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Junjie Zhang, Jun Zhao, Simin Xu, Junhua Li, Shanping He, Yi Zeng, Linshen Xie, Na Xie, Ting Liu, Katie Lee, Gil Ju Seo, Lin Chen, Alex C Stabell, Zanxian Xia, Sara L Sawyer, Jae Jung, Canhua Huang, Pinghui Feng
Herpes simplex virus 1 (HSV-1) establishes infections in humans and mice, but some non-human primates exhibit resistance via unknown mechanisms. Innate immune recognition pathways are highly conserved but are pivotal in determining susceptibility to DNA virus infections. We report that variation of a single amino acid residue in the innate immune sensor cGAS determines species-specific inactivation by HSV-1. The HSV-1 UL37 tegument protein deamidates human and mouse cGAS. Deamidation impairs the ability of cGAS to catalyze cGAMP synthesis, which activates innate immunity...
August 8, 2018: Cell Host & Microbe
Lizhen Wu, Jian Cao, Wesley L Cai, Sabine M Lang, John R Horton, Daniel J Jansen, Zongzhi Z Liu, Jocelyn F Chen, Meiling Zhang, Bryan T Mott, Katherine Pohida, Ganesha Rai, Stephen C Kales, Mark J Henderson, Xin Hu, Ajit Jadhav, David J Maloney, Anton Simeonov, Shu Zhu, Akiko Iwasaki, Matthew D Hall, Xiaodong Cheng, Gerald S Shadel, Qin Yan
Cyclic GMP-AMP (cGAMP) synthase (cGAS) stimulator of interferon genes (STING) senses pathogen-derived or abnormal self-DNA in the cytosol and triggers an innate immune defense against microbial infection and cancer. STING agonists induce both innate and adaptive immune responses and are a new class of cancer immunotherapy agents tested in multiple clinical trials. However, STING is commonly silenced in cancer cells via unclear mechanisms, limiting the application of these agonists. Here, we report that the expression of STING is epigenetically suppressed by the histone H3K4 lysine demethylases KDM5B and KDM5C and is activated by the opposing H3K4 methyltransferases...
August 6, 2018: PLoS Biology
Nathan Meade, Colleen Furey, Hua Li, Rita Verma, Qingqing Chai, Madeline G Rollins, Stephen DiGiuseppe, Mojgan H Naghavi, Derek Walsh
Viruses employ elaborate strategies to coopt the cellular processes they require to replicate while simultaneously thwarting host antiviral responses. In many instances, how this is accomplished remains poorly understood. Here, we identify a protein, F17 encoded by cytoplasmically replicating poxviruses, that binds and sequesters Raptor and Rictor, regulators of mammalian target of rapamycin complexes mTORC1 and mTORC2, respectively. This disrupts mTORC1-mTORC2 crosstalk that coordinates host responses to poxvirus infection...
July 18, 2018: Cell
Joel S Riley, Giovanni Quarato, Catherine Cloix, Jonathan Lopez, Jim O'Prey, Matthew Pearson, James Chapman, Hiromi Sesaki, Leo M Carlin, João F Passos, Ann P Wheeler, Andrew Oberst, Kevin M Ryan, Stephen Wg Tait
During apoptosis, pro-apoptotic BAX and BAK are activated, causing mitochondrial outer membrane permeabilisation (MOMP), caspase activation and cell death. However, even in the absence of caspase activity, cells usually die following MOMP Such caspase-independent cell death is accompanied by inflammation that requires mitochondrial DNA (mtDNA) activation of cGAS-STING signalling. Because the mitochondrial inner membrane is thought to remain intact during apoptosis, we sought to address how matrix mtDNA could activate the cytosolic cGAS-STING signalling pathway...
