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cGAS Sting

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https://www.readbyqxmd.com/read/29760876/rinck-mediated-monoubiquitination-of-cgas-promotes-antiviral-innate-immune-responses
#1
Zhao-Shan Liu, Zi-Yu Zhang, Hong Cai, Ming Zhao, Jie Mao, Jiang Dai, Tian Xia, Xue-Min Zhang, Tao Li
Background: As an important danger signal, the presence of DNA in cytoplasm triggers potent immune responses. Cyclic GMP-AMP synthase (cGAS) is a recently characterized key sensor for cytoplasmic DNA. The engagement of cGAS with DNA leads to the synthesis of a second messenger, cyclic GMP-AMP (cGAMP), which binds and activates the downstream adaptor protein STING to promote type I interferon production. Although cGAS has been shown to play a pivotal role in innate immunity, the exact regulation of cGAS activation is not fully understood...
2018: Cell & Bioscience
https://www.readbyqxmd.com/read/29694889/pro-inflammation-associated-with-a-gain-of-function-mutation-r284s-in-the-innate-immune-sensor-sting
#2
Hiroyasu Konno, Ivan K Chinn, Diana Hong, Jordan S Orange, James R Lupski, Alejandra Mendoza, Luis A Pedroza, Glen N Barber
The cellular sensor stimulator of interferon genes (STING) initiates type I interferon (IFN) and cytokine production following association with cyclic dinucleotides (CDNs) generated from intracellular bacteria or via a cellular synthase, cGAS, after binding microbial or self-DNA. Although essential for protecting the host against infection, unscheduled STING signaling is now known to be responsible for a variety of autoinflammatory disorders. Here, we report a gain-of-function mutation in STING (R284S), isolated from a patient who did not require CDNs to augment activity and who manifested a constitutively active phenotype...
April 24, 2018: Cell Reports
https://www.readbyqxmd.com/read/29686682/targeting-cytosolic-nucleic-acid-sensing-pathways-for-cancer-immunotherapies
#3
REVIEW
Sandra Iurescia, Daniela Fioretti, Monica Rinaldi
The innate immune system provides the first line of defense against pathogen infection though also influences pathways involved in cancer immunosurveillance. The innate immune system relies on a limited set of germ line-encoded sensors termed pattern recognition receptors (PRRs), signaling proteins and immune response factors. Cytosolic receptors mediate recognition of danger damage-associated molecular patterns (DAMPs) signals. Once activated, these sensors trigger multiple signaling cascades, converging on the production of type I interferons and proinflammatory cytokines...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29670289/samhd1-acts-at-stalled-replication-forks-to-prevent-interferon-induction
#4
Flavie Coquel, Maria-Joao Silva, Hervé Técher, Karina Zadorozhny, Sushma Sharma, Jadwiga Nieminuszczy, Clément Mettling, Elodie Dardillac, Antoine Barthe, Anne-Lyne Schmitz, Alexy Promonet, Alexandra Cribier, Amélie Sarrazin, Wojciech Niedzwiedz, Bernard Lopez, Vincenzo Costanzo, Lumir Krejci, Andrei Chabes, Monsef Benkirane, Yea-Lih Lin, Philippe Pasero
SAMHD1 was previously characterized as a dNTPase that protects cells from viral infections. Mutations in SAMHD1 are implicated in cancer development and in a severe congenital inflammatory disease known as Aicardi-Goutières syndrome. The mechanism by which SAMHD1 protects against cancer and chronic inflammation is unknown. Here we show that SAMHD1 promotes degradation of nascent DNA at stalled replication forks in human cell lines by stimulating the exonuclease activity of MRE11. This function activates the ATR-CHK1 checkpoint and allows the forks to restart replication...
April 18, 2018: Nature
https://www.readbyqxmd.com/read/29662124/stag2-deficiency-induces-interferon-responses-via-cgas-sting-pathway-and-restricts-virus-infection
#5
Siyuan Ding, Jonathan Diep, Ningguo Feng, Lili Ren, Bin Li, Yaw Shin Ooi, Xin Wang, Kevin F Brulois, Linda L Yasukawa, Xingnan Li, Calvin J Kuo, David A Solomon, Jan E Carette, Harry B Greenberg
Cohesin is a multi-subunit nuclear protein complex that coordinates sister chromatid separation during cell division. Highly frequent somatic mutations in genes encoding core cohesin subunits have been reported in multiple cancer types. Here, using a genome-wide CRISPR-Cas9 screening approach to identify host dependency factors and novel innate immune regulators of rotavirus (RV) infection, we demonstrate that the loss of STAG2, an important component of the cohesin complex, confers resistance to RV replication in cell culture and human intestinal enteroids...
