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cGAS STING TBK1 IRF3

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https://www.readbyqxmd.com/read/28771599/ester-alkaloids-from-cephalotaxus-interfere-with-the-2-3-cgamp-induced-type-i-interferon-pathway-in-vitro
#1
Gayoung Park, Sun Yeou Kim, Yoon-Jae Song
Dysregulated activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway by self-DNA contributes to interferonopathy and promotes autoimmune diseases. To identify potential suppressors of STING-induced type I interferon (IFN) induction, ethanol extracts of medicinal plants were screened for inhibitory activity against IFN-ß promoter activation. Notably, 70% ethanol extract of Cephalotaxus koreana specifically down-regulated STING-induced, but not TBK1- or IRF3-induced, IFN-ß promoter activity...
2017: PloS One
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
#2
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 focused on the obligate pathogen Mycobacterium avium ssp paratuberculosis (MAP) and the opportunistic M...
April 19, 2017: Virulence
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...
July 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
REVIEW
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'-cyclic GMP-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)...
June 20, 2017: Annual Review of Biochemistry
https://www.readbyqxmd.com/read/28132838/human-cytomegalovirus-tegument-protein-ul82-inhibits-sting-mediated-signaling-to-evade-antiviral-immunity
#5
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/28069950/chronic-innate-immune-activation-of-tbk1-suppresses-mtorc1-activity-and-dysregulates-cellular-metabolism
#6
Maroof Hasan, Vijay K Gonugunta, Nicole Dobbs, Aktar Ali, Guillermo Palchik, Maria A Calvaruso, Ralph J DeBerardinis, Nan Yan
Three-prime repair exonuclease 1 knockout (Trex1(-/-)) mice suffer from systemic inflammation caused largely by chronic activation of the cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) signaling pathway. We showed previously that Trex1-deficient cells have reduced mammalian target of rapamycin complex 1 (mTORC1) activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1(-/-) mice and cells that revealed both cellular and systemic metabolic defects, including reduced mitochondrial respiration and increased glycolysis, energy expenditure, and fat metabolism...
January 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28041929/the-chlamydia-trachomatis-inclusion-membrane-protein-cpos-counteracts-sting-mediated-cellular-surveillance-and-suicide-programs
#7
Barbara S Sixt, Robert J Bastidas, Ryan Finethy, Ryan M Baxter, Victoria K Carpenter, Guido Kroemer, Jörn Coers, Raphael H Valdivia
Evading cell death is critical for Chlamydia to maintain a replicative niche, but the underlying mechanisms are unknown. We screened a library of Chlamydia mutants for modulators of cell death. Inactivation of the inclusion membrane protein CpoS (Chlamydia promoter of survival) induced rapid apoptotic and necrotic death in infected cells. The protection afforded by CpoS is limited to the inclusion in which it resides, indicating that it counteracts a spatially restricted pro-death signal. CpoS-deficient Chlamydia induced an exacerbated type I interferon response that required the host cGAS/STING/TBK1/IRF3 signaling pathway...
January 11, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/27764250/histone-h2b-ifi16-recognition-of-nuclear-herpesviral-genome-induces-cytoplasmic-interferon-%C3%AE-responses
#8
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/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/27696330/dna-sensor-cgas-mediated-immune-recognition
#10
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/27234299/hsv-1-icp27-targets-the-tbk1-activated-sting-signalsome-to-inhibit-virus-induced-type-i-ifn%C3%A2-expression
#11
Maria H Christensen, Søren B Jensen, Juho J Miettinen, Stefanie Luecke, Thaneas Prabakaran, Line S Reinert, Thomas Mettenleiter, Zhijian J Chen, David M Knipe, Rozanne M Sandri-Goldin, Lynn W Enquist, Rune Hartmann, Trine H Mogensen, Stephen A Rice, Tuula A Nyman, Sampsa Matikainen, Søren R Paludan
Herpes simplex virus (HSV) 1 stimulates type I IFN expression through the cGAS-STING-TBK1 signaling axis. Macrophages have recently been proposed to be an essential source of IFN during viral infection. However, it is not known how HSV-1 inhibits IFN expression in this cell type. Here, we show that HSV-1 inhibits type I IFN induction through the cGAS-STING-TBK1 pathway in human macrophages, in a manner dependent on the conserved herpesvirus protein ICP27. This viral protein was expressed de novo in macrophages with early nuclear localization followed by later translocation to the cytoplasm where ICP27 prevented activation of IRF3...
