RT Journal Article
SR Electronic
T1 BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 864702
DO 10.1101/864702
A1 Zsófia A. Bittner
A1 Xiao Liu
A1 Sangeetha Shankar
A1 Ana Tapia-Abellán
A1 Hubert Kalbacher
A1 Liudmila Andreeva
A1 Matthew Mangan
A1 Peter Düwell
A1 Marta Lovotti
A1 Karlotta Bosch
A1 Sabine Dickhöfer
A1 Ana Marcu
A1 Stefan Stevanović
A1 Franziska Herster
A1 Markus W. Löffler
A1 Olaf-Oliver Wolz
A1 Nadine A. Schilling
A1 Jasmin Kümmerle-Deschner
A1 Samuel Wagner
A1 Anita Delor
A1 Bodo Grimbacher
A1 Hao Wu
A1 Eicke Latz
A1 Alexander N. R. Weber
YR 2020
UL http://biorxiv.org/content/early/2020/06/25/864702.abstract
AB Activity of the NLRP3 inflammasome, a critical mediator of inflammation (1), is controlled by accessory proteins (2, 3), post-translational modifications (4, 5), cellular localization (6, 7) and oligomerization (8). How these factors relate, is unclear. We show that the established drug target, Bruton’s Tyrosine Kinase (BTK) (2, 9), integrates several levels of NLRP3 regulation: BTK phosphorylation of four conserved tyrosine residues, by neutralizing the charge of a polybasic linker region, weakens the interaction of NLRP3 with Golgi phospholipids and may thus guide NLRP3 cytosolic localization. BTK activity also promotes NLRP3 oligomerization and subsequent formation of inflammasomes. As NLRP3 tyrosine modification ultimately also impacts on IL-1β release, we propose BTK-mediated, charge-switch-based NLRP3 regulation as a novel and therapeutically tractable step in the control of inflammation.One Sentence Summary Multi-phosphorylation of NLRP3 by Bruton’s tyrosine kinase modulates NLRP3 cellular localization, inflammasome assembly, and IL-1β release.Competing Interest StatementThe authors have declared no competing interest.AIM2Interferon-inducible protein absent in melanoma 2ASCApoptosis-associated speck-like protein containing a Caspase activation and recruitment domain (CARD)BMDMbone marrow-derived macrophagesBTKBruton’s Tyrosine KinaseFPhenylalanineFDAFood and Drug AdministrationCAPSCryopyrin-associated periodic syndromeGM-CSFGranulocyte-macrophage colony-stimulating factorHDhealthy (blood) donorHEKhuman embryonic kidneyIFNInterferonILInterleukinIPimmunoprecipitationKDkinase-deadLPSLipopolysaccharideLRRleucine-rich repeatNEK7NIMA related kinase 7NACHTNAIP, CIITA, HET-E and TEP1NLRNod-like receptorNLRP3NACHT, LRR and PYD domains-containing protein 3PBMCperipheral blood mononuclear cellPHPleckstrin homologyPI4Pphosphatidylinositol-4-phosphatePMAPhorbol-12-myristate-13-acetatep-Yphospho-tyrosinePYDPyrin domainSHSrc homologyTGNtrans-Golgi networkTHTec homologyTLRToll-like receptorTNFTumor necrosis factorXLAX-linked agammaglobulinemiaYTyrosine.