April 16, 2018: Nature Communications
https://www.readbyqxmd.com/read/29622565/the-cgas-cgamp-sting-pathway-connects-dna-damage-to-inflammation-senescence-and-cancer
#6
REVIEW
Tuo Li, Zhijian J Chen
Detection of microbial DNA is an evolutionarily conserved mechanism that alerts the host immune system to mount a defense response to microbial infections. However, this detection mechanism also poses a challenge to the host as to how to distinguish foreign DNA from abundant self-DNA. Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) is a DNA sensor that triggers innate immune responses through production of the second messenger cyclic GMP-AMP (cGAMP), which binds and activates the adaptor protein STING...
April 5, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29608601/sting-agonists-enable-antiviral-cross-talk-between-human-cells-and-confer-protection-against-genital-herpes-in-mice
#7
Morten K Skouboe, Alice Knudsen, Line S Reinert, Cedric Boularan, Thierry Lioux, Eric Perouzel, Martin K Thomsen, Søren R Paludan
In recent years, there has been an increasing interest in immunomodulatory therapy as a means to treat various conditions, including infectious diseases. For instance, Toll-like receptor (TLR) agonists have been evaluated for treatment of genital herpes. However, although the TLR7 agonist imiquimod was shown to have antiviral activity in individual patients, no significant effects were observed in clinical trials, and the compound also exhibited significant side effects, including local inflammation. Cytosolic DNA is detected by the enzyme cyclic GMP-AMP (2'3'-cGAMP) synthase (cGAS) to stimulate antiviral pathways, mainly through induction of type I interferon (IFN)s...
April 2, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29593264/downregulation-of-cytoplasmic-dnases-is-implicated-in-cytoplasmic-dna-accumulation-and-sasp-in-senescent-cells
#8
Akiko Takahashi, Tze Mun Loo, Ryo Okada, Fumitaka Kamachi, Yoshihiro Watanabe, Masahiro Wakita, Sugiko Watanabe, Shimpei Kawamoto, Kenichi Miyata, Glen N Barber, Naoko Ohtani, Eiji Hara
Accumulating evidence indicates that the senescence-associated secretory phenotype (SASP) contributes to many aspects of physiology and disease. Thus, controlling the SASP will have tremendous impacts on our health. However, our understanding of SASP regulation is far from complete. Here, we show that cytoplasmic accumulation of nuclear DNA plays key roles in the onset of SASP. Although both DNase2 and TREX1 rapidly remove the cytoplasmic DNA fragments emanating from the nucleus in pre-senescent cells, the expression of these DNases is downregulated in senescent cells, resulting in the cytoplasmic accumulation of nuclear DNA...
March 28, 2018: Nature Communications
https://www.readbyqxmd.com/read/29579113/streptococcal-m-protein-promotes-il-10-production-by-cgas-independent-activation-of-the-sting-signaling-pathway
#9
Elin Movert, Julia Lienard, Christine Valfridsson, Therése Nordström, Bengt Johansson-Lindbom, Fredric Carlsson
From an evolutionary point of view a pathogen might benefit from regulating the inflammatory response, both in order to facilitate establishment of colonization and to avoid life-threatening host manifestations, such as septic shock. In agreement with this notion Streptococcus pyogenes exploits type I IFN-signaling to limit detrimental inflammation in infected mice, but the host-pathogen interactions and mechanisms responsible for induction of the type I IFN response have remained unknown. Here we used a macrophage infection model and report that S...
March 26, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29570996/snapshot-cgas-sting-signaling
#10
Lorenzo Galluzzi, Claire Vanpouille-Box, Samuel F Bakhoum, Sandra Demaria
CGAS responds to cytosolic DNA by initiating a STING-dependent response that ultimately engages innate immune effectors to ensure the preservation of organismal homeostasis.
March 22, 2018: Cell
https://www.readbyqxmd.com/read/29558821/suramin-potently-inhibits-cgamp-synthase-cgas-in-thp1-cells-to-modulate-ifn-%C3%AE-levels
#11
Modi Wang, Moloud A Sooreshjani, Clinton Mikek, Clement Opoku-Temeng, Herman O Sintim
AIM: Persistent activation of STING pathway is the basis for several autoimmune diseases. STING is activated by cGAMP, which is produced by cGAS in the presence of DNA. Results/methodology: HPLC-based medium throughput screening for inhibitors of cGAS identified suramin as a potent inhibitor. Unlike other reported cGAS inhibitors, which bind to the ATP/GTP binding site, suramin displaced the bound DNA from cGAS. Addition of suramin to THP1 cells reduced the levels of IFN-β mRNA and protein...
