BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity
Open Access
- 23 September 2021
- journal article
- research article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 218 (11)
- https://doi.org/10.1084/jem.20201656
Abstract
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.Funding Information
- Else-Kröner-Fresenius Stiftung
- Deutsche Forschungsgemeinschaft (CRC TR156, We-4195/15-1)
- University Hospital Tübingen (2310-0-0, 2615-0-0)
- IFM Therapeutics
- E-Rare program
- German Research Foundation (GR1617/14-1/iPAD)
- Federal Ministry of Education and Research (GAIN_01GM1910A)
- Damon Runyon Cancer Research Foundation
- University of Tübingen
- University Hospital Tübingen
- Deutsche Forschungsgemeinschaft (EXC 2180, EXC 2124, EXC 2189, EXC 2155, EXC 2151)
- Deutsche Forschungsgemeinschaft (EXC 2180 (390900677), EXC 2124, EXC 2189 (390939984), EXC 2155 (39087428), EXC 2151 (390873048))
This publication has 47 references indexed in Scilit:
- ASC Speck Formation as a Readout for Inflammasome ActivationPublished by Springer Science and Business Media LLC ,2013
- NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystalsNature, 2010
- Function and dysfunction of the PI system in membrane traffickingThe EMBO Journal, 2008
- Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilizationNature Immunology, 2008
- CHARMM‐GUI: A web‐based graphical user interface for CHARMMJournal of Computational Chemistry, 2008
- PBEQ-Solver for online visualization of electrostatic potential of biomoleculesNucleic Acids Research, 2008
- A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responsesNature Immunology, 2007
- Acute Inflammatory Response to Endotoxin in Mice and HumansClinical and Vaccine Immunology, 2005
- All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of ProteinsThe Journal of Physical Chemistry B, 1998
- Defective B cell development and function in Btk-deficient miceImmunity, 1995