Tespal通过IP3R1调控T细胞受体（TCR）诱导的钙离子信号通路

发布时间：2018-10-05 08:22

【摘要】：T细胞受体(T cell receptor,TCR)信号在胸腺T细胞发育和外周T细胞活化过程中均发挥关键作用。TCR刺激能诱导细胞膜附近LAT信号复合体形成,招募并活化一系列信号分子,传导信号。我们研究团队近期的研究发现,一个新的信号传导接头蛋白Tespa1,能在TCR活化后被招募到LAT信号复合体中,参与调控下游MAPKs信号通路以及Ca~(2+)信号通路的活化。然而,Tespa1调控下游信号的具体分子机制尚不清楚。本论文的研究发现,Tespa1通过F187和F188位点直接与IP3R1结合,并将IP3R1招募到TCR信号复合体。这一招募不仅促进胞膜附近Fyn激酶对IP3R1的Tyr353的磷酸化,还有效促进了 TCR信号复合体附近钙离子信号的最大活化。当我们将Tespa1与IP3R1的结合位点突变之后,TCR活化诱导的胞内钙离子信号活化受到了显著抑制。最后,携带这一突变的Tespa1-FFAA转基因小鼠完全模拟了 Tespa1敲除小鼠的表型,提示Tespa1与IP3R1的相互作用在胸腺细胞的阳性选择过程中发挥了主要作用。综上所述,我们的工作揭示了Tespa1调控TCR信号传导和胸腺细胞发育全新的分子机制。
[Abstract]:T cell receptor (T cell receptor,TCR) signal plays a key role in the development of thymus T cells and the activation of peripheral T cells. TCR stimulation can induce the formation of LAT signal complex near cell membrane, recruit and activate a series of signal molecules, and conduct signals. Our team recently found that a new signal transduction junction protein (Tespa1,) can be recruited into the LAT signaling complex after TCR activation to regulate the activation of downstream MAPKs signaling pathways and Ca~ (2) signaling pathways. However, the specific molecular mechanism of Tespa1 regulating downstream signals is unclear. In this study, it was found that Tespa1 binds directly to IP3R1 through F187 and F188 sites, and enlists IP3R1 into TCR signal complex. This recruitment not only promoted the phosphorylation of IP3R1 Tyr353 by Fyn kinase near the cell membrane, but also promoted the maximum activation of calcium signal near the TCR signal complex. When we mutated the binding site between Tespa1 and IP3R1, the activation of intracellular calcium signal induced by Tespa1 activation was significantly inhibited. Finally, the Tespa1-FFAA transgenic mice carrying this mutation completely mimic the phenotype of Tespa1 knockout mice, suggesting that the interaction between Tespa1 and IP3R1 plays a major role in the positive selection of thymocytes. In conclusion, our work reveals a new molecular mechanism of Tespa1 regulating TCR signal transduction and thymocyte development.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：Q25

【相似文献】