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BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity.

The Journal of experimental medicine

Authors: Zsófia Agnes Bittner, Xiao Liu, Maria Mateo Tortola, Ana Tapia-Abellán, Sangeetha Shankar, Liudmila Andreeva, Matthew Mangan, Marianne Spalinger, Hubert Kalbacher, Peter Düwell, Marta Lovotti, Karlotta Bosch, Sabine Dickhöfer, Ana Marcu, Stefan Stevanović, Franziska Herster, Yamel Cardona Gloria, Tzu-Hsuan Chang, Francesca Bork, Carsten L Greve, Markus W Löffler, Olaf-Oliver Wolz, Nadine A Schilling, Jasmin B Kümmerle-Deschner, Samuel Wagner, Anita Delor, Bodo Grimbacher, Oliver Hantschel, Michael Scharl, Hao Wu, Eicke Latz, Alexander N R Weber

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.

© 2021 Bittner et al.

PMID: 34554188

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