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https://www.readbyqxmd.com/read/28934246/discovery-of-pf-06928215-as-a-high-affinity-inhibitor-of-cgas-enabled-by-a-novel-fluorescence-polarization-assay
#1
Justin Hall, Amy Brault, Fabien Vincent, Shawn Weng, Hong Wang, Darren Dumlao, Ann Aulabaugh, Dikran Aivazian, Dana Castro, Ming Chen, Jeffrey Culp, Ken Dower, Joseph Gardner, Steven Hawrylik, Douglas Golenbock, David Hepworth, Mark Horn, Lyn Jones, Peter Jones, Eicke Latz, Jing Li, Lih-Ling Lin, Wen Lin, David Lin, Frank Lovering, Nootaree Niljanskul, Ryan Nistler, Betsy Pierce, Olga Plotnikova, Daniel Schmitt, Suman Shanker, James Smith, William Snyder, Timothy Subashi, John Trujillo, Edyta Tyminski, Guoxing Wang, Jimson Wong, Bruce Lefker, Leslie Dakin, Karen Leach
Cyclic GMP-AMP synthase (cGAS) initiates the innate immune system in response to cytosolic dsDNA. After binding and activation from dsDNA, cGAS uses ATP and GTP to synthesize 2', 3' -cGAMP (cGAMP), a cyclic dinucleotide second messenger with mixed 2'-5' and 3'-5' phosphodiester bonds. Inappropriate stimulation of cGAS has been implicated in autoimmune disease such as systemic lupus erythematosus, thus inhibition of cGAS may be of therapeutic benefit in some diseases; however, the size and polarity of the cGAS active site makes it a challenging target for the development of conventional substrate-competitive inhibitors...
2017: PloS One
https://www.readbyqxmd.com/read/28930687/the-rab2b-garil5-complex-promotes-cytosolic-dna-induced-innate-immune-responses
#2
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
#3
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/28920955/mir-25-93-mediates-hypoxia-induced-immunosuppression-by-repressing-cgas
#4
Min-Zu Wu, Wei-Chung Cheng, Su-Feng Chen, Shin Nieh, Carolyn O'Connor, Chia-Lin Liu, Wen-Wei Tsai, Cheng-Jang Wu, Lorena Martin, Yaoh-Shiang Lin, Kou-Juey Wu, Li-Fan Lu, Juan Carlos Izpisua Belmonte
The mechanisms by which hypoxic tumours evade immunological pressure and anti-tumour immunity remain elusive. Here, we report that two hypoxia-responsive microRNAs, miR-25 and miR-93, are important for establishing an immunosuppressive tumour microenvironment by downregulating expression of the DNA sensor cGAS. Mechanistically, miR-25/93 targets NCOA3, an epigenetic factor that maintains basal levels of cGAS expression, leading to repression of cGAS during hypoxia. This allows hypoxic tumour cells to escape immunological responses induced by damage-associated molecular pattern molecules, specifically the release of mitochondrial DNA...
September 18, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28918319/determination-of-chlorogenic-acids-and-caffeine-in-homemade-brewed-coffee-prepared-under-various-conditions
#5
Jong-Sup Jeon, Han-Taek Kim, Il-Hyung Jeong, Se-Ra Hong, Moon-Seog Oh, Kwang-Hee Park, Jae-Han Shim, A M Abd El-Aty
Coffee, a complex mixture of more than 800 volatile compounds, is one of the most valuable commodity in the world, whereas caffeine and chlorogenic acids (CGAs) are the most common compounds. CGAs are mainly composed of caffeoylquinic acids (CQAs), dicaffeoylquinic acids (diCQAs), and feruloylquinic acids (FQAs). The major CGAs in coffee are neochlorogenic acid (3-CQA), cryptochlorogenic acid (4-CQA), and chlorogenic acid (5-CQA). Many studies have shown that it is possible to separate the isomers of FQAs by high-performance liquid chromatography (HPLC)...
