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  • 1
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    Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-04-03
    Description: Fungal infections represent a serious threat, particularly in immunocompromised patients. Interleukin-1beta (IL-1beta) is a key pro-inflammatory factor in innate antifungal immunity. The mechanism by which the mammalian immune system regulates IL-1beta production after fungal recognition is unclear. Two signals are generally required for IL-1beta production: an NF-kappaB-dependent signal that induces the synthesis of pro-IL-1beta (p35), and a second signal that triggers proteolytic pro-IL-1beta processing to produce bioactive IL-1beta (p17) via Caspase-1-containing multiprotein complexes called inflammasomes. Here we demonstrate that the tyrosine kinase Syk, operating downstream of several immunoreceptor tyrosine-based activation motif (ITAM)-coupled fungal pattern recognition receptors, controls both pro-IL-1beta synthesis and inflammasome activation after cell stimulation with Candida albicans. Whereas Syk signalling for pro-IL-1beta synthesis selectively uses the Card9 pathway, inflammasome activation by the fungus involves reactive oxygen species production and potassium efflux. Genetic deletion or pharmalogical inhibition of Syk selectively abrogated inflammasome activation by C. albicans but not by inflammasome activators such as Salmonella typhimurium or the bacterial toxin nigericin. Nlrp3 (also known as NALP3) was identified as the critical NOD-like receptor family member that transduces the fungal recognition signal to the inflammasome adaptor Asc (Pycard) for Caspase-1 (Casp1) activation and pro-IL-1beta processing. Consistent with an essential role for Nlrp3 inflammasomes in antifungal immunity, we show that Nlrp3-deficient mice are hypersusceptible to Candida albicans infection. Thus, our results demonstrate the molecular basis for IL-1beta production after fungal infection and identify a crucial function for the Nlrp3 inflammasome in mammalian host defence in vivo.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gross, Olaf -- Poeck, Hendrik -- Bscheider, Michael -- Dostert, Catherine -- Hannesschlager, Nicole -- Endres, Stefan -- Hartmann, Gunther -- Tardivel, Aubry -- Schweighoffer, Edina -- Tybulewicz, Victor -- Mocsai, Attila -- Tschopp, Jurg -- Ruland, Jurgen -- MC_U117527252/Medical Research Council/United Kingdom -- England -- Nature. 2009 May 21;459(7245):433-6. doi: 10.1038/nature07965. Epub 2009 Apr 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universitat Munchen, Ismaninger Str. 22, 81675 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19339971" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Candida albicans/*immunology/physiology ; Carrier Proteins/*immunology/*metabolism ; Caspase 1/metabolism ; Enzyme Activation ; Humans ; Inflammation/immunology ; Interleukin-1beta/biosynthesis/immunology ; Intracellular Signaling Peptides and Proteins/antagonists & ; inhibitors/deficiency/genetics/*metabolism ; Macrophages/metabolism ; Mice ; Monocytes/metabolism ; Nigericin/pharmacology ; Potassium/metabolism ; Protein-Tyrosine Kinases/antagonists & inhibitors/deficiency/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; *Signal Transduction
    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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    5'-Triphosphate RNA is the ligand for RIG-I (2006)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2006-10-14
    Description: The structural basis for the distinction of viral RNA from abundant self RNA in the cytoplasm of virally infected cells is largely unknown. We demonstrated that the 5'-triphosphate end of RNA generated by viral polymerases is responsible for retinoic acid-inducible protein I (RIG-I)-mediated detection of RNA molecules. Detection of 5'-triphosphate RNA is abrogated by capping of the 5'-triphosphate end or by nucleoside modification of RNA, both occurring during posttranscriptional RNA processing in eukaryotes. Genomic RNA prepared from a negative-strand RNA virus and RNA prepared from virus-infected cells (but not from noninfected cells) triggered a potent interferon-alpha response in a phosphatase-sensitive manner. 5'-triphosphate RNA directly binds to RIG-I. Thus, uncapped 5'-triphosphate RNA (now termed 3pRNA) present in viruses known to be recognized by RIG-I, but absent in viruses known to be detected by MDA-5 such as the picornaviruses, serves as the molecular signature for the detection of viral infection by RIG-I.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hornung, Veit -- Ellegast, Jana -- Kim, Sarah -- Brzozka, Krzysztof -- Jung, Andreas -- Kato, Hiroki -- Poeck, Hendrik -- Akira, Shizuo -- Conzelmann, Karl-Klaus -- Schlee, Martin -- Endres, Stefan -- Hartmann, Gunther -- New York, N.Y. -- Science. 2006 Nov 10;314(5801):994-7. Epub 2006 Oct 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Clinical Pharmacology, Department of Internal Medicine, University of Munich, 80336 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17038590" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cells, Cultured ; Cytosol/metabolism/virology ; DEAD-box RNA Helicases/*metabolism ; DNA-Directed RNA Polymerases/metabolism ; Humans ; Interferon-alpha/biosynthesis ; Interferon-beta/biosynthesis ; Ligands ; Mice ; Monocytes/metabolism ; Oligoribonucleotides/metabolism ; Phosphates/metabolism ; Phosphorylation ; RNA/chemistry/*metabolism ; RNA Caps/metabolism ; RNA, Double-Stranded/chemistry/metabolism ; RNA, Viral/chemistry/*metabolism ; Rabies virus/genetics/immunology/physiology ; Transcription, Genetic ; Transfection ; Viral Proteins/metabolism ; Virus Replication
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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