BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity
| Autor: | Sabine Dickhöfer, Oliver Hantschel, Hubert Kalbacher, Anita Delor, Franziska Herster, Jasmin Kümmerle-Deschner, Bodo Grimbacher, Carsten L. Greve, Xiao Liu, Ana Marcu, Samuel Wagner, Hao Wu, Liudmila Andreeva, Ana Tapia-Abellán, Yamel Cardona Gloria, Alexander N.R. Weber, Marta Lovotti, Eicke Latz, Michael Scharl, Markus W. Löffler, Maria Mateo Tortola, Olaf-Oliver Wolz, Nadine A. Schilling, Peter Düwell, Matthew Mangan, Sangeetha Shankar, Tzu-Hsuan Chang, Zsofia Bittner, Stefan Stevanovic, Karlotta Bosch, Francesca Bork, Marianne R. Spalinger |
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| Rok vydání: | 2020 |
| Předmět: |
Inflammasomes
metabolism [NLR Family Pyrin Domain-Containing 3 Protein] Immunology Interleukin-1beta symbols.namesake Mice Mediator metabolism [Interleukin-1beta] immune system diseases hemic and lymphatic diseases NLR Family Pyrin Domain-Containing 3 Protein medicine Agammaglobulinaemia Tyrosine Kinase Immunology and Allergy Bruton's tyrosine kinase Animals ddc:610 Tyrosine Cellular localization Inflammation Mice Knockout metabolism [Inflammation] integumentary system biology Chemistry Inflammasome Golgi apparatus Cell biology Mice Inbred C57BL metabolism [Tyrosine] symbols biology.protein Phosphorylation metabolism [Agammaglobulinaemia Tyrosine Kinase] Tyrosine kinase metabolism [Inflammasomes] medicine.drug |
| Zdroj: | Journal of experimental medicine 218(11), e20201656 (2021). doi:10.1084/jem.20201656 |
| ISSN: | 1540-9538 |
| Popis: | Activity of the NLRP3 inflammasome, a critical mediator of inflammation, is controlled by accessory proteins, posttranslational modifications, cellular localization, and oligomerization. How these factors relate is unclear. We show that a well-established drug target, Bruton’s tyrosine kinase (BTK), affects several levels of NLRP3 regulation. BTK directly interacts with NLRP3 in immune cells and phosphorylates four conserved tyrosine residues upon inflammasome activation, in vitro and in vivo. Furthermore, BTK promotes NLRP3 relocalization, oligomerization, ASC polymerization, and full inflammasome assembly, probably by charge neutralization, upon modification of a polybasic linker known to direct NLRP3 Golgi association and inflammasome nucleation. As NLRP3 tyrosine modification by BTK also positively regulates IL-1β release, we propose BTK as a multifunctional positive regulator of NLRP3 regulation and BTK phosphorylation of NLRP3 as a novel and therapeutically tractable step in the control of inflammation. |
| Databáze: | OpenAIRE |
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