Read by QxMD icon Read


Hella Luksch, W Alexander Stinson, Derek J Platt, Wei Qian, Gowri Kalugotla, Cathrine A Miner, Brock G Bennion, Alexander Gerbaulet, Angela Rösen-Wolff, Jonathan J Miner
BACKGROUND: Monogenic interferonopathies are thought to be mediated by type I interferon (IFN). For example, a gain-of-function mutation in STING (STING N153S) up-regulates type I IFN-stimulated genes (ISGs) and causes perivascular inflammatory lung disease in mice. The equivalent mutation in humans also causes lung disease, which is thought to require signaling through the cGAS-STING pathway and subsequent activation of IFN regulatory factors (IRF) 3/7, type I IFN, and ISGs. OBJECTIVE: We set out to define the roles of cGAS, IRF3, IRF7, the type I IFN receptor (IFNAR1), T cells, and B cells in spontaneous lung disease in STING N153S mice...
February 14, 2019: Journal of Allergy and Clinical Immunology
Yuk Yuen Lan, James M Heather, Thomas Eisenhaure, Christopher Stuart Garris, David Lieb, Raktima Raychowdhury, Nir Hacohen
Systemic inflammation is central to aging-related conditions. However, the intrinsic factors that induce inflammation are not well understood. We previously identified a cell-autonomous pathway through which damaged nuclear DNA is trafficked to the cytosol where it activates innate cytosolic DNA sensors that trigger inflammation. These results led us to hypothesize that DNA released after cumulative damage contributes to persistent inflammation in aging cells through a similar mechanism. Consistent with this notion, we found that older cells harbored higher levels of extranuclear DNA compared to younger cells...
January 31, 2019: Aging Cell
Takayuki Abe, Yuki Marutani, Ikuo Shoji
It has not been fully elucidated how host cells recognize many kinds of RNA and DNA viruses and initiate innate antiviral responses against them. Over the past decade, investigations into the mechanisms underlying these antiviral responses have focused extensively on immune surveillance sensors that recognize virus-derived components (such as lipids, sugars, and nucleic acids). These researches have suggested that the antiviral responses are mediated by cytosolic or intracellular compartment sensors and their adaptor molecules (e...
January 24, 2019: Microbiology and Immunology
Joe Nassour, Robert Radford, Adriana Correia, Javier Miralles Fusté, Brigitte Schoell, Anna Jauch, Reuben J Shaw, Jan Karlseder
Replicative crisis is a senescence-independent process that acts as a final barrier against oncogenic transformation by eliminating pre-cancerous cells with disrupted cell cycle checkpoints1 . It functions as a potent tumour suppressor and culminates in extensive cell death. Cells rarely evade elimination and evolve towards malignancy, but the mechanisms that underlie cell death in crisis are not well understood. Here we show that macroautophagy has a dominant role in the death of fibroblasts and epithelial cells during crisis...
January 23, 2019: Nature
Alfred C Chin
The recent discovery of cyclic GMP-AMP synthase (cGAS) as the mammalian cytosolic DNA sensor has profound therapeutic implications for infection, immunology, and cancer. Because neurovirology, neuroimmunology, neuro-oncology, and neurodegeneration implicate cytosolic DNA sensing, cGAS activation and induction of the downstream signaling protein stimulator of intereferon genes (STING) has become increasingly recognized as a crucial determinant of neuropathophysiology. This Neuro Forum article reviews recent advances on the role of cGAS-STING signaling in neuroinflammation and neurological disease...