July 1, 2016: EMBO Journal
https://www.readbyqxmd.com/read/27076640/herpes-simplex-virus-1-serine-protease-vp24-blocks-the-dna-sensing-signal-pathway-by-abrogating-activation-of-interferon-regulatory-factor-3
#12
Dandan Zhang, Chenhe Su, Chunfu Zheng
UNLABELLED: The interferon (IFN)-mediated antiviral response is a central aspect of host defense; however, viruses have evolved multiple strategies to counteract IFN-mediated responses in order to successfully infect the host. Herpes simplex virus 1 (HSV-1), a typical human-restricted DNA virus, is capable of counteracting host immune responses via several distinct viral proteins, thus establishing a lifelong latent infection. In this study, we demonstrate that the VP24 protein, a serine protease of HSV-1 essential for the formation and maturation of capsids, is a novel antagonist of the beta interferon (IFN-β) pathway...
June 15, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27043414/s6k-sting-interaction-regulates-cytosolic-dna-mediated-activation-of-the-transcription-factor-irf3
#13
Fuan Wang, Tommy Alain, Kristy J Szretter, Kyle Stephenson, Jonathan G Pol, Matthew J Atherton, Huy-Dung Hoang, Bruno D Fonseca, Chadi Zakaria, Lan Chen, Zainab Rangwala, Adam Hesch, Eva Sin Yan Chan, Carly Tuinman, Mehul S Suthar, Zhaozhao Jiang, Ali A Ashkar, George Thomas, Sara C Kozma, Michael Gale, Katherine A Fitzgerald, Michael S Diamond, Karen Mossman, Nahum Sonenberg, Yonghong Wan, Brian D Lichty
Cytosolic DNA-mediated activation of the transcription factor IRF3 is a key event in host antiviral responses. Here we found that infection with DNA viruses induced interaction of the metabolic checkpoint kinase mTOR downstream effector and kinase S6K1 and the signaling adaptor STING in a manner dependent on the DNA sensor cGAS. We further demonstrated that the kinase domain, but not the kinase function, of S6K1 was required for the S6K1-STING interaction and that the TBK1 critically promoted this process. The formation of a tripartite S6K1-STING-TBK1 complex was necessary for the activation of IRF3, and disruption of this signaling axis impaired the early-phase expression of IRF3 target genes and the induction of T cell responses and mucosal antiviral immunity...
May 2016: Nature Immunology
https://www.readbyqxmd.com/read/26915459/trim9-short-isoform-preferentially-promotes-dna-and-rna-virus-induced-production-of-type-i-interferon-by-recruiting-gsk3%C3%AE-to-tbk1
#14
Yunfei Qin, Qingxiang Liu, Shuo Tian, Weihong Xie, Jun Cui, Rong-Fu Wang
Type I interferon (IFN) is an important component of antiviral innate immune signaling mediated by viral DNA and RNA recognition by the DNA sensor cGAS and RNA sensors RIG-I and MDA5. Activation of these DNA and RNA sensors leads to the recruitment of STING and MAVS, respectively, and converges on TANK-binding kinase 1 (TBK1) signaling for subsequent phosphorylation of IFN regulatory factor 3 (IRF3). However, the mechanisms that control TBK1 activation are still poorly defined. Here, we identify tripartite motif 9 short isoform (TRIM9s) as a positive regulator in type I IFN signaling...
May 2016: Cell Research
https://www.readbyqxmd.com/read/26811480/cytoplasmic-isoforms-of-kaposi-sarcoma-herpesvirus-lana-recruit-and-antagonize-the-innate-immune-dna-sensor-cgas
#15
Guigen Zhang, Baca Chan, Naira Samarina, Bizunesh Abere, Magdalena Weidner-Glunde, Anna Buch, Andreas Pich, Melanie M Brinkmann, Thomas F Schulz
The latency-associated nuclear antigen (LANA) of Kaposi sarcoma herpesvirus (KSHV) is mainly localized and functions in the nucleus of latently infected cells, playing a pivotal role in the replication and maintenance of latent viral episomal DNA. In addition, N-terminally truncated cytoplasmic isoforms of LANA, resulting from internal translation initiation, have been reported, but their function is unknown. Using coimmunoprecipitation and MS, we found the cGMP-AMP synthase (cGAS), an innate immune DNA sensor, to be a cellular interaction partner of cytoplasmic LANA isoforms...
