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

PLoS Pathogens

Florian Zwolanek¹  Karl Kuchler¹  Valentina Stolz¹  Sabrina Jenull¹  Michael Riedelberger¹  Fabian Istel¹  Afitap Derya Köprülü²  Wilfried Ellmeier² 

[1] Department of Molecular Genetics, Medical University of Vienna, Max F. Perutz Laboratories, Vienna, Austria;Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria

关键词: C;    ida albicans;    Inflammasomes;    Inflammation;    Fungal pathogens;    Immune response;    Enzyme-linked immunoassays;    Fungal diseases;    Macrophages;   

DOI  :  10.1371/journal.ppat.1004525

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY