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https://www.readbyqxmd.com/read/27902332/inhibition-of-hepatitis-b-virus-replication-by-activation-of-the-cgas-sting-pathway
#1
Jing He, Ruidong Hao, Dan Liu, Xing Liu, Shaoshuai Wu, Shuting Guo, Yuan Wang, Deyin Guo
Cyclic GMP-AMP (cGAMP) synthase (cGAS) senses cytosolic DNA and catalyzes synthesis of the second messenger cGAMP, which activates the downstream signaling 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 cGAS pathway in the restriction of HBV replication in infection systems remain to be elucidated. In this study, we showed that the 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...
October 31, 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
#2
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...
November 18, 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
#3
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
https://www.readbyqxmd.com/read/27824940/invertebrate-iridescent-virus-6-a-dna-virus-stimulates-a-mammalian-innate-immune-response-through-rig-i-like-receptors
#4
Laura R H Ahlers, Reginaldo G Bastos, Aoi Hiroyasu, Alan G Goodman
Insects are not only major vectors of mammalian viruses, but are also host to insect-restricted viruses that can potentially be transmitted to mammals. While mammalian innate immune responses to arboviruses are well studied, less is known about how mammalian cells respond to viruses that are restricted to infect only invertebrates. Here we demonstrate that IIV-6, a DNA virus of the family Iridoviridae, is able to induce a type I interferon-dependent antiviral immune response in mammalian cells. Although IIV-6 is a DNA virus, we demonstrate that the immune response activated during IIV-6 infection is mediated by the RIG-I-like receptor (RLR) pathway, and not the canonical DNA sensing pathway via cGAS/STING...
2016: PloS One
https://www.readbyqxmd.com/read/27813878/antimalarial-drugs-as-immune-modulators-new-mechanisms-for-old-drugs
#5
Jie An, Mark Minie, Tomikazu Sasaki, Joshua J Woodward, Keith B Elkon
The best known of the naturally occurring antimalarial compounds are quinine, extracted from cinchona bark, and artemisinin (qinghao), extracted from Artemisia annua in China. These and other derivatives are now chemically synthesized and remain the mainstay of therapy to treat malaria. The beneficial effects of several of the antimalarial drugs (AMDs) on clinical features of autoimmune disorders were discovered by chance during WorldWar II. In this review, we discuss the chemistry of AMDs and their mechanisms of action, emphasizing how they may impact multiple pathways of innate immunity...
October 21, 2016: Annual Review of Medicine
https://www.readbyqxmd.com/read/27793594/cross-regulation-of-two-type-i-interferon-signaling-pathways-in-plasmacytoid-dendritic-cells-controls-anti-malaria-immunity-and-host-mortality
#6
Xiao Yu, Baowei Cai, Mingjun Wang, Peng Tan, Xilai Ding, Jian Wu, Jian Li, Qingtian Li, Pinghua Liu, Changsheng Xing, Helen Y Wang, Xin-Zhuan Su, Rong-Fu Wang
Type I interferon (IFN) is critical for controlling pathogen infection; however, its regulatory mechanisms in plasmacytoid cells (pDCs) still remain unclear. Here, we have shown that nucleic acid sensors cGAS-, STING-, MDA5-, MAVS-, or transcription factor IRF3-deficient mice produced high amounts of type I IFN-α and IFN-β (IFN-α/β) in the serum and were resistant to lethal plasmodium yoelii YM infection. Robust IFN-α/β production was abolished when gene encoding nucleic acid sensor TLR7, signaling adaptor MyD88, or transcription factor IRF7 was ablated or pDCs were depleted...
