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http://purl.uniprot.org/citations/28216434http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/28216434http://www.w3.org/2000/01/rdf-schema#comment"

Background

The Nod-like receptor NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) and Bruton tyrosine kinase (BTK) are protagonists in innate and adaptive immunity, respectively. NLRP3 senses exogenous and endogenous insults, leading to inflammasome activation, which occurs spontaneously in patients with Muckle-Wells syndrome; BTK mutations cause the genetic immunodeficiency X-linked agammaglobulinemia (XLA). However, to date, few proteins that regulate NLRP3 inflammasome activity in human primary immune cells have been identified, and clinically promising pharmacologic targeting strategies remain elusive.

Objective

We sought to identify novel regulators of the NLRP3 inflammasome in human cells with a view to exploring interference with inflammasome activity at the level of such regulators.

Methods

After proteome-wide phosphoproteomics, the identified novel regulator BTK was studied in human and murine cells by using pharmacologic and genetic BTK ablation.

Results

Here we show that BTK is a critical regulator of NLRP3 inflammasome activation: pharmacologic (using the US Food and Drug Administration-approved inhibitor ibrutinib) and genetic (in patients with XLA and Btk knockout mice) BTK ablation in primary immune cells led to reduced IL-1β processing and secretion in response to nigericin and the Staphylococcus aureus toxin leukocidin AB (LukAB). BTK affected apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and caspase-1 cleavage and interacted with NLRP3 and ASC. S aureus infection control in vivo and IL-1β release from cells of patients with Muckle-Wells syndrome were impaired by ibrutinib. Notably, IL-1β processing and release from immune cells isolated from patients with cancer receiving ibrutinib therapy were reduced.

Conclusion

Our data suggest that XLA might result in part from genetic inflammasome deficiency and that NLRP3 inflammasome-linked inflammation could potentially be targeted pharmacologically through BTK."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.org/dc/terms/identifier"doi:10.1016/j.jaci.2017.01.017"xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Liu X."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Miller L."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Macek B."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Hartl D."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Franz-Wachtel M."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Pichulik T."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Grimbacher B."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Kraus H."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Latz E."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Wolz C."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Brunner C."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Vogel S."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Stilgenbauer S."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Weber A.N.R."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Wolz O.O."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Rieber N."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Stutz A."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Schulte B."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Dillen C."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Dang T.M."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Walz J.S."xsd:string
http://purl.uniprot.org/citations/28216434http://purl.uniprot.org/core/author"Wahl S."xsd:string
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