February 23, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/26048136/the-cytosolic-sensor-cgas-detects-mycobacterium-tuberculosis-dna-to-induce-type-i-interferons-and-activate-autophagy
#16
Robert O Watson, Samantha L Bell, Donna A MacDuff, Jacqueline M Kimmey, Elie J Diner, Joanna Olivas, Russell E Vance, Christina L Stallings, Herbert W Virgin, Jeffery S Cox
Type I interferons (IFNs) are critical mediators of antiviral defense, but their elicitation by bacterial pathogens can be detrimental to hosts. Many intracellular bacterial pathogens, including Mycobacterium tuberculosis, induce type I IFNs following phagosomal membrane perturbations. Cytosolic M. tuberculosis DNA has been implicated as a trigger for IFN production, but the mechanisms remain obscure. We report that the cytosolic DNA sensor, cyclic GMP-AMP synthase (cGAS), is required for activating IFN production via the STING/TBK1/IRF3 pathway during M...
June 10, 2015: Cell Host & Microbe
https://www.readbyqxmd.com/read/25811886/induction-of-interferon-stimulated-genes-by-irf3-promotes-replication-of-toxoplasma-gondii
#17
Tanmay Majumdar, Saurabh Chattopadhyay, Evgeny Ozhegov, Jayeeta Dhar, Ramansu Goswami, Ganes C Sen, Sailen Barik
Innate immunity is the first line of defense against microbial insult. The transcription factor, IRF3, is needed by mammalian cells to mount innate immune responses against many microbes, especially viruses. IRF3 remains inactive in the cytoplasm of uninfected cells; upon virus infection, it gets phosphorylated and then translocates to the nucleus, where it binds to the promoters of antiviral genes and induces their expression. Such genes include type I interferons (IFNs) as well as Interferon Stimulated Genes (ISGs)...
March 2015: PLoS Pathogens
https://www.readbyqxmd.com/read/25810395/casein-kinase-ii-controls-tbk1-irf3-activation-in-ifn-response-against-viral-infection
#18
Min Du, Jinghua Liu, Xia Chen, Yadong Xie, Chuanping Yuan, Yu Xiang, Bing Sun, Ke Lan, Mingzhou Chen, Sharmy J James, Yongliang Zhang, Jin Zhong, Hui Xiao
By sensing viral nucleic acids, host innate receptors elicit signaling pathways converging on TBK1-IFN regulatory factor (IRF)3 axis in mediating IFN-αβ induction and defense mechanisms. In contrast, viruses have evolved with diverse immune evasion/interference mechanisms to undermine innate receptor signaling and IFN response. In this regard, approaches enabling host to overcome such immune evasion/interference mechanisms are urgently needed to combat infections by epidemic/pandemic viruses. In this study, we report that protein kinase CK2 serves as a key component controlling TBK1 and IRF3 activation in IFN-inducing TLR, RIG-I-like receptors, and cGAS/STING signaling pathways...
May 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/25790474/single-amino-acid-change-in-sting-leads-to-constitutive-active-signaling
#19
Eric D Tang, Cun-Yu Wang
The production of cytokines by the immune system in response to cytosolic DNA plays an important role in host defense, autoimmune disease, and cancer immunogenicity. Recently a cytosolic DNA signaling pathway that is dependent on the endoplasmic reticulum adaptor and cyclic dinucleotide sensor protein STING has been identified. Association of cytosolic DNA with cyclic-GMP-AMP synthase (cGAS) activates its enzymatic activity to synthesize the cyclic dinucleotide second messenger cGAMP from GTP and ATP. Direct detection of cGAMP by STING triggers the activation of IRF3 and NF-kB, and the production of type I interferons and proinflammatory cytokines...
2015: PloS One
https://www.readbyqxmd.com/read/25636800/phosphorylation-of-innate-immune-adaptor-proteins-mavs-sting-and-trif-induces-irf3-activation
#20
Siqi Liu, Xin Cai, Jiaxi Wu, Qian Cong, Xiang Chen, Tuo Li, Fenghe Du, Junyao Ren, You-Tong Wu, Nick V Grishin, Zhijian J Chen
During virus infection, the adaptor proteins MAVS and STING transduce signals from the cytosolic nucleic acid sensors RIG-I and cGAS, respectively, to induce type I interferons (IFNs) and other antiviral molecules. Here we show that MAVS and STING harbor two conserved serine and threonine clusters that are phosphorylated by the kinases IKK and/or TBK1 in response to stimulation. Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1...
March 13, 2015: Science
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