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  • 1
    Language: English
    Description: Cytosolic DNA arising from intracellular bacterial or viral infections is a powerful pathogen-associated molecular pattern (PAMP) that leads to innate immune host defence by the production of type I interferon and inflammatory cytokines. Recognition of cytosolic DNA by the recently discovered cyclic-GMP-AMP (cGAMP) synthase (cGAS) induces the production of cGAMP to activate the stimulator of interferon genes (STING). Here we report the crystal structure of cGAS alone and in complex with DNA, ATP and GTP along with functional studies. Our results explain the broad DNA sensing specificity of cGAS, show how cGAS catalyses dinucleotide formation and indicate activation by a DNA-induced structural switch. cGAS possesses a remarkable structural similarity to the antiviral cytosolic double-stranded RNA sensor 2'-5'oligoadenylate synthase (OAS1), but contains a unique zinc thumb that recognizes B-form double-stranded DNA. Our results mechanistically unify dsRNA and dsDNA innate immune sensing by OAS1 and cGAS nucleotidyl transferases.
    Keywords: Cytosol
    ISSN: 00280836
    E-ISSN: 14764687
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  • 2
    Language: English
    In: 2015, Vol.10(6), p.e0131702
    Description: Mice lacking DNase II display a polyarthritis-like disease phenotype that is driven by translocation of self-DNA into the cytoplasm of phagocytic cells, where it is sensed by pattern recognition receptors. While pro-inflammatory gene expression is non-redundantly linked to the presence of STING in these mice, the contribution of the inflammasome pathway has not been explored. To this end, we studied the role of the DNA-sensing inflammasome receptor AIM2 in this self-DNA driven disease model. Arthritis-prone mice lacking AIM2 displayed strongly decreased signs of joint inflammation and associated histopathological findings. This was paralleled with a reduction of caspase-1 activation and pro-inflammatory cytokine production in diseased joints. Interestingly, systemic signs of inflammation that are associated with the lack of DNase II were not dependent on AIM2. Taken together, these data suggest a tissue-specific role for the AIM2 inflammasome as a sensor for endogenous DNA species in the course of a ligand-dependent autoinflammatory condition.
    Keywords: Research Article
    E-ISSN: 1932-6203
    Source: PLoS
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  • 3
    In: PLoS ONE, 2018, Vol.13(8)
    Description: [This corrects the article DOI: 10.1371/journal.pone.0131702.].
    Keywords: Correction
    E-ISSN: 1932-6203
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  • 4
    In: Nature, 2013, Vol.503(7477), p.530
    Description: The innate immune defence of multicellular organisms against microbial pathogens requires cellular collaboration. Information exchange allowing immune cells to collaborate is generally attributed to soluble protein factors secreted by pathogen-sensing cells. Cytokines, such as type I interferons (IFNs), serve to alert non-infected cells to the possibility of pathogen challenge (1). Moreover, in conjunction with chemokines they can instruct specialized immune cells to contain and eradicate microbial infection. Several receptors and signalling pathways exist that couple pathogen sensing to the induction of cytokines, whereas cytosolic recognition of nucleic acids seems to be exquisitely important for the activation of type I IFNs, master regulators of antiviral immunity (2). Cytosolic DNA is sensed by the receptor cyclic GMP-AMP (cGAMP) synthase (cGAS), which catalyses the synthesis of the second messenger cGAMP(2'-5') (3-8). This molecule in turn activates the endoplasmic reticulum (ER)-resident receptor STING (9-11), thereby inducing an antiviral state and the secretion of type I IFNs. Here we find in murine and human cells that cGAS-synthesized cGAMP (2'-5') is transferred from producing cells to neighbouring cells through gap junctions, where it promotes STING activation and thus antiviral immunity independently of type I IFN signalling. In line with the limited cargo specificity of connexins, the proteins that assemble gap junction channels, most connexins tested were able to confer this bystander immunity, thus indicating a broad physiological relevance of this local immune collaboration. Collectively, these observations identify cGAS-triggered cGAMP(2'-5') transfer as a novel host strategy that serves to rapidly convey antiviral immunity in a transcription-independent, horizontal manner.
    Keywords: Cellular Immunity -- Research ; Cyclic Adenosine Monophosphate -- Properties;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 5
    Language: English
    In: Immunity, 20 November 2014, Vol.41(5), pp.868-868.e1
    Description: The innate immune system has evolved sensors that can detect specific molecular fingerprints of non-self RNA or DNA. At the same time, some receptors respond to nucleic acids of both exogenous and endogenous origin, yet they are spatially segregated from endogenous nucleic acids. This SnapShot schematizes families and individual members of nucleic acid sensors with a focus on their ligands and the signaling pathways they employ.
