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cGAS Sting

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
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
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
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
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
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...
September 30, 2016: Protein & Cell
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
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
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
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
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
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
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
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
Chan-Wang J Lio, Bryan McDonald, Mariko Takahashi, Rekha Dhanwani, Nikita Sharma, Jenny Huang, Elise Pham, Chris A Benedict, Sonia Sharma
UNLABELLED: Several innate sensing pathways contribute to the control of early cytomegalovirus (CMV) infection, leading to a multiphasic type I interferon (IFN-I) response that limits viral replication and promotes host defenses. Toll-like receptor (TLR)-dependent pathways induce IFN-I production in CMV-infected plasmacytoid dendritic cells; however, the initial burst of IFN-I that occurs within the first few hours in vivo is TLR independent and emanates from stromal cells. Here we show that primary human endothelial cells mount robust IFN-I responses to human CMV that are dependent upon cyclic GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3) signaling...
September 1, 2016: Journal of Virology
Martin K Thomsen, Ramya Nandakumar, Daniela Stadler, Antje Malo, Roser Marin Valls, Fan Wang, Line S Reinert, Frederik Dagnaes-Hansen, Anne Kruse Hollensen, Jacob Giehm Mikkelsen, Ulrike Protzer, Søren R Paludan
UNLABELLED: Hepatitis B virus (HBV) is a major human pathogen, and about one third of the global population will be exposed to the virus in their lifetime. HBV infects hepatocytes, where it replicates its DNA and infection can lead to acute and chronic hepatitis with a high risk of liver cirrhosis and hepatocellular carcinoma. Despite this, there is limited understanding of how HBV establishes chronic infections. In recent years it has emerged that foreign DNA potently stimulates the innate immune response, particularly type 1 interferon (IFN) production; and this occurs through a pathway dependent on the DNA sensor cyclic guanosine monophosphate-adenosine monophosphate synthase and the downstream adaptor protein stimulator of IFN genes (STING)...
September 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Warrison A Andrade, Sarika Agarwal, Shunyan Mo, Scott A Shaffer, Joseph P Dillard, Tobias Schmidt, Veit Hornung, Katherine A Fitzgerald, Evelyn A Kurt-Jones, Douglas T Golenbock
The innate immune system is the first line of defense against Neisseria gonorrhoeae (GC). Exposure of cells to GC lipooligosaccharides induces a strong immune response, leading to type I interferon (IFN) production via TLR4/MD-2. In addition to living freely in the extracellular space, GC can invade the cytoplasm to evade detection and elimination. Double-stranded DNA introduced into the cytosol binds and activates the enzyme cyclic-GMP-AMP synthase (cGAS), which produces 2'3'-cGAMP and triggers STING/TBK-1/IRF3 activation, resulting in type I IFN expression...
June 14, 2016: Cell Reports
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
Ruihua Ma, Tiantian Ji, Degao Chen, Wenqian Dong, Huafeng Zhang, Xiaonan Yin, Jingwei Ma, Xiaoyu Liang, Yi Zhang, Guanxin Shen, Xiaofeng Qin, Bo Huang
Despite identification of macrophages in tumors (tumor-associated macrophages, TAM) as potential targets for cancer therapy, the origin and function of TAM in the context of malignancy remain poorly characterized. Here, we show that microparticles (MPs), as a by-product, released by tumor cells act as a general mechanism to mediate M2 polarization of TAM. Taking up tumor MPs by macrophages is a very efficient process, which in turn results in the polarization of macrophages into M2 type, not only leading to promoting tumor growth and metastasis but also facilitating cancer stem cell development...
April 2016: Oncoimmunology
Christian Bode, Mario Fox, Poonam Tewary, Almut Steinhagen, Richard K Ellerkmann, Dennis Klinman, Georg Baumgarten, Veit Hornung, Folkert Steinhagen
Plasmacytoid dendritic cells (pDCs) are a major source of type I interferon (IFN) and are important for host defense by sensing microbial DNA via TLR9. pDCs also play a critical role in the pathogenesis of IFN-driven autoimmune diseases. Yet, this autoimmune reaction is caused by the recognition of self-DNA and has been linked to TLR9-independent pathways. Increasing evidence suggests that the cytosolic DNA receptor cyclic GMP-AMP (cGAMP) synthase (cGAS) is a critical component in the detection of pathogens and contributes to autoimmune diseases...
July 2016: European Journal of Immunology
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