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浙江大學(xué)魯林榮課題組與清華劉萬(wàn)里課題組合作發(fā)文闡明TCR信號(hào)調(diào)控新機(jī)制

       2017年6月9日，國(guó)際學(xué)術(shù)權(quán)威刊物自然出版集團(tuán)旗下子刊《Nature Communications》雜志上在線發(fā)表了浙江大學(xué)醫(yī)學(xué)院魯林榮教授課題組和清華大學(xué)生命科學(xué)學(xué)院劉萬(wàn)里教授研究組合作的一篇研究論文。論文題為“Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors”，研究闡明了T 細(xì)胞發(fā)育相關(guān)蛋白Tesap1調(diào)控TCR下游鈣信號(hào)傳導(dǎo)的調(diào)控機(jī)制。本文的第一作者為博士生梁靜靜和呂俊，本文的通訊作者為魯林榮教授和清華大學(xué)劉萬(wàn)里教授。

       T細(xì)胞是一類在胸腺中發(fā)育成熟的關(guān)鍵免疫細(xì)胞。胸腺T細(xì)胞發(fā)育的后期依賴其表面抗原受體(TCR)的信號(hào)。TCR信號(hào)的調(diào)節(jié)對(duì)T細(xì)胞的成熟至關(guān)重要，不僅能決定T細(xì)胞對(duì)抗原的特異性反應(yīng)，還幫助建立其對(duì)機(jī)體自身的耐受。因此胸腺T細(xì)胞發(fā)育過(guò)程中TCR信號(hào)的調(diào)節(jié)機(jī)制一直是T細(xì)胞免疫學(xué)的研究重點(diǎn)。

       魯林榮教授課題組于2012年在《Nature Immunology》發(fā)表了題為“Tespa1 is involved in late thymocyte development through the regulation of TCR-mediated signaling.”的論文，發(fā)現(xiàn)并命名一個(gè)參與T 細(xì)胞發(fā)育調(diào)控的新分子Tespa1。本研究在原有的研究基礎(chǔ)上進(jìn)一步闡明了Tespa1的作用 分子機(jī)制：當(dāng)TCR接受信號(hào)后，Tespa1通過(guò)與TCR信號(hào)復(fù)合體中磷脂酶PLCg1的結(jié)合參與TCR信號(hào)復(fù)合體的組裝;與此同時(shí)，Tespa1能通過(guò)其PFF基序特異性結(jié)合內(nèi)質(zhì)網(wǎng)上鈣離子通道IP3R，從而將IP3R招募至TCR復(fù)合體附近。IP3R在TCR信號(hào)復(fù)合物附近的重新定位，不但直接促進(jìn)細(xì)胞膜上的激酶Fyn對(duì)IP3R的磷酸化，而且加速了其與配體IP3的結(jié)合，確保鈣離子信號(hào)的快速高效啟動(dòng)。這一工作不僅闡明了Tespa1對(duì)TCR信號(hào)的調(diào)控機(jī)制， 而且揭示了鈣離子通道的空間分布在TCR信號(hào)傳導(dǎo)中的重要性。

Working Model：Tespa1 regulates TCR-induced calcium flux through the recruitment of IP3R to TCR signaling complex.

原文鏈接：

        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, wher 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.