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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...
September 25, 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
Kun Yang, Ryan Huang, Haruhiko Fujihira, Tadashi Suzuki, Nan Yan
Mutations in the NGLY1 (N-glycanase 1) gene, encoding an evolutionarily conserved deglycosylation enzyme, are associated with a rare congenital disorder leading to global developmental delay and neurological abnormalities. The molecular mechanism of the NGLY1 disease and its function in tissue and immune homeostasis remain unknown. Here, we find that NGLY1 -deficient human and mouse cells chronically activate cytosolic nucleic acid-sensing pathways, leading to elevated interferon gene signature. We also find that cellular clearance of damaged mitochondria by mitophagy is impaired in the absence of NGLY1, resulting in severely fragmented mitochondria and activation of cGAS-STING as well as MDA5-MAVS pathways...
October 1, 2018: Journal of Experimental Medicine
Guoxin Ni, Zhe Ma, Blossom Damania
No abstract text is available yet for this article.
August 2018: PLoS Pathogens
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 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...
August 23, 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...
September 3, 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...
October 2018: Annals of the Rheumatic Diseases
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