March 21, 2018: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/29548644/sting-dependent-sensing-does-hiv-actually-care
#12
REVIEW
Christian Krapp, Kasper Jønsson, Martin R Jakobsen
Sensing of DNA is essential for the innate immune system to detect threats, like viruses, intracellular bacteria or cellular DNA damage. At the centre of this conserved mammalian mechanism stands the adaptor protein STING. STING is highly regulated and is part of a complex signalling network. This network depends on the sensors cGAS and IFI16 to detect misplaced DNA in the cytoplasm as well as on the kinase TBK1 and the transcription factor IRF3. The DNA sensing machinery has been implicated in many diseases, among others HIV...
March 9, 2018: Cytokine & Growth Factor Reviews
https://www.readbyqxmd.com/read/29547894/a-novel-transcript-isoform-of-sting-that-sequesters-cgamp-and-dominantly-inhibits-innate-nucleic-acid-sensing
#13
Pei-Hui Wang, Sin-Yee Fung, Wei-Wei Gao, Jian-Jun Deng, Yun Cheng, Vidyanath Chaudhary, Kit-San Yuen, Ting-Hin Ho, Ching-Ping Chan, Yan Zhang, Kin-Hang Kok, Wanling Yang, Chi-Ping Chan, Dong-Yan Jin
STING is a core adaptor in innate nucleic acid sensing in mammalian cells, on which different sensing pathways converge to induce type I interferon (IFN) production. Particularly, STING is activated by 2'3'-cGAMP, a cyclic dinucleotide containing mixed phosphodiester linkages and produced by cytoplasmic DNA sensor cGAS. Here, we reported on a novel transcript isoform of STING designated STING-β that dominantly inhibits innate nucleic acid sensing. STING-β without transmembrane domains was widely expressed at low levels in various human tissues and viral induction of STING-β correlated inversely with IFN-β production...
March 14, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29544097/reshaping-of-the-dendritic-cell-chromatin-landscape-and-interferon-pathways-during-hiv-infection
#14
Jarrod S Johnson, Sasha Y Lucas, Lynn M Amon, Stephanie Skelton, Rodolfo Nazitto, Sara Carbonetti, D Noah Sather, Dan R Littman, Alan Aderem
Myeloid dendritic cells (DCs) have the innate capacity to sense pathogens and orchestrate immune responses. However, DCs do not mount efficient immune responses to HIV-1, primarily due to restriction of virus reverse transcription, which prevents accumulation of viral cDNA and limits its detection through the cGAS-STING pathway. By allowing reverse transcription to proceed, we find that DCs detect HIV-1 in distinct phases, before and after virus integration. Blocking integration suppresses, but does not abolish, activation of the transcription factor IRF3, downstream interferon (IFN) responses, and DC maturation...
March 14, 2018: Cell Host & Microbe
https://www.readbyqxmd.com/read/29540580/intracellular-nucleic-acid-sensing-triggers-necroptosis-through-synergistic-type-i-ifn-and-tnf-signaling
#15
Michelle Brault, Tayla M Olsen, Jennifer Martinez, Daniel B Stetson, Andrew Oberst
The sensing of viral nucleic acids within the cytosol is essential for the induction of innate immune responses following infection. However, this sensing occurs within cells that have already been infected. The death of infected cells can be beneficial to the host by eliminating the virus's replicative niche and facilitating the release of inflammatory mediators. In this study, we show that sensing of intracellular DNA or RNA by cGAS-STING or RIG-I-MAVS, respectively, leads to activation of RIPK3 and necroptosis in bone marrow-derived macrophages...
March 14, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29525183/line1-contributes-to-autoimmunity-through-both-rig-i-and-mda5-mediated-rna-sensing-pathways
#16
Ke Zhao, Juan Du, Yanfeng Peng, Peng Li, Shaohua Wang, Yu Wang, Jingwei Hou, Jian Kang, Wenwen Zheng, Shucheng Hua, Xiao-Fang Yu
Improper host immune activation leads to the development of the autoimmune disease Aicardi-Goutières syndrome (AGS), which is attributed to defined genetic mutations in such proteins as TREX1 and ADAR1. The mechanism of immune activation in AGS patients has not been thoroughly elucidated to date. In this study, we report that endogenous LINE1 components trigger IFNβ production in multiple human cell types, including those defective for cGAS/STING-mediated DNA sensing. In these cells, LINE1 DNA synthesis and retrotransposition were not required for LINE1-triggered immune activation, but RNA sensing pathways were essential...
