BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity PMID: 34554188

ADC Targets in Oncology

2026-04-10

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

J Exp Med. 2021 Nov 1;218(11):e20201656. doi: 10.1084/jem.20201656.

Zsófia Agnes Bittner ¹ , Xiao Liu ¹ , Maria Mateo Tortola ¹ , Ana Tapia-Abellán ¹ , Sangeetha Shankar ¹ , Liudmila Andreeva ² ³ , Matthew Mangan ⁴ ⁵ , Marianne Spalinger ⁶ , Hubert Kalbacher ⁷ , Peter Düwell ⁴ , Marta Lovotti ⁴ , Karlotta Bosch ¹ , Sabine Dickhöfer ¹ , Ana Marcu ¹ , Stefan Stevanović ¹ , Franziska Herster ¹ , Yamel Cardona Gloria ¹ , Tzu-Hsuan Chang ¹ , Francesca Bork ¹ , Carsten L Greve ¹ , Markus W Löffler ¹ ⁸ ⁹ ¹⁰ , Olaf-Oliver Wolz ¹ , Nadine A Schilling ¹¹ , Jasmin B Kümmerle-Deschner ¹² , Samuel Wagner ¹³ ¹⁴ , Anita Delor ¹⁵ , Bodo Grimbacher ¹⁵ ¹⁶ ¹⁷ ¹⁸ ¹⁹ , Oliver Hantschel ²⁰ , Michael Scharl ⁶ , Hao Wu ² ³ , Eicke Latz ⁴ ²¹ , Alexander N R Weber ¹ ¹⁰ ¹⁴ ²²

Affiliations

1. Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.
2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA.
3. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA.
4. Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany.
5. German Center for Neurodegenerative Diseases, Bonn, Germany.
6. Department for Gastroenterology and Hepatology, University Hospital Zürich and University of Zürich, Zürich, Switzerland.
7. Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
8. Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.
9. Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany.
10. Cluster of Excellence 2180, Image-Guided and Functionally Instructed Tumor Therapies, University of Tübingen, Tübingen, Germany.
11. Institute of Organic Chemistry, University of Tübingen, Tübingen, Germany.
12. Division of Pediatric Rheumatology and Autoinflammation Reference Center Tübingen, Department of Pediatrics, University Hospital Tübingen, Tübingen, Germany.
13. Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Tübingen, Germany.
14. Cluster of Excellence 2124, Controlling Microbes to Fight Infection, University of Tübingen, Tübingen, Germany.
15. Centre of Chronic Immunodeficiency, University Hospital Freiburg, Freiburg, Germany.
16. Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs University, Freiburg, Germany.
17. German Center for Infection Research, Freiburg, Germany.
18. Center for Integrative Biological Signaling Studies, Albert-Ludwigs University, Freiburg, Germany.
19. Cluster of Excellence 2155, Resolving Infection Susceptibility, Hanover Medical School, Freiburg, Germany.
20. Institute of Physiological Chemistry, Faculty of Medicine, Philipps University of Marburg, Marburg, Germany.
21. Division of Infectious Diseases and Immunology, University of Massachusetts, Worcester, MA.
22. German Cancer Consortium, Tübingen, Germany.

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.