    Keywords: Medicine ; Biology
    ISSN: 1074-7613
    E-ISSN: 1097-4180
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  • 6
    Language: English
    In: Immunity, 18 December 2014, Vol.41(6), pp.1066-1066.e1
    Description: The innate immune system has evolved sensors that can detect specific molecular fingerprints of non-self RNA or DNA. At the same time, some receptors respond to nucleic acids of both exogenous and endogenous origin, yet they are spatially segregated from endogenous nucleic acids. This SnapShot schematizes families and individual members of nucleic acid sensors with a focus on their ligands and the signaling pathways they employ.
    Keywords: Medicine ; Biology
    ISSN: 1074-7613
    E-ISSN: 1097-4180
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  • 7
    In: Nature Reviews Immunology, 2010, Vol.10(2), p.123
    Description: The recognition of nucleic acids is one strategy by which cells can detect infectious agents. As life is ultimately determined by the existence of nucleic acids, this defence strategy has evolved in many different organisms and operates effectively in many different cell types. Here, we review the recent progress in our understanding of the molecular mechanisms by which DNA activates cells to induce inflammation and antimicrobial immunity. DNA can be detected in different cellular compartments and can induce a range of cellular responses, such as an antiviral response and pyroptotic cell death together with the maturation and release of active interleukin-1[beta].
    Keywords: Cell Receptors -- Physiological Aspects ; Cell Receptors -- Genetic Aspects ; Cell Receptors -- Research ; Cellular Signal Transduction -- Physiological Aspects ; Cellular Signal Transduction -- Genetic Aspects ; Cellular Signal Transduction -- Research ; Dna Identification -- Usage ; Immune Response -- Genetic Aspects ; Immune Response -- Research;
    ISSN: 1474-1733
    E-ISSN: 14741741
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  • 8
    Language: English
    In: Journal of Molecular Biology, 19 January 2018, Vol.430(2), pp.133-141
    Description: NLRP3 is the most studied inflammasome sensor due to its crucial involvement in sterile and infection-triggered inflammation. Although its molecular mode of activation remains to be defined, it is well established that low intracellular potassium concentrations result in its activation. This functionality allows the classical NLRP3 pathway to serve as a highly sensitive, but non-specific surveillance mechanism responding to any type of perturbation that breaches plasma membrane integrity and the associated potassium gradient across the membrane. Here, we review our current knowledge on potassium efflux-dependent NLRP3 activation, with a special focus on how major cell death programs are rendered pro-inflammatory by secondary NLRP3 activation. Apart from the “alternative inflammasome” as the major exception to the rule, this connection explains the fundamental importance of NLRP3 in cell death-associated inflammation and firmly establishes NLRP3 as a principal surveillance mechanism of cellular integrity.
    Keywords: Nlrp3 ; Inflammasome ; Il-1β ; Potassium Efflux ; Inflammation ; Programmed Cell Death ; Biology ; Chemistry
    ISSN: 0022-2836
    E-ISSN: 1089-8638
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  • 9
    In: Nature, 2013, Vol.498(7454), p.380
    Keywords: Immune Response -- Genetic Aspects ; Cellular Signal Transduction -- Research ; Nucleotides -- Properties;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 10
    In: PLoS ONE, 2015, Vol.10(6)
    Description: Mice lacking DNase II display a polyarthritis-like disease phenotype that is driven by translocation of self-DNA into the cytoplasm of phagocytic cells, where it is sensed by pattern recognition receptors. While pro-inflammatory gene expression is non-redundantly linked to the presence of STING in these mice, the contribution of the inflammasome pathway has not been explored. To this end, we studied the role of the DNA-sensing inflammasome receptor AIM2 in this self-DNA driven disease model. Arthritis-prone mice lacking AIM2 displayed strongly decreased signs of joint inflammation and associated histopathological findings. This was paralleled with a reduction of caspase-1 activation and pro-inflammatory cytokine production in diseased joints. Interestingly, systemic signs of inflammation that are associated with the lack of DNase II were not dependent on AIM2. Taken together, these data suggest a tissue-specific role for the AIM2 inflammasome as a sensor for endogenous DNA species in the course of a ligand-dependent autoinflammatory condition.
    Keywords: Research Article
    E-ISSN: 1932-6203
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