January 23, 2019: Journal of Neurophysiology
Arundhati Ghosh, Lulu Shao, Padmavathi Sampath, Baoyu Zhao, Nidhi V Patel, Jianzhong Zhu, Bharat Behl, Robert A Parise, Jan H Beumer, Roderick J O'Sullivan, Neal A DeLuca, Stephen H Thorne, Vijay A K Rathinam, Pingwei Li, Saumendra N Sarkar
Interferon-inducible human oligoadenylate synthetase-like (OASL) and its mouse ortholog, Oasl2, enhance RNA-sensor RIG-I-mediated type I interferon (IFN) induction and inhibit RNA virus replication. Here, we show that OASL and Oasl2 have the opposite effect in the context of DNA virus infection. In Oasl2-/- mice and OASL-deficient human cells, DNA viruses such as vaccinia, herpes simplex, and adenovirus induced increased IFN production, which resulted in reduced virus replication and pathology. Correspondingly, ectopic expression of OASL in human cells inhibited IFN induction through the cGAS-STING DNA-sensing pathway...
January 15, 2019: Immunity
Anna C Wilkins, Emmanuel C Patin, Kevin J Harrington, Alan A Melcher
Historically, our understanding of the cytotoxicity of radiation has centred on tumour cell-autonomous mechanisms of cell death. Here, tumour cell death occurs when a threshold number of radiation-induced non-reparable double-stranded DNA breaks is exceeded. However, in recent years, the importance of immune mechanisms of cell death has been increasingly recognised, as well as the impact of radiotherapy on non-malignant cellular components of the tumour microenvironment. Conserved anti-viral pathways that detect foreign nucleic acid in the cytosol and drive downstream interferon responses via the cGAS/STING pathway are key components of the immune response to radiation-induced DNA damage...
January 10, 2019: Journal of Pathology
Anne Margriet Heijink, Francien Talens, Lucas T Jae, Stephanie E van Gijn, Rudolf S N Fehrmann, Thijn R Brummelkamp, Marcel A T M van Vugt
Loss of BRCA2 affects genome stability and is deleterious for cellular survival. Using a genome-wide genetic screen in near-haploid KBM-7 cells, we show that tumor necrosis factor-alpha (TNFα) signaling is a determinant of cell survival upon BRCA2 inactivation. Specifically, inactivation of the TNF receptor (TNFR1) or its downstream effector SAM68 rescues cell death induced by BRCA2 inactivation. BRCA2 inactivation leads to pro-inflammatory cytokine production, including TNFα, and increases sensitivity to TNFα...
January 9, 2019: Nature Communications
Roman M Chabanon, Gareth Muirhead, Dragomir B Krastev, Julien Adam, Daphné Morel, Marlène Garrido, Andrew Lamb, Clémence Hénon, Nicolas Dorvault, Mathieu Rouanne, Rebecca Marlow, Ilirjana Bajrami, Marta Llorca Cardeñosa, Asha Konde, Benjamin Besse, Alan Ashworth, Stephen J Pettitt, Syed Haider, Aurélien Marabelle, Andrew Nj Tutt, Jean-Charles Soria, Christopher J Lord, Sophie Postel-Vinay
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with DNA repair deficiencies such as those caused by BRCA1 mutations or ERCC1 defects. Using isogenic cell lines and patient-derived samples, we showed that ERCC1-defective non-small cell lung cancer (NSCLC) cells exhibit an enhanced type I interferon transcriptomic signature, and that low ERCC1 expression correlates with increased lymphocytic infiltration...
December 27, 2018: Journal of Clinical Investigation
Glen N Barber, Nina Mari Gual Pimenta de Queiroz, Tianli Xia, Hiroyasu Konno
Ovarian cancer is the sixth most prevalent cancer in women and the most lethal of the gynecologic malignancies. Treatments have comprised the use of immunotherapeutic agents as well as oncolytic viruses, with varying results for reasons that remain to be clarified. To better understand the mechanisms which may help predict treatment outcome, we have evaluated innate immune signaling in select ovarian cancer cell-lines, governed by the Stimulator of Interferon Genes (STING) which controls self or viral DNA triggered cytokine production...