March 7, 2018: Journal of Autoimmunity
https://www.readbyqxmd.com/read/29496741/attenuation-of-cgas-sting-signaling-is-mediated-by-a-p62-sqstm1-dependent-autophagy-pathway-activated-by-tbk1
#17
Thaneas Prabakaran, Chiranjeevi Bodda, Christian Krapp, Bao-Cun Zhang, Maria H Christensen, Chenglong Sun, Line Reinert, Yujia Cai, Søren B Jensen, Morten K Skouboe, Jens R Nyengaard, Craig B Thompson, Robert Jan Lebbink, Ganes C Sen, Geert van Loo, Rikke Nielsen, Masaaki Komatsu, Lene N Nejsum, Martin R Jakobsen, Mads Gyrd-Hansen, Søren R Paludan
Negative regulation of immune pathways is essential to achieve resolution of immune responses and to avoid excess inflammation. DNA stimulates type I IFN expression through the DNA sensor cGAS, the second messenger cGAMP, and the adaptor molecule STING Here, we report that STING degradation following activation of the pathway occurs through autophagy and is mediated by p62/SQSTM1, which is phosphorylated by TBK1 to direct ubiquitinated STING to autophagosomes. Degradation of STING was impaired in p62-deficient cells, which responded with elevated IFN production to foreign DNA and DNA pathogens...
April 13, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29491158/virulent-poxviruses-inhibit-dna-sensing-by-preventing-sting-activation
#18
Iliana Georgana, Rebecca P Sumner, Greg J Towers, Carlos Maluquer de Motes
Cytosolic recognition of DNA has emerged as a critical cellular mechanism of host immune activation upon pathogen invasion. The central cytosolic DNA sensor cGAS activates STING, which is phosphorylated, dimerises and translocates from the ER to a perinuclear region to mediate IRF-3 activation. Poxviruses are dsDNA viruses replicating in the cytosol and hence likely to trigger cytosolic DNA sensing. Here we investigated the activation of innate immune signalling by 4 different strains of the prototypic poxvirus vaccinia virus (VACV) in a cell line proficient in DNA sensing...
February 28, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29472455/bak-bax-macropores-facilitate-mitochondrial-herniation-and-mtdna-efflux-during-apoptosis
#19
Kate McArthur, Lachlan W Whitehead, John M Heddleston, Lucy Li, Benjamin S Padman, Viola Oorschot, Niall D Geoghegan, Stephane Chappaz, Sophia Davidson, Hui San Chin, Rachael M Lane, Marija Dramicanin, Tahnee L Saunders, Canny Sugiana, Romina Lessene, Laura D Osellame, Teng-Leong Chew, Grant Dewson, Michael Lazarou, Georg Ramm, Guillaume Lessene, Michael T Ryan, Kelly L Rogers, Mark F van Delft, Benjamin T Kile
Mitochondrial apoptosis is mediated by BAK and BAX, two proteins that induce mitochondrial outer membrane permeabilization, leading to cytochrome c release and activation of apoptotic caspases. In the absence of active caspases, mitochondrial DNA (mtDNA) triggers the innate immune cGAS/STING pathway, causing dying cells to secrete type I interferon. How cGAS gains access to mtDNA remains unclear. We used live-cell lattice light-sheet microscopy to examine the mitochondrial network in mouse embryonic fibroblasts...
February 23, 2018: Science
https://www.readbyqxmd.com/read/29472271/tnf%C3%AE-and-radioresistant-stromal-cells-are-essential-for-therapeutic-efficacy-of-cyclic-dinucleotide-sting-agonists-in-nonimmunogenic-tumors
#20
Brian J Francica, Ali Ghasemzadeh, Anthony L Desbien, Debebe Theodros, Kelsey E Sivick, Gabrielle L Reiner, Laura Hix Glickman, Ariel E Marciscano, Andrew B Sharabi, Meredith L Leong, Sarah M McWhirter, Thomas W Dubensky, Drew M Pardoll, Charles G Drake
The cGAS-STING cytosolic DNA sensing pathway may play an integral role in the initiation of antitumor immune responses. Studies evaluating the immunogenicity of various cyclic dinucleotide (CDN) STING agonists administered by intratumoral (i.t.) injection showed potent induction of inflammation, tumor necrosis, and, in some cases, durable tumor-specific adaptive immunity. However, the specific immune mechanisms underlying these responses remain incompletely defined. The majority of these studies have focused on the effect of CDNs on immune cells but have not conclusively interrogated the role of stromal cells in the acute rejection of the CDN-injected tumor...
April 2018: Cancer Immunology Research
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