Influenza virus activates inflammasomes via its intracellular M2 ion channel.
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.
Ichinohe
Takeshi
T
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
Pang
Iris K
IK
Iwasaki
Akiko
A
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D005818:Genetic Engineering; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007473:Ion Channels / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008985:Monensin / Q000494:pharmacology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009856:Oncogene Proteins, Viral / Q000494:pharmacology; D009975:Orthomyxoviridae / Q000472:pathogenicity / Q000502:physiology*; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000503:physiopathology; D011189:Potassium Chloride / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D011522:Protons; D017384:Sequence Deletion / Q000235:genetics; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014779:Virus Replication; D000086082:Viroporin Proteins
D002352:Carrier Proteins; D016207:Cytokines; D007473:Ion Channels; D008562:Membrane Glycoproteins; D008985:Monensin; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009856:Oncogene Proteins, Viral; D011189:Potassium Chloride; D011522:Protons; D051199:Toll-Like Receptor 7; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins; C492716:Nlrp3 protein, mouse; C477038:Tlr7 protein, mouse; C054304:oncogene protein E5, Bovine papillomavirus type 1
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