Article ; Online: Type I IFN triggers RIG-I/TLR3/NLRP3-dependent inflammasome activation in influenza A virus infected cells.
2013 Volume 9, Issue 4, Page(s) e1003256
Abstract: ... These findings demonstrate that in IAV-infected lung epithelial cells RIG-I activates the inflammasome ... signaling pathway upstream of TLR3 and NLRP3. Notably, RIG-I also activated the inflammasome through interaction ... in macrophages. RIG-I had the strongest effect through a MAVS/TRIM25/Riplet-dependent type I IFN ...
| Abstract | Influenza A virus (IAV) triggers a contagious and potentially lethal respiratory disease. A protective IL-1β response is mediated by innate receptors in macrophages and lung epithelial cells. NLRP3 is crucial in macrophages; however, which sensors elicit IL-1β secretion in lung epithelial cells remains undetermined. Here, we describe for the first time the relative roles of the host innate receptors RIG-I (DDX58), TLR3, and NLRP3 in the IL-1β response to IAV in primary lung epithelial cells. To activate IL-1β secretion, these cells employ partially redundant recognition mechanisms that differ from those described in macrophages. RIG-I had the strongest effect through a MAVS/TRIM25/Riplet-dependent type I IFN signaling pathway upstream of TLR3 and NLRP3. Notably, RIG-I also activated the inflammasome through interaction with caspase 1 and ASC in primary lung epithelial cells. Thus, NS1, an influenza virulence factor that inhibits the RIG-I/type I IFN pathway, strongly modulated the IL-1β response in lung epithelial cells and in ferrets. The NS1 protein derived from a highly pathogenic strain resulted in increased interaction with RIG-I and inhibited type I IFN and IL-1β responses compared to the least pathogenic virus strains. These findings demonstrate that in IAV-infected lung epithelial cells RIG-I activates the inflammasome both directly and through a type I IFN positive feedback loop. |
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| MeSH term(s) | Adaptor Proteins, Signal Transducing/metabolism ; Animals ; CARD Signaling Adaptor Proteins ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Caspase 1/genetics ; Caspase 1/metabolism ; Cells, Cultured ; Cytoskeletal Proteins/metabolism ; DEAD Box Protein 58 ; DEAD-box RNA Helicases/genetics ; DEAD-box RNA Helicases/metabolism ; Epithelial Cells/metabolism ; Ferrets ; HEK293 Cells ; Humans ; Inflammasomes/metabolism ; Influenza A Virus, H1N1 Subtype/metabolism ; Interferon-beta/metabolism ; Lung/metabolism ; Lung/virology ; Macrophages/immunology ; Male ; NLR Family, Pyrin Domain-Containing 3 Protein ; RNA Interference ; Receptors, Immunologic ; Respiratory Mucosa/cytology ; Respiratory Mucosa/immunology ; Signal Transduction ; Toll-Like Receptor 3/genetics ; Toll-Like Receptor 3/metabolism ; Transcription Factors/metabolism ; Tripartite Motif Proteins ; Ubiquitin-Protein Ligases/metabolism ; Viral Nonstructural Proteins/metabolism |
| Chemical Substances | Adaptor Proteins, Signal Transducing ; CARD Signaling Adaptor Proteins ; Carrier Proteins ; Cytoskeletal Proteins ; INS1 protein, influenza virus ; Inflammasomes ; MAVS protein, human ; NLR Family, Pyrin Domain-Containing 3 Protein ; NLRP3 protein, human ; PYCARD protein, human ; Receptors, Immunologic ; TLR3 protein, human ; Toll-Like Receptor 3 ; Transcription Factors ; Tripartite Motif Proteins ; Viral Nonstructural Proteins ; Interferon-beta (77238-31-4) ; TRIM25 protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Caspase 1 (EC 3.4.22.36) ; RIGI protein, human (EC 3.6.1.-) ; DEAD Box Protein 58 (EC 3.6.4.13) ; DEAD-box RNA Helicases (EC 3.6.4.13) |
| Language | English |
| Publishing date | 2013-04-11 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2205412-1 |
| ISSN | 1553-7374 ; 1553-7374 |
| ISSN (online) | 1553-7374 |
| ISSN | 1553-7374 |
| DOI | 10.1371/journal.ppat.1003256 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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