Abstract
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 Statement
The authors have declared no competing interest.
Footnotes
Supplemental discussion added
Abbreviations
- AIM2
- Interferon-inducible protein absent in melanoma 2
- ASC
- Apoptosis-associated speck-like protein containing a Caspase activation and recruitment domain (CARD)
- BMDM
- bone marrow-derived macrophages
- BTK
- Bruton’s Tyrosine Kinase
- F
- Phenylalanine
- FDA
- Food and Drug Administration
- CAPS
- Cryopyrin-associated periodic syndrome
- GM-CSF
- Granulocyte-macrophage colony-stimulating factor
- HD
- healthy (blood) donor
- HEK
- human embryonic kidney
- IFN
- Interferon
- IL
- Interleukin
- IP
- immunoprecipitation
- KD
- kinase-dead
- LPS
- Lipopolysaccharide
- LRR
- leucine-rich repeat
- NEK7
- NIMA related kinase 7
- NACHT
- NAIP, CIITA, HET-E and TEP1
- NLR
- Nod-like receptor
- NLRP3
- NACHT, LRR and PYD domains-containing protein 3
- PBMC
- peripheral blood mononuclear cell
- PH
- Pleckstrin homology
- PI4P
- phosphatidylinositol-4-phosphate
- PMA
- Phorbol-12-myristate-13-acetate
- p-Y
- phospho-tyrosine
- PYD
- Pyrin domain
- SH
- Src homology
- TGN
- trans-Golgi network
- TH
- Tec homology
- TLR
- Toll-like receptor
- TNF
- Tumor necrosis factor
- XLA
- X-linked agammaglobulinemia
- Y
- Tyrosine.