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.
BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity
Disclosures: J.B. Kümmerle-Deschner reported grants from Novartis, personal fees from Novartis, grants from SOBI, and personal fees from SOBI outside the submitted work. B. Grimbacher reported grants from BMBF, grants from DFG, grants from several pharmaceutical companies, personal fees from several pharmaceutical companies, and grants from foundations outside the submitted work. E. Latz is co-founder and consultant to IFM Therapeutics. No other disclosures were reported.
Z.A. Bittner’s present address is Prime Vector Technologies GmbH, Tübingen, Germany.
O.-O. Wolz’s present address is CureVac AG, Tübingen, Germany.
- Award Id(s): CRC TR156,We-4195/15-1
- Award Id(s): 2310-0-0,2615-0-0
- Award Id(s): GR1617/14-1/iPAD
- Award Id(s): GAIN_01GM1910A
- Award Id(s): EXC 2180,EXC 2124,EXC 2189,EXC 2155,EXC 2151
- Award Id(s): EXC 2180 (390900677),EXC 2124,EXC 2189 (390939984),EXC 2155 (39087428),EXC 2151 (390873048)
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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; BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity. J Exp Med 1 November 2021; 218 (11): e20201656. doi: https://doi.org/10.1084/jem.20201656
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