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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
Li Teng Khoo, Liuh-Yow Chen
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway mediates anti-microbial innate immunity by inducing the production of type I interferons (IFNs) and inflammatory cytokines upon recognition of microbial DNA. Recent studies reveal that self-DNA from tumors and by-products of genomic instability also activates the cGAS-STING pathway and either promotes or inhibits tumor development. This has led to the development of cancer therapeutics using STING agonists alone and in combination with conventional cancer treatment or immune checkpoint targeting...
November 16, 2018: EMBO Reports
Lele Zhang, Ning Wei, Ye Cui, Ze Hong, Xing Liu, Qiang Wang, Senlin Li, Heng Liu, Huansha Yu, Yanni Cai, Quanyi Wang, Juanjuan Zhu, Wei Meng, Zhengjun Chen, Chen Wang
Stimulator of interferon genes (STING) is critical for cytosolic DNA-triggered innate immunity. STING is modified by several types of polyubiquitin chains. Here, we report that the deubiquitinase CYLD sustains STING signaling by stabilizing the STING protein. CYLD deficiency promoted the K48-linked polyubiquitination and degradation of STING, attenuating the induction of IRF3-responsive genes after HSV-1 infection or the transfection of DNA ligands. Additionally, CYLD knockout mice were more susceptible to HSV-1 infection than their wild-type (WT) littermates...
November 2018: PLoS Pathogens
Robert M Samstein, Nadeem Riaz
Purpose: Deficiencies in DNA damage repair (DDR) and response represent a common alteration in tumors, and exploitation of this feature using therapeutics has become more prominent. Methods and materials: Recent work has highlighted the important interaction between DDR defects, as well as DDR targeting agents such as radiation and the immunogenicity of the tumor. This relationship emphasizes the potential for combination therapeutics with immune checkpoint inhibitors (ICI)...
October 2018: Advances in Radiation Oncology
Lutz Hamann, Juan S Ruiz-Moreno, Malgorzata Szwed, Malgorzata Mossakowska, Linn Lundvall, Ralf R Schumann, Bastian Opitz, Monika Puzianowska-Kuznicka
BACKGROUND: Aging is a multifactorial process driven by several conditions. Among them, inflamm-aging is characterized by chronic low-grade inflammation driving aging-related diseases. The aged immune system is characterized by the senescence-associated secretory phenotype, resulting in the release of proinflammatory cytokines contributing to inflamm-aging. Another possible mechanism resulting in inflamm-aging could be the increased release of danger- associated molecular patterns (DAMPs) by increased cell death in the elderly, leading to a chronic low-grade inflammatory response...
October 26, 2018: Gerontology
Haipeng Liu, Haiping Zhang, Xiangyang Wu, Dapeng Ma, Juehui Wu, Lin Wang, Yan Jiang, Yiyan Fei, Chenggang Zhu, Rong Tan, Peter Jungblut, Gang Pei, Anca Dorhoi, Qiaoling Yan, Fan Zhang, Ruijuan Zheng, Siyu Liu, Haijiao Liang, Zhonghua Liu, Hua Yang, Jianxia Chen, Peng Wang, Tianqi Tang, Wenxia Peng, Zhangsen Hu, Zhu Xu, Xiaochen Huang, Jie Wang, Haohao Li, Yilong Zhou, Feng Liu, Dapeng Yan, Stefan H E Kaufmann, Chang Chen, Zhiyong Mao, Baoxue Ge
Accurate repair of DNA double-stranded breaks by homologous recombination preserves genome integrity and inhibits tumorigenesis. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that activates innate immunity by initiating the STING-IRF3-type I IFN signalling cascade1,2 . Recognition of ruptured micronuclei by cGAS links genome instability to the innate immune response3,4 , but the potential involvement of cGAS in DNA repair remains unknown. Here we demonstrate that cGAS inhibits homologous recombination in mouse and human models...
November 2018: Nature
Kazuki Kato, Hiroshi Nishimasu, Daisuke Oikawa, Seiichi Hirano, Hisato Hirano, Go Kasuya, Ryuichiro Ishitani, Fuminori Tokunaga, Osamu Nureki
ENPP1 (Ecto-nucleotide pyrophosphatase phosphodiesterase 1), a type II transmembrane glycoprotein, hydrolyzes ATP to produce AMP and diphosphate, thereby inhibiting bone mineralization. A recent study showed that ENPP1 also preferentially hydrolyzes 2'3'-cGAMP (cyclic GMP-AMP) but not its linkage isomer 3'3'-cGAMP, and negatively regulates the cGAS-STING pathway in the innate immune system. Here, we present the high-resolution crystal structures of ENPP1 in complex with 3'3'-cGAMP and the reaction intermediate pA(3',5')pG...
