The non-receptor tyrosine kinase Tec controls assembly and activity of the noncanonical caspase-8 inflammasome

PLoS Pathog. 2014 Dec 4;10(12):e1004525. doi: 10.1371/journal.ppat.1004525. eCollection 2014 Dec.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspase 8 / genetics
  • Caspase 8 / immunology*
  • Enzyme Activation / genetics
  • Enzyme Activation / immunology
  • Humans
  • Inflammasomes / genetics
  • Inflammasomes / immunology*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / immunology
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / immunology
  • Lectins, C-Type / genetics
  • Lectins, C-Type / immunology
  • Mice
  • Mice, Knockout
  • Mycoses / genetics
  • Mycoses / immunology
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / immunology*
  • Sepsis / genetics
  • Sepsis / immunology
  • Syk Kinase

Substances

  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • Intracellular Signaling Peptides and Proteins
  • Lectins, C-Type
  • dectin 1
  • Tec protein-tyrosine kinase
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • Syk protein, mouse
  • Casp8 protein, mouse
  • Caspase 8

Grant support

This work was supported by a sugar grant from the Medical University and the University of Vienna to KK and WE, in part by grants from the Austrian Science Foundation (FWF-I-746-B11, FWF-P25333-B22) to KK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.