mDia1/3-dependent actin polymerization spatiotemporally controls LAT phosphorylation by Zap70 at the immune synapse.
mDia1/3-dependent actin polymerization spatiotemporally controls LAT phosphorylation by Zap70 at the immune synapse.
复制标题
mDia1/3 依赖性肌动蛋白聚合在时空上控制 Zap70 在免疫突触处的 LAT 磷酸化。
DOI：
10.1126/sciadv.aay2432
复制
发表时间：
2020
期刊：
影响因子：
13.6
通讯作者：
Narumiya,S
中科院分区：
文献类型：
--
作者：
Thumkeo,D;Katsura,Y;Nishimura,Y;Kanchanawong,P;Tohyama,K;Ishizaki,T;Kitajima,S;Takahashi,C;Hirata,T;Watanabe,N;Krummel,MF;Narumiya,S
胞浆蛋白ZAP70与其底物跨膜蛋白LAT在T细胞受体(TCR)刺激下物理相互作用和磷酸化的机制仍很不清楚。在这项研究中，我们发现，尽管依赖TCR刺激的ZAP70磷酸化保持不变，但主要的肌动蛋白核心剂福林斯的药理抑制作用抑制了ZAP70对LAT的磷酸化。高分辨率成像和三维图像重建显示，磷酸化的ZAP70在免疫突触(IS)上的定位和随后的LAT磷酸化严重依赖于Forin介导的肌动蛋白聚合。利用基因敲除小鼠，我们发现在T细胞中高表达并在TCR激活时定位于IS的mDia1和mDia3是介导这一过程的关键福尔马林。因此，我们的发现描述了mDia1和mDia3通过调节丝状肌动蛋白在IS依赖于ZAP70的LAT磷酸化的时空控制中的先前未知的作用，并强调了它们在TCR信号转导中的生理重要性。
The mechanism by which the cytosolic protein Zap70 physically interacts with and phosphorylates its substrate, the transmembrane protein LAT, upon T cell receptor (TCR) stimulation remains largely obscure. In this study, we found that the pharmacological inhibition of formins, a major class of actin nucleators, suppressed LAT phosphorylation by Zap70, despite TCR stimulation–dependent phosphorylation of Zap70 remaining intact. High-resolution imaging and three-dimensional image reconstruction revealed that localization of phosphorylated Zap70 to the immune synapse (IS) and subsequent LAT phosphorylation are critically dependent on formin-mediated actin polymerization. Using knockout mice, we identify mDia1 and mDia3, which are highly expressed in T cells and which localize to the IS upon TCR activation, as the critical formins mediating this process. Our findings therefore describe previously unsuspected roles for mDia1 and mDia3 in the spatiotemporal control of Zap70-dependent LAT phosphorylation at the IS through regulation of filamentous actin, and underscore their physiological importance in TCR signaling.