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

  1. Zsófia A. Bittner
  2. Xiao Liu
  3. Sangeetha Shankar
  4. Ana Tapia-Abellán
  5. Hubert Kalbacher
  6. Liudmila Andreeva
  7. Matthew Mangan
  8. Peter Düwell
  9. Marta Lovotti
  10. Karlotta Bosch
  11. Sabine Dickhöfer
  12. Ana Marcu
  13. Stefan Stevanović
  14. Franziska Herster
  15. Markus W. Löffler
  16. Olaf-Oliver Wolz
  17. Nadine A. Schilling
  18. Jasmin Kümmerle-Deschner
  19. Samuel Wagner
  20. Anita Delor
  21. Bodo Grimbacher
  22. Hao Wu
  23. Eicke Latz
  24. Alexander N. R. Weber
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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.

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