Abstract
Influenza virus, a negative-stranded RNA virus that causes severe illness in humans and animals, stimulates the inflammasome through the Nod-like receptor NLRP3. However, the mechanism by which influenza virus activates the NLRP3 inflammasome is unknown. Here we show that the influenza virus M2 protein, a proton-selective ion channel important in viral pathogenesis, stimulates the NLRP3 inflammasome pathway. M2 channel activity was required for the activation of inflammasomes by influenza and was sufficient to activate inflammasomes in primed macrophages and dendritic cells. M2-induced activation of inflammasomes required its localization to the Golgi apparatus and was dependent on the pH gradient. Our results show a mechanism by which influenza virus infection activates inflammasomes and identify the sensing of disturbances in intracellular ionic concentrations as a previously unknown pathogen-recognition pathway.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / immunology
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Carrier Proteins / metabolism*
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Cells, Cultured
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Cytokines / genetics
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Cytokines / metabolism
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Dendritic Cells / drug effects
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Dendritic Cells / immunology
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Dendritic Cells / metabolism*
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Dendritic Cells / pathology
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Dendritic Cells / virology
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Genetic Engineering
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Golgi Apparatus / drug effects
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Golgi Apparatus / metabolism
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Golgi Apparatus / virology
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Hydrogen-Ion Concentration / drug effects
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Ion Channels / genetics
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Ion Channels / immunology
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Ion Channels / metabolism*
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Macrophages / drug effects
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Macrophages / immunology
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Macrophages / metabolism*
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Macrophages / pathology
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Macrophages / virology
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / immunology
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Monensin / pharmacology
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NLR Family, Pyrin Domain-Containing 3 Protein
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Oncogene Proteins, Viral / pharmacology
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Orthomyxoviridae / pathogenicity
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Orthomyxoviridae / physiology*
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Orthomyxoviridae Infections / immunology*
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Orthomyxoviridae Infections / physiopathology
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Potassium Chloride / pharmacology
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Protein Transport / drug effects
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Protons
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Sequence Deletion / genetics
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Toll-Like Receptor 7 / genetics
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Toll-Like Receptor 7 / immunology
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Toll-Like Receptor 7 / metabolism
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Viral Matrix Proteins / genetics
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Viral Matrix Proteins / immunology
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Viral Matrix Proteins / metabolism*
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Virus Replication
Substances
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Carrier Proteins
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Cytokines
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Ion Channels
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M2 protein, Influenza A virus
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Membrane Glycoproteins
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Oncogene Proteins, Viral
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Protons
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Tlr7 protein, mouse
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Toll-Like Receptor 7
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Viral Matrix Proteins
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oncogene protein E5, Bovine papillomavirus type 1
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Potassium Chloride
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Monensin