PDF(Pubmed)
Abstract：
Actin dynamics control early T-cell receptor (TCR) signalling during T-cell activation. However, the precise regulation of initial actin rearrangements is not completely understood. Here, we have investigated the regulatory role of the phosphatase Slingshot-1 (SSH1) in this process. Our data show that SSH1 rapidly polarises to nascent cognate synaptic contacts and later relocalises to peripheral F-actin networks organised at the mature immunological synapse. Knockdown of SSH1 expression by CRISPR/Cas9-mediated genome editing or small interfering RNA reveal a regulatory role for SSH1 in CD3ε conformational change, allowing Nck binding and proper downstream signalling and immunological synapse organisation. TCR triggering induces SSH1-mediated activation of actin dynamics through a mechanism mediated by Limk-1 inactivation. These data suggest that during early TCR activation, SSH1 is required for rapid F-actin rearrangements that mediate initial conformational changes of the TCR, integrin organisation and proximal signalling events for proper synapse organisation. Therefore, the SSH1 and Limk-1 axis is a key regulatory element for full T cell activation.
摘要：
肌动蛋白动力学在T细胞活化期间控制早期T细胞受体(TCR)信号传导。然而,最初的肌动蛋白重排的精确调节尚不完全清楚。这里,我们研究了磷酸酶Slingshot-1（SSH1）在此过程中的调节作用。我们的数据表明，SSH1迅速极化为新生的同源突触接触，然后重新定位为在成熟的免疫突触中组织的外周F-肌动蛋白网络。通过CRISPR/Cas9介导的基因组编辑或小干扰RNA敲低SSH1表达揭示了SSH1在CD3ε构象变化中的调节作用。允许Nck结合和适当的下游信号和免疫突触组织。TCR触发通过Limk-1失活介导的机制诱导SSH1介导的肌动蛋白动力学激活。这些数据表明，在早期TCR激活期间，SSH1对于介导TCR初始构象变化的快速F-肌动蛋白重排是必需的，整合素组织和近端信号事件，以实现适当的突触组织。因此,SSH1和Limk-1轴是全T细胞活化的关键调控元件。
