title: The non-receptor tyrosine kinase Tec controls assembly and activity of the noncanonical caspase-8 inflammasome.
abstract: Tec family kinases are intracellular non-receptor tyrosine kinases implicated in numerous functions, including T cell and B cell regulation. However, a role in microbial pathogenesis has not been described. Here, we identified Tec kinase as a novel key mediator of the inflammatory immune response in macrophages invaded by the human fungal pathogen C. albicans. Tec is required for both activation and assembly of the noncanonical caspase-8, but not of the caspase-1 inflammasome, during infections with fungal but not bacterial pathogens, triggering the antifungal response through IL-1β. Furthermore, we identify dectin-1 as the pathogen recognition receptor being required for Syk-dependent Tec activation. Hence, Tec is a novel innate-specific inflammatory kinase, whose genetic ablation or inhibition by small molecule drugs strongly protects mice from fungal sepsis. These data demonstrate a therapeutic potential for Tec kinase inhibition to combat invasive microbial infections by attenuating the host inflammatory response.
authors.affiliation: Department of Molecular Genetics, Medical University of Vienna, Max F. Perutz Laboratories, Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Zwolanek
authors.affiliation: Department of Molecular Genetics, Medical University of Vienna, Max F. Perutz Laboratories, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Riedelberger
authors.affiliation: Department of Molecular Genetics, Medical University of Vienna, Max F. Perutz Laboratories, Vienna, Austria.
authors.forename: Valentina
authors.initials: V
authors.lastname: Stolz
authors.affiliation: Department of Molecular Genetics, Medical University of Vienna, Max F. Perutz Laboratories, Vienna, Austria.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Jenull
authors.affiliation: Department of Molecular Genetics, Medical University of Vienna, Max F. Perutz Laboratories, Vienna, Austria.
authors.forename: Fabian
authors.initials: F
authors.lastname: Istel
authors.affiliation: Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Afitap Derya
authors.initials: AD
authors.lastname: Köprülü
authors.affiliation: Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Ellmeier
authors.affiliation: Department of Molecular Genetics, Medical University of Vienna, Max F. Perutz Laboratories, Vienna, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Kuchler
mesh_terms: D000818:Animals; D053181:Caspase 8 / Q000235:genetics / Q000276:immunology*; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009181:Mycoses / Q000235:genetics / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D018805:Sepsis / Q000235:genetics / Q000276:immunology; D000072377:Syk Kinase; D000099181:Dectin-1
chemical_list: D053181:Caspase 8; D058847:Inflammasomes; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; D000099181:Dectin-1; C587672:IL1B protein, mouse; C089848:Tec protein-tyrosine kinase; C000606896:SYK protein, human; C000606897:Syk protein, mouse; C505526:Casp8 protein, mouse