October 24, 2018: Nature Communications
Xixi Wang, Jing Wu, Yingtong Wu, Hongjun Chen, Shoufeng Zhang, Jinxiang Li, Ting Xin, Hong Jia, Shaohua Hou, Yitong Jiang, Hongfei Zhu, Xiaoyu Guo
African swine fever virus (ASFV) is a highly pathogenic large DNA virus that causes African swine fever (ASF) in domestic pigs and European wild boars with mortality rate up to 100%. The DP96R gene of ASFV encodes one of the viral virulence factors, yet its action mechanism remains unknown. In this study, we report that DP96R of ASFV China 2018/1 strain subverts type I IFN production in cGAS sensing pathway. DP96R inhibited the cGAS/STING, and TBK1 but not IRF3-5D mediated IFN-β and ISRE promoters activation...
October 19, 2018: Biochemical and Biophysical Research Communications
Shunbin Ning, Ling Wang
The multifunctional signaling hub p62 is well recognized as ubiquitin sensor and selective autophagy adaptor under myriad stress conditions including cancer. As a ubiquitin sensor, p62 promotes NFκB activation by facilitating TRAF6 ubiquitination and aggregation. As a selective autophagy receptor, p62 links ubiquitinated substrates including p62 itself for lysosome-mediated degradation. p62 plays crucial roles in myriad cellular processes including DNA damage response, aging/senescence, infection and immunity, chronic inflammation, and cancerogenesis, dependent on or independent of autophagy...
October 16, 2018: Current Cancer Drug Targets
Assaf Marcus, Amy J Mao, Monisha Lensink-Vasan, LeeAnn Wang, Russell E Vance, David H Raulet
Detection of cytosolic DNA by the enzyme cGAS triggers the production of cGAMP, a second messenger that binds and activates the adaptor protein STING, which leads to interferon (IFN) production. Here, we found that in vivo natural killer (NK) cell killing of tumor cells, but not of normal cells, depends on STING expression in non-tumor cells. Experiments using transplantable tumor models in STING- and cGAS-deficient mice revealed that cGAS expression by tumor cells was critical for tumor rejection by NK cells...
October 16, 2018: Immunity
Selene Glück, Andrea Ablasser
Senescence is a multistep cellular program featuring a stable cell cycle arrest, which occurs upon exposure to various stressors. Senescent cells exhibit metabolic activity and hypertrophy and produce a multitude of factors with both cell intrinsic as well as non-cell autonomous functions. These factors are collectively referred to as the senescence-associated secretory phenotype (SASP). Recently, the DNA sensor cyclic GMP AMP synthase (cGAS) and the adaptor stimulator of interferon genes (STING) have been reported to be critically involved in the regulation of senescence...
October 5, 2018: Current Opinion in Immunology
Flavie Coquel, Christoph Neumayer, Yea-Lih Lin, Philippe Pasero
Cytosolic DNA of endogenous or exogenous origin is sensed by the cGAS-STING pathway to activate innate immune responses. Besides microbial DNA, this pathway detects self-DNA in the cytoplasm of damaged or abnormal cells and plays a central role in antitumor immunity. The mechanism by which cytosolic DNA accumulates under genotoxic stress conditions is currently unclear, but recent studies on factors mutated in the Aicardi-Goutières syndrome cells, such as SAMHD1, RNase H2 and TREX1, are shedding new light on this key process...
October 4, 2018: Current Opinion in Immunology
Konrad Aden, Florian Tran, Go Ito, Raheleh Sheibani-Tezerji, Simone Lipinski, Jan W Kuiper, Markus Tschurtschenthaler, Svetlana Saveljeva, Joya Bhattacharyya, Robert Häsler, Kareen Bartsch, Anne Luzius, Marlene Jentzsch, Maren Falk-Paulsen, Stephanie T Stengel, Lina Welz, Robin Schwarzer, Björn Rabe, Winfried Barchet, Stefan Krautwald, Gunther Hartmann, Manolis Pasparakis, Richard S Blumberg, Stefan Schreiber, Arthur Kaser, Philip Rosenstiel
A coding variant of the inflammatory bowel disease (IBD) risk gene ATG16L1 has been associated with defective autophagy and deregulation of endoplasmic reticulum (ER) function. IL-22 is a barrier protective cytokine by inducing regeneration and antimicrobial responses in the intestinal mucosa. We show that ATG16L1 critically orchestrates IL-22 signaling in the intestinal epithelium. IL-22 stimulation physiologically leads to transient ER stress and subsequent activation of STING-dependent type I interferon (IFN-I) signaling, which is augmented in Atg16l1 ΔIEC intestinal organoids...