November 15, 2016: Immunity
https://www.readbyqxmd.com/read/27764250/histone-h2b-ifi16-recognition-of-nuclear-herpesviral-genome-induces-cytoplasmic-interferon-%C3%AE-responses
#7
Jawed Iqbal, Mairaj Ahmed Ansari, Binod Kumar, Dipanjan Dutta, Arunava Roy, Leela Chikoti, Gina Pisano, Sujoy Dutta, Shahrooz Vahedi, Mohanan Valiya Veettil, Bala Chandran
IFI16 (gamma-interferon-inducible protein 16), a predominantly nuclear protein involved in transcriptional regulation, also functions as an innate immune response DNA sensor and induces the IL-1β and antiviral type-1 interferon-β (IFN-β) cytokines. We have shown that IFI16, in association with BRCA1, functions as a sequence independent nuclear sensor of episomal dsDNA genomes of KSHV, EBV and HSV-1. Recognition of these herpesvirus genomes resulted in IFI16 acetylation, BRCA1-IFI16-ASC-procaspase-1 inflammasome formation, cytoplasmic translocation, and IL-1β generation...
October 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27736643/cgas-mediated-innate-immunity-spreads-intercellularly-through-hiv-1-env-induced-membrane-fusion-sites
#8
Shuting Xu, Aurélie Ducroux, Aparna Ponnurangam, Gabrielle Vieyres, Sergej Franz, Mathias Müsken, Thomas Zillinger, Angelina Malassa, Ellen Ewald, Veit Hornung, Winfried Barchet, Susanne Häussler, Thomas Pietschmann, Christine Goffinet
Upon sensing cytoplasmic retroviral DNA in infected cells, cyclic GMP-AMP (cGAMP) synthase (cGAS) produces the cyclic dinucleotide cGAMP, which activates STING to trigger a type I interferon (IFN) response. We find that membrane fusion-inducing contact between donor cells expressing the HIV envelope (Env) and primary macrophages endogenously expressing the HIV receptor CD4 and coreceptor enable intercellular transfer of cGAMP. This cGAMP exchange results in STING-dependent antiviral IFN responses in target macrophages and protection from HIV infection...
October 12, 2016: Cell Host & Microbe
https://www.readbyqxmd.com/read/27707838/activation-of-sting-dependent-innate-immune-signaling-by-s-phase-specific-dna-damage-in-breast-cancer
#9
Eileen E Parkes, Steven M Walker, Laura E Taggart, Nuala McCabe, Laura A Knight, Richard Wilkinson, Karen D McCloskey, Niamh E Buckley, Kienan I Savage, Manuel Salto-Tellez, Stephen McQuaid, Mary T Harte, Paul B Mullan, D Paul Harkin, Richard D Kennedy
BACKGROUND: Previously we identified a DNA damage response-deficient (DDRD) molecular subtype within breast cancer. A 44-gene assay identifying this subtype was validated as predicting benefit from DNA-damaging chemotherapy. This subtype was defined by interferon signaling. In this study, we address the mechanism of this immune response and its possible clinical significance. METHODS: We used immunohistochemistry (IHC) to characterize immune infiltration in 184 breast cancer samples, of which 65 were within the DDRD subtype...
January 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/27706894/cgas-cgamp-sting-the-three-musketeers-of-cytosolic-dna-sensing-and-signaling
#10
Jianli Tao, Xiang Zhou, Zhengfan Jiang
Innate immunity is the first line of host defense against invading pathogens. The detection of aberrant nucleic acids which represent some conserved PAMPs triggers robust type I IFN-mediated innate immune responses. Host- or pathogen-derived cytosolic DNA binds and activates the DNA sensor cGAS, which synthesizes the second messenger 2'3'-cGAMP and triggers STING-dependent downstream signaling. Here, we highlight recent progress in cGAS-cGAMP-STING, the Three Musketeers of cytosolic DNA sensing and signaling, and their essential roles in infection, autoimmune diseases, and cancer...
October 5, 2016: IUBMB Life
https://www.readbyqxmd.com/read/27705945/interaction-between-susceptibility-loci-in-cgas-sting-pathway-mhc-gene-and-hpv-infection-on-the-risk-of-cervical-precancerous-lesions-in-chinese-population
#11
Di Xiao, Weihuang Huang, Meiling Ou, Congcong Guo, Xingguang Ye, Yang Liu, Man Wang, Baohuan Zhang, Na Zhang, Shiqi Huang, Jiankun Zang, Zixing Zhou, Zihao Wen, Chengli Zeng, Chenfei Wu, Chuican Huang, Xiangcai Wei, Guang Yang, Chunxia Jing
Human papillomavirus (HPV) infection is a definite risk factor for cervical cancer. Nevertheless, only some infected individuals actually develop cervical cancer. The cGAS-STING pathway in innate immunity plays an important role in protecting against HPV infection. Chen et al. described that the rs2516448 SNP in the MHC locus may affect susceptibility to cervical cancer, a finding that we attempted to replicate in a Chinese population. To investigate the effects of cGAS, STING and MHC polymorphisms on susceptibility to cervical precancerous lesions, 9 SNPs were analyzed in 164 cervical precancerous lesion cases and 428 controls...