December 26, 2018: Molecular Cancer Research: MCR
Xiang An, Yuanyuan Zhu, Tongsen Zheng, Guangyu Wang, Minghui Zhang, Jiade Li, Hongbo Ji, Shijun Li, Shucai Yang, Dandan Xu, Zhiwei Li, Tianzhen Wang, Yan He, Lei Zhang, Weiwei Yang, Ran Zhao, Dapeng Hao, Xiaobo Li
Recent evidence shows that cyclic GMP-AMP synthase (cGAS)/stimulator of interferon (IFN) genes (STING) signaling is essential for antitumor immunity by inducing the production of type I IFN and thus activating both innate and adaptive immunity based on gene knockout mouse models. However, the extensive detection of the expression of cGAS/STING signaling in human cancer and mining the roles of this signaling pathway in human cancer immunity have not been performed until now. In this study, we revealed that four key molecules (cGAS, STING, TANK binding kinase 1 [TBK1], and IFN regulatory factor 3 [IRF3]) in the cGAS/STING signaling are highly expressed in cancer tissues, and the expression levels of these genes are negatively correlated with their methylation levels in most of the detected cancer types...
November 20, 2018: Molecular Therapy. Nucleic Acids
Dong Liu, Hao Wu, Chenguang Wang, Yanjun Li, Huabin Tian, Sami Siraj, Sheikh Arslan Sehgal, Xiaohui Wang, Jun Wang, Yingli Shang, Zhengfan Jiang, Lei Liu, Quan Chen
STING (stimulator of interferon genes) is a central molecule that binds to cyclic dinucleotides produced by the cyclic GMP-AMP synthase (cGAS) to activate innate immunity against microbial infection. Here we report that STING harbors classic LC-3 interacting regions (LIRs) and mediates autophagy through its direct interaction with LC3. We observed that poly(dA:dT), cGAMP, and HSV-1 induced STING-dependent autophagy and degradation of STING immediately after TBK1 activation. STING induces non-canonical autophagy that is dependent on ATG5, whereas other autophagy regulators such as Beclin1, Atg9a, ULK1, and p62 are dispensable...
December 19, 2018: Cell Death and Differentiation
Senlin Li, Ze Hong, Zhe Wang, Fei Li, Jiahao Mei, Lulu Huang, Xiwen Lou, Simeng Zhao, Lihua Song, Wei Chen, Qiang Wang, Heng Liu, Yanni Cai, Huansha Yu, Huimin Xu, Guangzhi Zeng, Quanyi Wang, Juanjuan Zhu, Xing Liu, Ninghua Tan, Chen Wang
cGAS-STING signaling is essential for innate immunity. Its misregulation promotes cancer or autoimmune and autoinflammatory diseases, and it is imperative to identify effective lead compounds that specifically downregulate the pathway. We report here that astin C, a cyclopeptide isolated from the medicinal plant Aster tataricus, inhibits cGAS-STING signaling and the innate inflammatory responses triggered by cytosolic DNAs. Moreover, mice treated with astin C are more susceptible to HSV-1 infection. Consistently, astin C markedly attenuates the autoinflammatory responses in Trex1-/- BMDM cells and in Trex1-/- mouse autoimmune disease model...
December 18, 2018: Cell Reports
Yu-Ting Kao, Michael M C Lai, Chia-Yi Yu
In the battle between a virus and its host, innate immunity serves as the first line of defense protecting the host against pathogens. The antiviral actions start with the recognition of pathogen-associated molecular patterns derived from the virus, then ultimately turning on particular transcription factors to generate antiviral interferons (IFNs) or proinflammatory cytokines via fine-tuned signaling cascades. With dengue virus (DENV) infection, its viral RNA is recognized by the host RNA sensors, mainly retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs) and toll-like receptors...
2018: Frontiers in Immunology
Kristin Schultz, Christina Grieger Lindner, Yong Li, Pavel Urbánek, Anne Ruschel, Kerstin Minnich, Dunja Bruder, Marcus Gereke, Antonio Sechi, Peter Herrlich
The adhesion molecule and co-receptor of receptor tyrosine kinases, CD44, is expressed in all cells of the immune system, but also in numerous non-immune cells. CD44 plays roles in the cellular response to different pathogens. The molecular actions of CD44 during these processes are by and large still unknown. The CD44 molecule undergoes a sequential proteolytic cleavage which leads to the release of a soluble intracellular domain (CD44-ICD). Previous reports had shown that the CD44-ICD is taken up into the nucleus where it enhances transcription of specific target genes...