August 31, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28902841/cgas-senses-long-and-hmgb-tfam-bound-u-turn-dna-by-forming-protein-dna-ladders
#6
Liudmila Andreeva, Björn Hiller, Dirk Kostrewa, Charlotte Lässig, Carina C de Oliveira Mann, David Jan Drexler, Andreas Maiser, Moritz Gaidt, Heinrich Leonhardt, Veit Hornung, Karl-Peter Hopfner
Cytosolic DNA arising from intracellular pathogens triggers a powerful innate immune response. It is sensed by cyclic GMP-AMP synthase (cGAS), which elicits the production of type I interferons by generating the second messenger 2'3'-cyclic-GMP-AMP (cGAMP). Endogenous nuclear or mitochondrial DNA can also be sensed by cGAS under certain conditions, resulting in sterile inflammation. The cGAS dimer binds two DNA ligands shorter than 20 base pairs side-by-side, but 20-base-pair DNA fails to activate cGAS in vivo and is a poor activator in vitro...
September 21, 2017: Nature
https://www.readbyqxmd.com/read/28901270/reappraisal-of-antimalarials-in-interferonopathies-new-perspectives-for-old-drugs
#7
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-ifn-lambda-induced-gene-expression-in-vivo
#8
Tanja Blumer, Mairene Coto-Llerena, Francois H T Duong, Markus H Heim
Type I (α and β) and type III (λ) interferons (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 signalling through the JAK-Stat pathway leading to the transcriptional induction of hundreds of IFN stimulated genes (ISGs), amongst them sensory pathway components such as cGAS, STING, RIG-I, MDA5 and the transcription factor IRF7 that enhance the induction of IFNαs and IFNλss...
September 12, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28889286/detection-of-cyclic-dinucleotides-by-sting
#9
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/28886908/dna-sensing-across-the-tree-of-life
#10
REVIEW
Stefania Gallucci, Massimo E Maffei
From plants to mammals, pattern recognition receptors (PRRs) specifically recognize DNA, as a potential marker of either infection or damage. These receptors play critical roles in inflammation, immunity, and pathogen resistance. Importantly, given the ubiquity of DNA, its sensing must be tightly regulated. DNA localization plays a key role in recognition, as highlighted by Toll-like receptor 9 (TLR9) in the endosomal compartment and cyclic GMP-AMP synthase (cGAS) and absent in melanoma 2 (AIM2) in the cytoplasm...
September 5, 2017: Trends in Immunology
https://www.readbyqxmd.com/read/28882413/cgas-conducts-micronuclei-dna-surveillance
#11
Carina C de Oliveira Mann, Philip J Kranzusch
DNA damage elicits a potent proinflammatory immune response. A collection of four papers now reveals that micronuclear DNA is a new cell intrinsic immunostimulatory molecule, and that accumulation of the immune sensor cyclic GMP-AMP synthase (cGAS) in micronuclei leads to a cell-cycle-dependent proinflammatory response following DNA damage.
September 4, 2017: Trends in Cell Biology
https://www.readbyqxmd.com/read/28874664/signalling-strength-determines-proapoptotic-functions-of-sting
#12
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
https://www.readbyqxmd.com/read/28871191/pharmacogenetics-of-methylphenidate-in-childhood-attention-deficit-hyperactivity-disorder-long-term-effects
#13
Clara I Gomez-Sanchez, Juan J Carballo, Rosa Riveiro-Alvarez, Victor Soto-Insuga, Maria Rodrigo, Ignacio Mahillo-Fernandez, Francisco Abad-Santos, Rafael Dal-Ré, Carmen Ayuso
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in which a significant proportion of patients do not respond to treatment. The objective of this study was to examine the role of genetic risk variants in the response to treatment with methylphenidate (MPH). The effectiveness of MPH was evaluated based on variations in the CGI-S and CGAS scales over a 12-month treatment period using linear mixed effects models. A total of 208 ADHD patients and 34 polymorphisms were included in the analysis...
September 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28860276/dna-damage-induced-immune-response-micronuclei-provide-key-platform
#14
Nelson O Gekara
DNA damage-induced activation of the cytoplasmic DNA sensor cGAS influences the outcome of infections, autoinflammation, and cancer. Recent studies by Harding et al. (2017. Nature. http://dx.doi.org/10.1038/nature23470), Mackenzie et al. (2017. Nature. http://dx.doi.org/10.1038/nature23449), and Bartsch et al. (2017. Human Molecular Genetics. https://doi.org/10.1093/hmg/ddx283) demonstrate a role for micronuclei formation in DNA damage-induced immune activation.