November 5, 2018: Journal of Experimental Medicine
Chan-Ki Min, Hong-Ii Kim, Na-Young Ha, Yuri Kim, Eun-Kyung Kwon, Nguyen Thi Hai Yen, Je-In Youn, Yoon Kyung Jeon, Kyung-Soo Inn, Myung-Sik Choi, Nam-Hyuk Cho
Despite the various roles of type I interferon (type I IFN) responses during bacterial infection, its specific effects in vivo have been poorly characterized in scrub typhus caused by Orientia tsutsugamushi infection. Here, we show that type I IFNs are primarily induced via intracellular nucleic acids sensors, including RIG-I/MAVS and cGAS/STING pathways, during O. tsutsugamushi invasion. However, type I IFN signaling did not significantly affect pathogenesis, mortality, or bacterial burden during primary infection in vivo , when assessed in a mice model lacking a receptor for type I IFNs (IFNAR KO)...
2018: Frontiers in Immunology
Rebecca Feltham, James E Vince
The pore-forming protein GSDMD promotes cytokine release and induces pyroptotic cell death. In this issue of Immunity, Banerjee et al. (2018) document how GSDMD triggers potassium efflux to inhibit cGAS-STING and prevent damaging interferon production after bacterial infection.
September 18, 2018: Immunity
Samuel F Bakhoum, Lewis C Cantley
Chromosomal instability (CIN) is a hallmark of human cancer, and it is associated with poor prognosis, metastasis, and therapeutic resistance. CIN results from errors in chromosome segregation during mitosis, leading to structural and numerical chromosomal abnormalities. In addition to generating genomic heterogeneity that acts as a substrate for natural selection, CIN promotes inflammatory signaling by introducing double-stranded DNA into the cytosol, engaging the cGAS-STING anti-viral pathway. These multipronged effects distinguish CIN as a central driver of tumor evolution and as a genomic source for the crosstalk between the tumor and its microenvironment, in the course of immune editing and evasion...
September 6, 2018: Cell
Gillian Dunphy, Sinéad M Flannery, Jessica F Almine, Dympna J Connolly, Christina Paulus, Kasper L Jønsson, Martin R Jakobsen, Michael M Nevels, Andrew G Bowie, Leonie Unterholzner
DNA damage can be sensed as a danger-associated molecular pattern by the innate immune system. Here we find that keratinocytes and other human cells mount an innate immune response within hours of etoposide-induced DNA damage, which involves the DNA sensing adaptor STING but is independent of the cytosolic DNA receptor cGAS. This non-canonical activation of STING is mediated by the DNA binding protein IFI16, together with the DNA damage response factors ATM and PARP-1, resulting in the assembly of an alternative STING signaling complex that includes the tumor suppressor p53 and the E3 ubiquitin ligase TRAF6...
September 6, 2018: Molecular Cell
Huan Lian, Jin Wei, Ru Zang, Wen Ye, Qing Yang, Xia-Nan Zhang, Yun-Da Chen, Yu-Zhi Fu, Ming-Ming Hu, Cao-Qi Lei, Wei-Wei Luo, Shu Li, Hong-Bing Shu
Cyclic GMP-AMP synthase (cGAS) senses double-strand (ds) DNA in the cytosol and then catalyzes synthesis of the second messenger cGAMP, which activates the adaptor MITA/STING to initiate innate antiviral response. How cGAS activity is regulated remains enigmatic. Here, we identify ZCCHC3, a CCHC-type zinc-finger protein, as a positive regulator of cytosolic dsDNA- and DNA virus-triggered signaling. We show that ZCCHC3-deficiency inhibits dsDNA- and DNA virus-triggered induction of downstream effector genes, and that ZCCHC3-deficient mice are more susceptible to lethal herpes simplex virus type 1 or vaccinia virus infection...
August 22, 2018: Nature Communications
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