October 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27696330/dna-sensor-cgas-mediated-immune-recognition
#12
REVIEW
Pengyan Xia, Shuo Wang, Pu Gao, Guangxia Gao, Zusen Fan
The host takes use of pattern recognition receptors (PRRs) to defend against pathogen invasion or cellular damage. Among microorganism-associated molecular patterns detected by host PRRs, nucleic acids derived from bacteria or viruses are tightly supervised, providing a fundamental mechanism of host defense. Pathogenic DNAs are supposed to be detected by DNA sensors that induce the activation of NFκB or TBK1-IRF3 pathway. DNA sensor cGAS is widely expressed in innate immune cells and is a key sensor of invading DNAs in several cell types...
November 2016: Protein & Cell
https://www.readbyqxmd.com/read/27680683/recurrent-loss-of-sting-signaling-in-melanoma-correlates-with-susceptibility-to-viral-oncolysis
#13
Tianli Xia, Hiroyasu Konno, Glen N Barber
The innate immune regulator STING stimulates cytokine production in response to the presence of cytosolic DNA, which can arise following DNA damage. Extrinsic STING signaling is also needed for antigen-presenting cells (APC) to stimulate antitumor T cell immunity. Here we show that STING signaling is recurrently suppressed in melanoma cells, where this event may enable immune escape after DNA damage. Mechanistically STING signaling was suppressed most frequently by epigenetic silencing of either STING or the cyclic GMP-AMP synthase (cGAS), which generates STING-activating cyclic dinucleotides (CDNs) after binding cytosolic DNA species...
September 28, 2016: Cancer Research
https://www.readbyqxmd.com/read/27648547/regulation-and-function-of-the-cgas-sting-pathway-of-cytosolic-dna-sensing
#14
REVIEW
Qi Chen, Lijun Sun, Zhijian J Chen
The recognition of microbial nucleic acids is a major mechanism by which the immune system detects pathogens. Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates innate immune responses through production of the second messenger cGAMP, which activates the adaptor STING. The cGAS-STING pathway not only mediates protective immune defense against infection by a large variety of DNA-containing pathogens but also detects tumor-derived DNA and generates intrinsic antitumor immunity. However, aberrant activation of the cGAS pathway by self DNA can also lead to autoimmune and inflammatory disease...
September 20, 2016: Nature Immunology
https://www.readbyqxmd.com/read/27637147/sumoylation-promotes-the-stability-of-the-dna-sensor-cgas-and-the-adaptor-sting-to-regulate-the-kinetics-of-response-to-dna-virus
#15
Ming-Ming Hu, Qing Yang, Xue-Qin Xie, Chen-Yang Liao, Heng Lin, Tian-Tian Liu, Lei Yin, Hong-Bing Shu
During viral infection, sensing of cytosolic DNA by the cyclic GMP-AMP synthase (cGAS) activates the adaptor protein STING and triggers an antiviral response. Little is known about the mechanisms that determine the kinetics of activation and deactivation of the cGAS-STING pathway, ensuring effective but controlled innate antiviral responses. Here we found that the ubiquitin ligase Trim38 targets cGas for sumoylation in uninfected cells and during the early phase of viral infection. Sumoylation of cGas prevented its polyubiquitination and degradation...