August 31, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28855731/dna-sensing-in-senescence
#15
Marina Ruiz de Galarreta, Amaia Lujambio
Cellular senescence, a cell-autonomous growth arrest program, also executes pleiotropic non-cell-autonomous activities through the senescence-associated secretory phenotype (SASP). The innate cGAS-STING DNA-sensing pathway is now shown to regulate senescence by recognizing cytosolic DNA and inducing SASP factors, uncovering an unexpected link between these two previously unrelated pathways.
August 31, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28830822/human-microglia-and-astrocytes-express-cgas-sting-viral-sensing-components
#16
Austin M Jeffries, Ian Marriott
While microglia and astrocytes are known to produce key inflammatory and anti-viral mediators following infection with replicative DNA viruses, the mechanisms by which these cell types perceive such threats are poorly understood. Recently, cyclic GMP-AMP synthase (cGAS) has been identified as an important cytosolic sensor for DNA viruses and retroviruses in peripheral leukocytes. Here we confirm the ability of human microglial and astrocytic cell lines and primary human glia to respond to foreign intracellular double stranded DNA...
August 19, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28830732/cgas-sting-and-cancer-dichotomous-roles-in-tumor-immunity-and-development
#17
REVIEW
Kevin W Ng, Erin A Marshall, John C Bell, Wan L Lam
cGMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) sensing has emerged as a key regulator of innate immune responses to both exogenous and endogenous DNA. Recent studies reveal critical roles for this pathway in natural antitumor immunity across cancer types as well as in immune checkpoint blockade therapy. However, it is also clear that some tumors evade cGAS-STING-mediated immune responses, and immunomodulatory therapeutics are currently being explored to target this pathway. Finally, we also discuss recent observations that cGAS-STING-mediated inflammation may promote tumor initiation, growth, and metastasis in certain malignancies and how this may complicate the utility of this pathway in therapeutic development...
August 19, 2017: Trends in Immunology
https://www.readbyqxmd.com/read/28829159/early-onset-bipolar-disorder-characteristics-and-outcomes-in-the-clinic
#18
Daniel F Connor, Julian D Ford, Geraldine S Pearson, Victoria L Scranton, Asha Dusad
OBJECTIVE: To assess patient characteristics and clinician-rated outcomes for children diagnosed with early-onset bipolar disorder in comparison to a depressive disorders cohort from a single clinic site. To assess predictors of bipolar treatment response. METHODS: Medical records from 714 consecutive pediatric patients evaluated and treated at an academic tertiary child and adolescent psychiatry clinic between 2006 and 2012 were reviewed. Charts of bipolar children (n = 49) and children with depressive disorders (n = 58) meeting study inclusion/exclusion criteria were compared on variables assessing clinical characteristics, treatments, and outcomes...
August 22, 2017: Journal of Child and Adolescent Psychopharmacology
https://www.readbyqxmd.com/read/28827471/length-does-matter-for-cgas
#19
Michael P Gantier
No abstract text is available yet for this article.
August 21, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28827286/anti-cancer-drug-hmba-acts-as-an-adjuvant-during-intracellular-bacterial-infections-by-inducing-type-i-ifn-through-sting
#20
Akshamal Mihiranga Gamage, Kok-Onn Lee, Yunn-Hwen Gan
The anti-proliferative agent hexamethylene bisacetamide (HMBA) belongs to a class of hybrid bipolar compounds developed more than 30 y ago for their ability to induce terminal differentiation of transformed cells. Recently, HMBA has also been shown to trigger HIV transcription from latently infected cells, via a CDK9/HMBA inducible protein-1 dependent process. However, the effect of HMBA on the immune response has not been explored. We observed that pretreatment of human peripheral blood mononuclear cells with HMBA led to a markedly increased production of IL-12 and IFN-γ, but not of TNF-α, IL-6, and IL-8 upon subsequent infection with Burkholderia pseudomallei and Salmonella enterica HMBA treatment was also associated with better intracellular bacterial control...
August 21, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
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