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  • 1
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    Rapid induction of inflammatory lipid mediators by the inflammasome in vivo (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-08-21
    Description: Detection of microbial products by host inflammasomes is an important mechanism of innate immune surveillance. Inflammasomes activate the caspase-1 (CASP1) protease, which processes the cytokines interleukin (IL)-1beta and IL-18, and initiates a lytic host cell death called pyroptosis. To identify novel CASP1 functions in vivo, we devised a strategy for cytosolic delivery of bacterial flagellin, a specific ligand for the NAIP5 (NLR family, apoptosis inhibitory protein 5)/NLRC4 (NLR family, CARD-domain-containing 4) inflammasome. Here we show that systemic inflammasome activation by flagellin leads to a loss of vascular fluid into the intestine and peritoneal cavity, resulting in rapid (less than 30 min) death in mice. This unexpected response depends on the inflammasome components NAIP5, NLRC4 and CASP1, but is independent of the production of IL-1beta or IL-18. Instead, inflammasome activation results, within minutes, in an 'eicosanoid storm'--a pathological release of signalling lipids, including prostaglandins and leukotrienes, that rapidly initiate inflammation and vascular fluid loss. Mice deficient in cyclooxygenase-1, a critical enzyme in prostaglandin biosynthesis, are resistant to these rapid pathological effects of systemic inflammasome activation by either flagellin or anthrax lethal toxin. Inflammasome-dependent biosynthesis of eicosanoids is mediated by the activation of cytosolic phospholipase A(2) in resident peritoneal macrophages, which are specifically primed for the production of eicosanoids by high expression of eicosanoid biosynthetic enzymes. Our results therefore identify eicosanoids as a previously unrecognized cell-type-specific signalling output of the inflammasome with marked physiological consequences in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465483/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465483/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉von Moltke, Jakob -- Trinidad, Norver J -- Moayeri, Mahtab -- Kintzer, Alexander F -- Wang, Samantha B -- van Rooijen, Nico -- Brown, Charles R -- Krantz, Bryan A -- Leppla, Stephen H -- Gronert, Karsten -- Vance, Russell E -- AI063302/AI/NIAID NIH HHS/ -- AI075039/AI/NIAID NIH HHS/ -- AI080749/AI/NIAID NIH HHS/ -- EY016136/EY/NEI NIH HHS/ -- EY022208/EY/NEI NIH HHS/ -- R01 EY016136/EY/NEI NIH HHS/ -- R01 EY022208/EY/NEI NIH HHS/ -- England -- Nature. 2012 Oct 4;490(7418):107-11. doi: 10.1038/nature11351. Epub 2012 Aug 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California at Berkeley, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22902502" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Bacterial/chemistry/genetics/metabolism ; Apoptosis Regulatory Proteins/deficiency/metabolism ; Bacterial Toxins/chemistry/genetics/metabolism ; Body Fluids/metabolism ; Body Temperature ; Calcium Signaling ; Calcium-Binding Proteins/deficiency/metabolism ; Capillary Permeability ; Caspase 1/deficiency/metabolism ; Cyclooxygenase 1/deficiency ; Cytosol/metabolism ; Death ; Eicosanoids/*biosynthesis/metabolism ; Female ; Flagellin/genetics/immunology/metabolism ; Fluid Shifts ; Hematocrit ; Immunity, Innate/immunology ; Inflammasomes/*metabolism ; Inflammation/immunology/metabolism/pathology ; Interleukin-18 ; Interleukin-1beta ; Intestines/metabolism ; Legionella pneumophila ; Macrophages, Peritoneal/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Neuronal Apoptosis-Inhibitory Protein/deficiency/metabolism ; Peritoneal Cavity ; Peritoneal Lavage ; Recombinant Fusion Proteins/genetics/metabolism ; Salmonella Infections/immunology ; Salmonella typhimurium/immunology ; Time Factors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Structure, inhibition and regulation of two-pore channel TPC1 from Arabidopsis thaliana (2016)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2016-03-11
    Description: Two-pore channels (TPCs) comprise a subfamily (TPC1-3) of eukaryotic voltage- and ligand-gated cation channels with two non-equivalent tandem pore-forming subunits that dimerize to form quasi-tetramers. Found in vacuolar or endolysosomal membranes, they regulate the conductance of sodium and calcium ions, intravesicular pH, trafficking and excitability. TPCs are activated by a decrease in transmembrane potential and an increase in cytosolic calcium concentrations, are inhibited by low luminal pH and calcium, and are regulated by phosphorylation. Here we report the crystal structure of TPC1 from Arabidopsis thaliana at 2.87 A resolution as a basis for understanding ion permeation, channel activation, the location of voltage-sensing domains and regulatory ion-binding sites. We determined sites of phosphorylation in the amino-terminal and carboxy-terminal domains that are positioned to allosterically modulate cytoplasmic Ca(2+) activation. One of the two voltage-sensing domains (VSD2) encodes voltage sensitivity and inhibition by luminal Ca(2+) and adopts a conformation distinct from the activated state observed in structures of other voltage-gated ion channels. The structure shows that potent pharmacophore trans-Ned-19 (ref. 17) acts allosterically by clamping the pore domains to VSD2. In animals, Ned-19 prevents infection by Ebola virus and other filoviruses, presumably by altering their fusion with the endolysosome and delivery of their contents into the cytoplasm.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863712/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863712/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kintzer, Alexander F -- Stroud, Robert M -- GM24485/GM/NIGMS NIH HHS/ -- P41-GM103311/GM/NIGMS NIH HHS/ -- P41-RR001614/RR/NCRR NIH HHS/ -- P41GM103393/GM/NIGMS NIH HHS/ -- R37 GM024485/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Mar 10;531(7593):258-62. doi: 10.1038/nature17194.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26961658" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation/drug effects ; Arabidopsis/*chemistry ; Arabidopsis Proteins/*antagonists & inhibitors/*chemistry/metabolism ; Binding Sites ; Calcium/metabolism/pharmacology ; Calcium Channels/*chemistry/metabolism ; Carbolines/metabolism/pharmacology ; Crystallography, X-Ray ; Ebolavirus/drug effects ; Endosomes/drug effects/metabolism/virology ; *Ion Channel Gating/drug effects ; Ion Transport/drug effects ; Models, Molecular ; Phosphorylation ; Piperazines/metabolism/pharmacology ; Protein Structure, Tertiary/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Anthrax toxin protective antigen integrates poly- -D-glutamate and pH signals to sense the optimal environment for channel formation (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-10-24
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    Anthrax toxin pH and capsule sensing [Biochemistry] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-11-08
    Description: Many toxins assemble into oligomers on the surface of cells. Local chemical cues signal and trigger critical rearrangements of the oligomer, inducing the formation of a membrane-fused or channel state. Bacillus anthracis secretes two virulence factors: a tripartite toxin and a poly-γ-d-glutamic acid capsule (γ-DPGA). The toxin’s channel-forming component, protective...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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