Verbon, Frank P Mockenhaupt, Monika Puzianowska-Kuznicka, Jan Naujoks, Leif E Sander, Martin Witzenrath, John C Cambier, Norbert Suttorp, Ralf R Schumann, Lei Jin, Thomas R Hawn, Bastian Opitz
ClinicalTrials.gov DRKS00005274, German Clinical Trials Register.
January 3, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29281834/sting-dependent-signaling-underlies-il-10-controlled-inflammatory-colitis
#3
Jeonghyun Ahn, Sehee Son, Sergio C Oliveira, Glen N Barber
Intestinal immune homeostasis is preserved by commensal bacteria interacting with the host to generate a balanced array of cytokines that are essential for wound repair and for combatting infection. Inflammatory bowel disease (IBD), which can lead to colitis-associated cancer (CAC), is thought to involve chronic microbial irritation following a breach of the mucosal intestinal epithelium. However, the innate immune pathways responsible for regulating these inflammatory processes remain to be fully clarified...
December 26, 2017: Cell Reports
https://www.readbyqxmd.com/read/29251796/lipotoxicity-induces-hepatic-protein-inclusions-through-tbk1-mediated-p62-sqstm1-phosphorylation
#4
Chun-Seok Cho, Hwan-Woo Park, Allison Ho, Ian A Semple, Boyoung Kim, Insook Jang, Haeli Park, Shannon Reilly, Alan R Saltiel, Jun Hee Lee
Obesity commonly leads to hepatic steatosis, which often provokes lipotoxic injuries to hepatocytes that cause non-alcoholic steatohepatitis (NASH). NASH in turn is associated with the accumulation of insoluble protein aggregates that are composed of ubiquitinated proteins and ubiquitin adaptor p62/sequestosome 1 (SQSTM1). The formation of p62 inclusions in hepatocytes is the critical marker that distinguishes simple fatty liver from NASH and predicts a poor prognostic outcome for subsequent liver carcinogenesis...
December 18, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29247853/cytosolic-sensing-of-immuno-stimulatory-dna-the-enemy-within
#5
REVIEW
Rekha Dhanwani, Mariko Takahashi, Sonia Sharma
In the cytoplasm, DNA is sensed as a universal danger signal by the innate immune system. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor/enzyme that catalyzes formation of 2'-5'-cGAMP, an atypical cyclic di-nucleotide second messenger that binds and activates the Stimulator of Interferon Genes (STING), resulting in recruitment of Tank Binding Kinase 1 (TBK1), activation of the transcription factor Interferon Regulatory Factor 3 (IRF3), and trans-activation of innate immune response genes, including type I Interferon cytokines (IFN-I)...
December 13, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/29212905/cyclic-gmp-amp-synthase-is-the-cytosolic-sensor-of-plasmodium-falciparum-genomic-dna-and-activates-type-i-ifn-in-malaria
#6
Carolina Gallego-Marin, Jacob E Schrum, Warrison A Andrade, Scott A Shaffer, Lina F Giraldo, Alvaro M Lasso, Evelyn A Kurt-Jones, Kate A Fitzgerald, Douglas T Golenbock
Innate immune receptors have a key role in the sensing of malaria and initiating immune responses. As a consequence of infection, systemic inflammation emerges and is directly related to signs and symptoms during acute disease. We have previously reported that plasmodial DNA is the primary driver of systemic inflammation in malaria, both within the phagolysosome and in the cytosol of effector cells. In this article, we demonstrate that Plasmodium falciparum genomic DNA delivered to the cytosol of human monocytes binds and activates cyclic GMP-AMP synthase (cGAS)...
December 6, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29203515/brucella-abortus-triggers-a-cgas-independent-sting-pathway-to-induce-host-protection-that-involves-guanylate-binding-proteins-and-inflammasome-activation
#7
Miriam M Costa Franco, Fernanda Marim, Erika S Guimarães, Natan R G Assis, Daiane M Cerqueira, Juliana Alves-Silva, Jerome Harms, Gary Splitter, Judith Smith, Thirumala-Devi Kanneganti, Nina M G P de Queiroz, Delia Gutman, Glen N Barber, Sergio C Oliveira
Immunity against microbes depends on recognition of pathogen-associated molecular patterns by innate receptors. Signaling pathways triggered by Brucella abortus DNA involves TLR9, AIM2, and stimulator of IFN genes (STING). In this study, we observed by microarray analysis that several type I IFN-associated genes, such as IFN-β and guanylate-binding proteins (GBPs), are downregulated in STING knockout (KO) macrophages infected with Brucella or transfected with DNA. Additionally, we determined that STING and cyclic GMP-AMP synthase (cGAS) are important to engage the type I IFN pathway, but only STING is required to induce IL-1β secretion, caspase-1 activation, and GBP2 and GBP3 expression...
December 4, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29189388/cd11c-targeted-delivery-of-dna-to-dendritic-cells-leads-to-cgas-and-sting-dependent-maturation
#8
Marlene F Laursen, Esben Christensen, Laura L T Degn, Kasper Jønsson, Martin R Jakobsen, Ralf Agger, Emil Kofod-Olsen
Immunotherapeutic activation of tumor-specific T cells has proven to be an interesting approach in anticancer treatment. Particularly, anti-CTLA-4 and anti-PD-1/PD-L1 treatment looks promising, and conceivably, even better clinical results might be obtained if such treatment could be combined with boosting the existing tumor-specific T-cell response. One way to achieve this could be by increasing the level of maturation of dendritic cells locally and in the draining lymph nodes. When exposed to cancer cells, dendritic cells may spontaneously mature because of danger-associated molecular patterns derived from the tumor cells...
November 17, 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/29169058/cyclic-di-amp-in-host-pathogen-interactions
#9
REVIEW
Laura Devaux, Pierre-Alexandre Kaminski, Patrick Trieu-Cuot, Arnaud Firon
Cyclic di-AMP (c-di-AMP) is a bacterial signaling nucleotide synthesized by several human pathogens. This widespread and specific bacterial product is recognized by infected host cells to trigger an innate immune response. Detection of c-di-AMP in the host cytosol leads primarily to the induction of type I interferon via the STING-cGAS signaling axis, while being also entangled in the activation of the NF-κB pathway. During their long-standing interaction, host and pathogens have co-evolved to control c-di-AMP activation of innate immunity...
November 20, 2017: Current Opinion in Microbiology
https://www.readbyqxmd.com/read/29156566/cgas-sting-pathway-in-cancer-jekyll-and-hyde-story-of-cancer-immune-response
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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