The Non-receptor Tyrosine Kinase Tec Controls Assembly and Activity of the Noncanonical Caspase-8 Inflammasome

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Inflammasomes represent multi-protein complexes and their activation during microbial infections is key in driving hyperinflammation through the maturation and release of IL-1β, as well as by directly inducing several pro-inflammatory cytokines during the host pathogen interaction. Thus, inflammasomes are involved in the induction of pathogen-induced sepsis in mice and men. However, the precise regulation and molecules involved in triggering the assembly and activation of inflammasomes remain enigmatic. In this study, we identify the Tec Kinase family member Tec as a novel central regulator of the noncanonical caspase-8 inflammasome, regulated via the C-type lectin receptor dectin-1. Tec is involved in the assembly and activation of the caspase-8 inflammasome in response to the major human fungal pathogen Candida albicans, but not involved in anti-bacterial immune responses. Furthermore, Tec specifically regulates the caspase-8 inflammasome leaving the caspase-1 inflammasome unaffected. Finally, we are able to define Tec as novel molecular fine tuner of anti-fungal immune responses in a mouse model of acute sepsis. Strikingly, chemical inhibition of Tec with a small molecule drug also strongly protected mice from fungal sepsis. Hence, these data demonstrate a therapeutic potential for Tec kinase inhibition to combat invasive microbial infections by attenuating the host inflammatory response.

Vyšlo v časopise: The Non-receptor Tyrosine Kinase Tec Controls Assembly and Activity of the Noncanonical Caspase-8 Inflammasome. PLoS Pathog 10(12): e32767. doi:10.1371/journal.ppat.1004525
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004525

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