2018: PloS One
Clemens Reto Dialer, Samuele Stazzoni, David J Drexler, Felix Moritz Müller, Simon Veth, Alexander Pichler, Hidenori Okamura, Gregor Witte, Karl-Peter Hopfner, Thomas Carell
2'3'-cGAMP is an uncanonical cyclic dinucleotide where one A and one G base are connected via a 3'-5' and a unique 2'-5' linkage. The molecule is produced by the cyclase cGAS in response to cytosolic DNA binding. cGAMP activates STING and hence one of the most powerful pathways of innate immunity. cGAMP analogs with uncharged linkages that feature better cellular penetrability are currently highly desired. Here, we report the synthesis of a cGAMP analog with one amide and one triazole linkage. The molecule is best prepared via a first Cu(I) catalysed click reaction which establishes the triazole, while the cyclization is achieved by macrolactamization...
December 10, 2018: Chemistry: a European Journal
Sulayman Benmerzoug, Stéphanie Rose, Badreddine Bounab, David Gosset, Laure Duneau, Pauline Chenuet, Lucile Mollet, Marc Le Bert, Christopher Lambers, Silvana Geleff, Michael Roth, Louis Fauconnier, Delphine Sedda, Clarisse Carvalho, Olivier Perche, David Laurenceau, Bernhard Ryffel, Lionel Apetoh, Ahmet Kiziltunc, Hakan Uslu, Fadime Sultan Albez, Metin Akgun, Dieudonnée Togbe, Valerie F J Quesniaux
Silica particles induce lung inflammation and fibrosis. Here we show that stimulator of interferon genes (STING) is essential for silica-induced lung inflammation. In mice, silica induces lung cell death and self-dsDNA release in the bronchoalveolar space that activates STING pathway. Degradation of extracellular self-dsDNA by DNase I inhibits silica-induced STING activation and the downstream type I IFN response. Patients with silicosis have increased circulating dsDNA and CXCL10 in sputum, and patients with fibrotic interstitial lung disease display STING activation and CXCL10 in the lung...
December 6, 2018: Nature Communications
Leonie Unterholzner, Jessica F Almine
Intracellular DNA and RNA sensors play a vital part in the innate immune response to viruses and other intracellular pathogens, causing the secretion of type I interferons, cytokines and chemokines from infected cells. Pathogen RNA can be detected by RIG-I-like receptors in the cytosol, while cytosolic DNA is recognised by DNA sensors such as cyclic GMP-AMP synthase (cGAS). The resulting local immune response, which is initiated within hours of infection, is able to eliminate many pathogens before they are able to establish an infection in the host...
November 30, 2018: Immunology
Jianfeng Shen, Wei Zhao, Zhenlin Ju, Lulu Wang, Yang Peng, Marilyne Labrie, Timothy A Yap, Gordon B Mills, Guang Peng
Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have shown remarkable therapeutic efficacy against BRCA1/2 mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of single-stranded DNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring BRCA1/2 mutations. Here we show that PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of BRCA1/2 mutations...
November 27, 2018: Cancer Research
Bei Huang, Lili Zhang, Mingqing Lu, Jiansheng Li, Yingjun Lv
PCV2 is a single-stranded DNA virus that we previously found to induce IFN-β production via RIG-I and MDA-5. cGAS is known to be the most important DNA sensor for the recognition of cytosolic DNA; however, it remains unclear whether the interferon production induced by PCV2 is associated with cGAS. In the present study, PCV2 infection was found to increase the level of cGAS and STING expression, promote the release of cyclic dinucleotide cGAMP, and induce STING dimerization and translocation into the nucleus of PK-15 cells...
December 2018: Veterinary Microbiology
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"