July 26, 2018: EMBO Journal
Daniel Torralba, Francesc Baixauli, Carolina Villarroya-Beltri, Irene Fernández-Delgado, Ana Latorre-Pellicer, Rebeca Acín-Pérez, Noa B Martín-Cófreces, Ángel Luis Jaso-Tamame, Salvador Iborra, Inmaculada Jorge, Gloria González-Aseguinolaza, Johan Garaude, Miguel Vicente-Manzanares, José Antonio Enríquez, María Mittelbrunn, Francisco Sánchez-Madrid
Interaction of T cell with antigen-bearing dendritic cells (DC) results in T cell activation, but whether this interaction has physiological consequences on DC function is largely unexplored. Here we show that when antigen-bearing DCs contact T cells, DCs initiate anti-pathogenic programs. Signals of this interaction are transmitted from the T cell to the DC, through extracellular vesicles (EV) that contain genomic and mitochondrial DNA, to induce antiviral responses via the cGAS/STING cytosolic DNA-sensing pathway and expression of IRF3-dependent interferon regulated genes...
July 9, 2018: Nature Communications
Beiyun C Liu, Joseph Sarhan, Alexander Panda, Hayley I Muendlein, Vladimir Ilyukha, Jörn Coers, Masahiro Yamamoto, Ralph R Isberg, Alexander Poltorak
Legionella pneumophila elicits caspase-11-driven macrophage pyroptosis through guanylate-binding proteins (GBPs) encoded on chromosome 3. It has been proposed that microbe-driven IFN upregulates GBPs to facilitate pathogen vacuole rupture and bacteriolysis preceding caspase-11 activation. We show here that macrophage death occurred independently of microbial-induced IFN signaling and that GBPs are dispensable for pathogen vacuole rupture. Instead, the host-intrinsic IFN status sustained sufficient GBP expression levels to drive caspase-1 and caspase-11 activation in response to cytosol-exposed bacteria...
July 3, 2018: Cell Reports
Wen-Yu Cheng, Xiao-Bing He, Huai-Jie Jia, Guo-Hua Chen, Qi-Wang Jin, Zhao-Lin Long, Zhi-Zhong Jing
Activation of the DNA-dependent innate immune pathway plays a pivotal role in the host defense against poxvirus. Cyclic GMP-AMP synthase (cGAS) is a key cytosolic DNA sensor that produces the cyclic dinucleotide cGMP-AMP (cGAMP) upon activation, which triggers stimulator of interferon genes (STING), leading to type I Interferons (IFNs) production and an antiviral response. Ectromelia virus (ECTV) has emerged as a valuable model for investigating the host-Orthopoxvirus relationship. However, the role of cGas-Sting pathway in response to ECTV is not clearly understood...
2018: Frontiers in Immunology
Yasuhiro Kato, JeongHoon Park, Hyota Takamatsu, Hachirou Konaka, Wataru Aoki, Syunsuke Aburaya, Mitsuyoshi Ueda, Masayuki Nishide, Shohei Koyama, Yoshitomo Hayama, Yuhei Kinehara, Toru Hirano, Yoshihito Shima, Masashi Narazaki, Atsushi Kumanogoh
OBJECTIVE: Despite the importance of type I interferon (IFN-I) in systemic lupus erythematosus (SLE) pathogenesis, the mechanisms of IFN-I production have not been fully elucidated. Recognition of nucleic acids by DNA sensors induces IFN-I and interferon-stimulated genes (ISGs), but the involvement of cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) and stimulator of interferon genes (STING) in SLE remains unclear. We studied the role of the cGAS-STING pathway in the IFN-I-producing cascade driven by SLE serum...
June 26, 2018: Annals of the Rheumatic Diseases
Zhe-Fu Huang, Hong-Mei Zou, Bo-Wei Liao, Hong-Yan Zhang, Yan Yang, Yu-Zhi Fu, Su-Yun Wang, Min-Hua Luo, Yan-Yi Wang
The cytosolic DNA sensor cGAS recognizes viral DNA and synthesizes the second messenger cGAMP upon viral infection. cGAMP binds to the adaptor protein MITA/STING to activate downstream signaling events, leading to induction of type I interferons (IFNs) and antiviral effector genes. Here we identify the human cytomegalovirus (HCMV) protein UL31 as an inhibitor of cGAS. UL31 interacts directly with cGAS and disassociates DNA from cGAS, thus inhibiting cGAS enzymatic functions and reducing cGAMP production. UL31 overexpression markedly reduces antiviral responses stimulated by cytosolic DNA, while knockdown or knockout of UL31 heightens HCMV-triggered induction of type I IFNs and downstream antiviral genes...
