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.

中文翻译：

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BTK 操作磷酸酪氨酸开关来调节 NLRP3 炎性体活性

NLRP3 炎症小体是炎症的关键介质，其活性受辅助蛋白、翻译后修饰、细胞定位和寡聚化控制。这些因素如何相关尚不清楚。我们展示了一个成熟的药物靶点，布鲁顿酪氨酸激酶 (BTK)，影响 NLRP3 调节的几个级别。BTK 直接与免疫细胞中的 NLRP3 相互作用，并在体外和体内炎症小体激活时磷酸化四个保守的酪氨酸残基。此外，BTK 促进 NLRP3 重新定位、寡聚化、ASC 聚合和完整的炎性体组装，可能通过电荷中和，在已知指导 NLRP3 高尔基体结合和炎性体成核的多元接头的修饰后。由于 BTK 对 NLRP3 酪氨酸的修饰也正向调节 IL-1β 的释放，