BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity-Reference-Cited by-同舟云学术

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

Published:2021-09-23 Issue:11 Volume:218 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Bittner Zsófia Agnes¹^ORCID,Liu Xiao¹^ORCID,Mateo Tortola Maria¹^ORCID,Tapia-Abellán Ana¹^ORCID,Shankar Sangeetha¹^ORCID,Andreeva Liudmila²³^ORCID,Mangan Matthew⁴⁵^ORCID,Spalinger Marianne⁶^ORCID,Kalbacher Hubert⁷^ORCID,Düwell Peter⁴^ORCID,Lovotti Marta⁴^ORCID,Bosch Karlotta¹^ORCID,Dickhöfer Sabine¹^ORCID,Marcu Ana¹^ORCID,Stevanović Stefan¹^ORCID,Herster Franziska¹^ORCID,Cardona Gloria Yamel¹^ORCID,Chang Tzu-Hsuan¹^ORCID,Bork Francesca¹^ORCID,Greve Carsten L.¹^ORCID,Löffler Markus W.¹⁸⁹¹⁰^ORCID,Wolz Olaf-Oliver¹^ORCID,Schilling Nadine A.¹¹^ORCID,Kümmerle-Deschner Jasmin B.¹²^ORCID,Wagner Samuel¹³¹⁴^ORCID,Delor Anita¹⁵^ORCID,Grimbacher Bodo¹⁵¹⁶¹⁷¹⁸¹⁹^ORCID,Hantschel Oliver²⁰^ORCID,Scharl Michael⁶^ORCID,Wu Hao²³^ORCID,Latz Eicke⁴²¹^ORCID,Weber Alexander N.R.¹¹⁰¹⁴²²^ORCID

Affiliation:

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.

Funder

Else-Kröner-Fresenius Stiftung

Deutsche Forschungsgemeinschaft

University Hospital Tübingen

IFM Therapeutics

E-Rare program

German Research Foundation

Federal Ministry of Education and Research

Damon Runyon Cancer Research Foundation

University of Tübingen

Publisher

Rockefeller University Press