July 11, 2018: Cell Host & Microbe
Johannes Laengle, Judith Stift, Agnes Bilecz, Brigitte Wolf, Andrea Beer, Balazs Hegedus, Stefan Stremitzer, Patrick Starlinger, Dietmar Tamandl, Dietmar Pils, Michael Bergmann
Preclinical models indicate that DNA damage induces type I interferon (IFN), which is crucial for the induction of an anti-tumor immune response. In human cancers, however, the association between DNA damage and an immunogenic cell death (ICD), including the release and sensing of danger signals, the subsequent ER stress response and a functional IFN system, is less clear. Methods: Neoadjuvant-treated colorectal liver metastases (CLM) patients, undergoing liver resection in with a curative intent, were retrospectively enrolled in this study (n=33)...
2018: Theranostics
Marina Martin, Aoi Hiroyasu, R Marena Guzman, Steven A Roberts, Alan G Goodman
The vertebrate protein STING, an intracellular sensor of cyclic dinucleotides, is critical to the innate immune response and the induction of type I interferon during pathogenic infection. Here, we show that a STING ortholog (dmSTING) exists in Drosophila, which, similar to vertebrate STING, associates with cyclic dinucleotides to initiate an innate immune response. Following infection with Listeria monocytogenes, dmSTING activates an innate immune response via activation of the NF-κB transcription factor Relish, part of the immune deficiency (IMD) pathway...
June 19, 2018: Cell Reports
Qiang Ding, Jenna M Gaska, Florian Douam, Lei Wei, David Kim, Metodi Balev, Brigitte Heller, Alexander Ploss
The limited host tropism of numerous viruses causing disease in humans remains incompletely understood. One example is Zika virus (ZIKV), an RNA virus that has reemerged in recent years. Here, we demonstrate that ZIKV efficiently infects fibroblasts from humans, great apes, New and Old World monkeys, but not rodents. ZIKV infection in human-but not murine-cells impairs responses to agonists of the cGMP-AMP synthase/stimulator of IFN genes (cGAS/STING) signaling pathway, suggesting that viral mechanisms to evade antiviral defenses are less effective in rodent cells...
July 3, 2018: Proceedings of the National Academy of Sciences of the United States of America
Julie M Diamond, Claire Vanpouille-Box, Sheila Spada, Nils-Petter Rudqvist, Jessica R Chapman, Beatrix M Ueberheide, Karsten A Pilones, Yasmeen Sarfraz, Silvia C Formenti, Sandra Demaria
Radiotherapy (RT) used at immunogenic doses leads to accumulation of cytosolic double-stranded DNA (dsDNA) in cancer cells, which activates type I IFN (IFN-I) via the cGAS/STING pathway. Cancer cell-derived IFN-I is required to recruit BATF3-dependent dendritic cells (DC) to poorly immunogenic tumors and trigger antitumor T-cell responses in combination with immune checkpoint blockade. We have previously demonstrated that the exonuclease TREX1 regulates radiation immunogenicity by degrading cytosolic dsDNA...
June 15, 2018: Cancer Immunology Research
Jiehua Wang, Min Dai, Yange Cui, Guojun Hou, Jun Deng, Xin Gao, Zhuojun Liao, Ya Liu, Yao Meng, Lingling Wu, Chao Yao, Yan Wang, Jie Qian, Qiang Guo, Huihua Ding, Bo Qu, Nan Shen
OBJECTIVE: Increasing evidence indicate a critical pathogenic role of cGAS-STING signaling pathway in systemic lupus erythematosus (SLE). Interferon(IFN) inducible gene, IFIT3, is elevated in SLE. However, it is still not clear how IFIT3 contributes to SLE pathogenesis. We undertook this study to investigate the activation of cGAS-STING signaling pathway in SLE monocytes, as well as how elevated IFIT3 contributes to the overactivation of cGAS-STING signaling pathway. METHODS: Monocytes from SLE patients or healthy controls were examined for the activity of cGAS-STING signaling pathway and expression of IFIT3...