September 20, 2016: Immunity
https://www.readbyqxmd.com/read/27500737/the-mechanism-for-type-i-interferon-induction-by-mycobacterium-tuberculosis-is-bacterial-strain-dependent
#16
Kirsten E Wiens, Joel D Ernst
Type I interferons (including IFNαβ) are innate cytokines that may contribute to pathogenesis during Mycobacterium tuberculosis (Mtb) infection. To induce IFNβ, Mtb must gain access to the host cytosol and trigger stimulator of interferon genes (STING) signaling. A recently proposed model suggests that Mtb triggers STING signaling through bacterial DNA binding cyclic GMP-AMP synthase (cGAS) in the cytosol. The aim of this study was to test the generalizability of this model using phylogenetically distinct strains of the Mtb complex (MTBC)...
August 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27477283/restriction-by-samhd1-limits-cgas-sting-dependent-innate-and-adaptive-immune-responses-to-hiv-1
#17
Jonathan Maelfait, Anne Bridgeman, Adel Benlahrech, Chiara Cursi, Jan Rehwinkel
SAMHD1 is a restriction factor for HIV-1 infection. SAMHD1 mutations cause the autoinflammatory Aicardi-Goutières syndrome that is characterized by chronic type I interferon (IFN) secretion. We show that the spontaneous IFN response in SAMHD1-deficient cells and mice requires the cGAS/STING cytosolic DNA-sensing pathway. We provide genetic evidence that cell-autonomous control of lentivirus infection in myeloid cells by SAMHD1 limits virus-induced production of IFNs and the induction of co-stimulatory markers...
August 9, 2016: Cell Reports
https://www.readbyqxmd.com/read/27428429/upregulated-line-1-activity-in-the-fanconi-anemia-cancer-susceptibility-syndrome-leads-to-spontaneous-pro-inflammatory-cytokine-production
#18
Christelle Brégnard, Jessica Guerra, Stéphanie Déjardin, Frank Passalacqua, Monsef Benkirane, Nadine Laguette
Fanconi Anemia (FA) is a genetic disorder characterized by elevated cancer susceptibility and pro-inflammatory cytokine production. Using SLX4(FANCP) deficiency as a working model, we questioned the trigger for chronic inflammation in FA. We found that absence of SLX4 caused cytoplasmic DNA accumulation, including sequences deriving from active Long INterspersed Element-1 (LINE-1), triggering the cGAS-STING pathway to elicit interferon (IFN) expression. In agreement, absence of SLX4 leads to upregulated LINE-1 retrotransposition...
June 2016: EBioMedicine
https://www.readbyqxmd.com/read/27414497/group-b-streptococcus-degrades-cyclic-di-amp-to-modulate-sting-dependent-type-i-interferon-production
#19
Warrison A Andrade, Arnaud Firon, Tobias Schmidt, Veit Hornung, Katherine A Fitzgerald, Evelyn A Kurt-Jones, Patrick Trieu-Cuot, Douglas T Golenbock, Pierre-Alexandre Kaminski
Induction of type I interferon (IFN) in response to microbial pathogens depends on a conserved cGAS-STING signaling pathway. The presence of DNA in the cytoplasm activates cGAS, while STING is activated by cyclic dinucleotides (cdNs) produced by cGAS or from bacterial origins. Here, we show that Group B Streptococcus (GBS) induces IFN-β production almost exclusively through cGAS-STING-dependent recognition of bacterial DNA. However, we find that GBS expresses an ectonucleotidase, CdnP, which hydrolyzes extracellular bacterial cyclic-di-AMP...
July 13, 2016: Cell Host & Microbe
https://www.readbyqxmd.com/read/27392950/the-chemistry-of-the-noncanonical-cyclic-dinucleotide-2-3-cgamp-and-its-analogs
#20
Frank Schwede, Hans-Gottfried Genieser, Andreas Rentsch
The cyclic dinucleotides (CDNs) cyclic diguanosine monophosphate (c-diGMP) and cyclic diadenosine monophosphate (c-diAMP) with two canonical 3'→5' internucleotide linkages are ubiquitous second messenger molecules in bacteria, regulating a multitude of physiological processes. Recently the noncanonical CDN cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) featuring a mixed linkage, which consists of a 2'→5' and a 3'→5' internucleotide bond, has been identified as a signaling molecule in metazoan species in late 2012...
July 9, 2016: Handbook of Experimental Pharmacology
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