Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors.
Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors.
复制标题
Tespa1 通过招募肌醇 1,4,5-三磷酸受体调节 T 细胞受体诱导的钙信号
DOI：
10.1038/ncomms15732
复制
发表时间：
2017-06-09
影响因子：
16.6
通讯作者：
Lu L
中科院分区：
文献类型：
--
作者：
Liang J;Lyu J;Zhao M;Li D;Zheng M;Fang Y;Zhao F;Lou J;Guo C;Wang L;Wang D;Liu W;Lu L
胸腺细胞表达的阳性选择相关基因1(Tespa1)在T细胞受体(TCR)驱动的胸腺细胞发育中起重要作用。在TCR下游，Tespa1是激活T细胞(LAT)信号小体的连接体的重要组成部分，促进钙信号转导和随后的MAPK激活。然而，尚不清楚Tespa1是如何引发钙信号转导的。在这里，我们证明了肌醇1，4，5-三磷酸受体1(IP3R1)对于Tespa1优化、TCR诱导的钙流动和胸腺细胞发育是至关重要的。在TCR刺激下，Tespa1直接与IP3R1相互作用，并将其招募到TCR复合体中，在TCR复合体中，IP3R1在Y353被Fyn磷酸化。这种Tespa1-IP3R1相互作用是由Tespa1的F187和F188残基以及IP3R1的氨基末端介导的。Tespa1-F187A/F188A突变小鼠与表型缺失的Tespa1小鼠相比，由于IP3R1移位到TCR近端区域的减少，导致胸腺细胞发育迟缓。我们的工作阐明了Tespa1在T细胞发育中的作用以及通过IP3R1调节TCR诱导的钙信号转导。胸腺细胞发育蛋白Tespa1已知通过影响钙信号级联来翻译T细胞受体信号，但如何翻译尚不清楚。在这里，作者证明了Tespa1将IP3R1招募到TCR信号复合体中。
Thymocyte-expressed, positive selection-associated 1 (Tespa1) is important in T cell receptor (TCR)-driven thymocyte development. Downstream of the TCR, Tespa1 is a crucial component of the linker for activation of T cells (LAT) signalosome, facilitating calcium signalling and subsequent MAPK activation. However, it is unknown how Tespa1 elicits calcium signalling. Here, we show that inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) is crucial for Tespa1-optimized, TCR-induced Ca2+ flux and thymocyte development. Upon TCR stimulation, Tespa1 directly interacts with IP3R1 and recruits it to the TCR complex, where IP3R1 is phosphorylated at Y353 by Fyn. This Tespa1-IP3R1 interaction is mediated by the F187 and F188 residues of Tespa1 and the amino-terminus of IP3R1. Tespa1-F187A/F188A mutant mice phenocopy Tespa1-deficient mice with impaired late thymocyte development due to reduced IP3R1 translocation to the TCR-proximal region. Our work elucidates the function of Tespa1 in T cell development and the regulation of TCR-induced Ca2+ signalling through IP3R1. The thymocyte development protein Tespa1 is known to translate T cell receptor signals by affecting the calcium signalling cascade, but it is not clear how. Here the authors show that Tespa1 recruits IP3R1 to the TCR signalling complex.