May 27, 2018: Arthritis & Rheumatology
Hannah M Burgess, Ian Mohr
In response to virus-induced shutoff host protein synthesis, dynamic aggregates containing mRNA, RNA-binding proteins and translation factors termed stress granules (SGs) often accumulate within the cytoplasm. SGs typically form following phosphorylation and inactivation of the eukaryotic translation initiation factor 2α (eIF2α), a substrate of the double-stranded RNA (dsRNA)-activated kinase protein kinase R (PKR). The detection of innate immune sensors and effectors like PKR at SGs suggests a role in pathogen nucleic acid sensing...
August 1, 2018: Journal of Virology
Jian Huang, Hongjuan You, Chenhe Su, Yangxin Li, Shunhua Chen, Chunfu Zheng
Cytosolic DNA arising from intracellular pathogens is sensed by cyclic GMP-AMP synthase (cGAS) and triggers a powerful innate immune response. However, herpes simplex virus 1 (HSV-1), a double-stranded DNA virus, has developed multiple mechanisms to attenuate host antiviral machinery and facilitate viral infection and replication. In the present study, we found that HSV-1 tegument protein VP22 acts as an inhibitor of cGAS/stimulator of interferon genes (cGAS/STING)-mediated production of interferon (IFN) and its downstream antiviral genes...
August 1, 2018: Journal of Virology
Fabio V Marinho, Sulayman Benmerzoug, Stephanie Rose, Priscila C Campos, João T Marques, André Báfica, Glen Barber, Bernhard Ryffel, Sergio C Oliveira, Valerie F J Quesniaux
Mycobacterium tuberculosis (Mtb) infection remains a major public health concern. The STING (stimulator of interferon genes) pathway contributes to the cytosolic surveillance of host cells. Most studies on the role of STING activation in Mtb infection have focused on macrophages. Moreover, a detailed investigation of the role of STING during Mtb infection in vivo is required. Here, we deciphered the involvement of STING in the activation of dendritic cells (DCs) and the host response to Mtb infection in vivo...
2018: Journal of Innate Immunity
Joseph Sarhan, Beiyun C Liu, Hayley I Muendlein, Chi G Weindel, Irina Smirnova, Amy Y Tang, Vladimir Ilyukha, Maxim Sorokin, Anton Buzdin, Katherine A Fitzgerald, Alexander Poltorak
Interferons (IFNs) are critical determinants in immune-competence and autoimmunity, and are endogenously regulated by a low-level constitutive feedback loop. However, little is known about the functions and origins of constitutive IFN. Recently, lipopolysaccharide (LPS)-induced IFN was implicated as a driver of necroptosis, a necrotic form of cell death downstream of receptor-interacting protein (RIP) kinase activation and executed by mixed lineage kinase like-domain (MLKL) protein. We found that the pre-established IFN status of the cell, instead of LPS-induced IFN, is critical for the early initiation of necroptosis in macrophages...
May 21, 2018: Cell Death and Differentiation
Jie An, Joshua J Woodward, Weinan Lai, Mark Minie, Xizhang Sun, Lena Tanaka, Jessica M Snyder, Tomikazu Sasaki, Keith B Elkon
OBJECTIVE: Type I interferon (IFN-I) is strongly implicated in the pathogenesis of Systemic Lupus Erythematosus (SLE) as well as rare monogenic 'interferonopathies' such as Aicardi-Goutieres Syndrome (AGS) caused by mutations in the DNA exonuclease, TREX1. The DNA-activated IFN-I pathway, cyclic GMP-AMP (cGAMP) synthase (cGAS), is linked to subsets of AGS and lupus. We identified inhibitors of DNA-cGAS interaction and tested lead candidate, X6, in a mouse model of AGS. METHODS: Trex1-/- mice were treated orally from birth with either X6 or HCQ for 8 weeks...
May 21, 2018: Arthritis & Rheumatology
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
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