BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity.
BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity.
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DOI：
10.1084/jem.20201656
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发表时间：
2021-11-01
期刊：
影响因子：
--
通讯作者：
Weber ANR
中科院分区：
文献类型：
--
作者：
Bittner ZA;Liu X;Mateo Tortola M;Tapia-Abellán A;Shankar S;Andreeva L;Mangan M;Spalinger M;Kalbacher H;Düwell P;Lovotti M;Bosch K;Dickhöfer S;Marcu A;Stevanović S;Herster F;Cardona Gloria Y;Chang TH;Bork F;Greve CL;Löffler MW;Wolz OO;Schilling NA;Kümmerle-Deschner JB;Wagner S;Delor A;Grimbacher B;Hantschel O;Scharl M;Wu H;Latz E;Weber ANR
Bittner等人发现，炎症体传感器NLRP 3通过公认的药物靶标布鲁顿酪氨酸激酶（BTK）的直接磷酸化促进炎症体组装并促进IL-1β释放。因此，BTK引起的NLRP 3磷酸化可能代表了炎症治疗干预的新靶点。NLRP 3炎性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。这些因素之间的关系尚不清楚。我们表明，一个完善的药物靶点，布鲁顿的酪氨酸激酶（BTK），影响几个层次的NLRP 3的调节。BTK直接与免疫细胞中的NLRP 3相互作用，并在体外和体内炎性小体激活后磷酸化四个保守的酪氨酸残基。此外，BTK促进NLRP 3重新定位，寡聚化，ASC聚合，和完全炎性小体组装，可能是通过电荷中和，在修饰已知指导NLRP 3高尔基体缔合和炎性小体成核的多元接头后。由于BTK对NLRP 3酪氨酸的修饰也能正向调节IL-1β的释放，因此我们提出BTK作为NLRP 3调节的多功能正调节剂，并提出NLRP 3的BTK磷酸化作为炎症控制中一种新的治疗上易于处理的步骤。
Bittner et al. discovered that direct phosphorylation of the inflammasome sensor NLRP3, by the well-established drug target Bruton’s tyrosine kinase (BTK), promotes inflammasome assembly and boosts IL-1β release. NLRP3 phosphorylation by BTK may thus represent a novel target for therapeutic intervention in inflammation. 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.
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影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
16.6
作者：
Ito, Minako;Shichita, Takashi;Okada, Masahiro;Komine, Ritsuko;Noguchi, Yoshiko;Yoshimura, Akihiko;Morita, Rimpei
通讯作者：
Morita, Rimpei
DOI：
10.1007/978-1-4939-3566-6_8
发表时间：
2016
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Khare, Sonal;Radian, Alexander D;Dorfleutner, Andrea;Stehlik, Christian
通讯作者：
Stehlik, Christian
影响因子：
16.6
作者：
Duarte, Daniel P.;Lamontanara, Allan J.;Hantschel, Oliver
通讯作者：
Hantschel, Oliver
影响因子：
15.1
作者：
Franke, Maximilian;Bieber, Michael;Schuhmann, Michael K.
通讯作者：
Schuhmann, Michael K.