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

2019 ◽  
Author(s):  
Zsófia A. Bittner ◽  
Xiao Liu ◽  
Sangeetha Shankar ◽  
Ana Tapia-Abellán ◽  
Hubert Kalbacher ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Nlrp3 Inflammasome ◽  
Drug Target ◽  
Cellular Localization ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Subsequent Formation ◽  
Post Translational Modifications ◽  
Tyrosine Modification ◽  
Inflammasome Activity

AbstractActivity 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 SummaryMulti-phosphorylation of NLRP3 by Bruton’s tyrosine kinase modulates NLRP3 cellular localization, inflammasome assembly, and IL-1β release.

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

2021 ◽  
Vol 218 (11) ◽  
Author(s):  
Zsófia Agnes Bittner ◽  
Xiao Liu ◽  
Maria Mateo Tortola ◽  
Ana Tapia-Abellán ◽  
Sangeetha Shankar ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Nlrp3 Inflammasome ◽  
Drug Target ◽  
Cellular Localization ◽  
Inflammasome Activation ◽  
Tyrosine Residues ◽  
Tyrosine Modification ◽  
Inflammasome Activity

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.

Bruton’s Tyrosine Kinase (BTK) Is Not Required for BCR-ABL-Mediated Transformation of Hematopoietic Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1015-1015 ◽  
Author(s):  
Mary MacPartlin ◽  
Lee A. Honigberg ◽  
Brian J. Druker ◽  
Michael W. Deininger
Keyword(s):  
Cell Proliferation ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Drug Target ◽  
Hematopoietic Cells ◽  
Kinase Domain ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Imatinib Resistant

Abstract Background: Bruton’s tyrosine kinase (BTK) is a member of the Tec family of protein tyrosine kinases. Mutations of BTK have been associated with a block in B cell development, and are causal to X-linked agammaglobulinemia (XLA) in humans. Bcr-Abl is a constitutively active tyrosine kinase that is essential for the transforming capacity of Bcr-Abl. Using phosphoproteomics we have shown that BTK is consistently tyrosine phosphorylated in Bcr-Abl expressing Ba/F3 cells [Griswold et al. Mol Cell Biol.2006;26(16):6082–93.]. Since BTK has also been implicated in resistance to imatinib [Hofmann et al. Lancet2002;359(9305):481–6] and one study [Feldhahn et al. J Exp Med.2005; 201(11):1837–52] had suggested a role of BTK in Bcr-Abl-induced transformation we decided to test whether BTK may be a critical node in Bcr-Abl transformation and potential drug target in imatinib-resistant Bcr-Abl-positive cells. Results: We depleted BTK in Ba/F3 and 32D cells expressing native and kinase domain (KD) mutant (E255K and T315I) Bcr-Abl, using shRNA. BTK levels were reduced to <10% of controls, but no differences in viability and cell proliferation were observed. Additionally, responses to imatinib were not affected by BTK depletion. We further tested the effects of reversible (PCI-33918) and irreversible (PCI-31523) small molecule inhibitors of BTK on the above cell lines as well as human Ph+ B-lymphoblastic lines. Selective BTK inhibition did not impact cell proliferation. Lastly, BTK inhibition had no effect on Bcr-Abl-mediated transformation of primary murine hematopoietic cells in colony forming assays. Conclusion: Despite the fact the BTK is consistently tyrosine phosophorylated in Bcr-Abl expressing cells, our data suggests it is not essential for Bcr-Abl-mediated transformation of lymphoid or myeloid cells.

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