中国科学院生物化学与细胞生物学研究所/国家蛋白质科学中心(上海)最新研究发现在细胞里的钙离子,能帮助人体内T淋巴细胞的活化,提高T淋巴细胞对“外敌入侵”的敏感性,从而帮助机体清除病原体。

-2013年1月3日《自然》


中文翻译


【题目】Ca2+ 通过调节脂质电荷性质调控T细胞受体活化

【译文】对于膜受体、离子通道、整联蛋白等蛋白的结构和功能来说,离子蛋白质-脂质相互作用至关重要。然而,人们对这些相互间作用的调控机制知之甚少。本研究表明Ca2+可以直接结合至阴离子磷脂并因此调控膜蛋白功能。T细胞抗原受体-CD3复合物(TCR,适应性免疫的一种关键膜受体)的活化受到质膜上带正电的CD3 ε /ζ胞质域(CD3CD)和带负电荷的磷脂间的相互作用的调控。重要酪氨酸埋入膜中并受到静止T细胞的磷酸化保护。目前,人们尚不清楚CD3CD是如何从抗原刺激的T细胞膜上解离的。甚至单TCR的抗原衔接可以触发Ca2+流和TCR邻近Ca2+浓度比平均胞质内Ca2+浓度更高。我们的生化、活细胞荧光共振能量转移和NMR实验表明钙离子浓度增加可诱导膜上CD3CD的分离和酪氨酸残基的溶剂暴露。因此,随着Ca2 +的涌入,CD3酪氨酸磷酸化显着增强。此外,与野生型细胞相比,Ca 2 +通道缺陷的T细胞在接受刺激后,CD3磷酸化水平大幅较低。Ca 2 +对促进CD3磷酸化的影响主要是由于Ca2 +的离子电荷效应。通过用非生理性锶离子(Sr2+)取代Ca 2 +实验,发现具有相同的效果。最后,利用31P NMR光谱实验表明,生理浓度下Ca 2 +绑定阴离子磷脂中的磷酸基团,从而中和了负电荷的磷脂。这种Ca 2 +调控途径并非是激活了CD3的磷酸化,而是对扩大和维持CD3磷酸化及提高T细胞的外来抗原的敏感性具有正效应,这种监管途径的Ca2 +有放大和维持CD3磷酸化的正反馈效应,应加强对外来抗原的T-细胞的敏感性。因此,我们的研究钙离子对参与直接脂质处理的T细胞活化提供了新的调控机制。

英文原稿


[Title]: Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids

[Authors]:Xiaoshan Shi,1, 2, 5 Yunchen Bi,3, 5 Wei Yang,1, 2, 5 Xingdong Guo,1, 2 Yan Jiang,1, 2 Chanjuan Wan,3 Lunyi Li,1, 2 Yibing Bai,1, 2 Jun Guo,1, 2 Yujuan Wang,3 Xiangjun Chen,4 Bo Wu,3 Hongbin Sun,3 Wanli Liu,4 Junfeng Wang3 & Chenqi Xu1, 2

[Abstract]Ionic protein–lipid interactions are critical for the structure and function of membrane receptors, ion channels, integrins and many other proteins. However, the regulatory mechanism of these interactions is largely unknown. Here we show that Ca2+ can bind directly to anionic phospholipids and thus modulate membrane protein function. The activation of T-cell antigen receptor–CD3 complex (TCR), a key membrane receptor for adaptive immunity, is regulated by ionic interactions between positively charged CD3ε/ζ cytoplasmic domains (CD3CD) and negatively charged phospholipids in the plasma membrane. Crucial tyrosines are buried in the membrane and are largely protected from phosphorylation in resting T cells. It is not clear how CD3CD dissociates from the membrane in antigen-stimulated T cells. The antigen engagement of even a single TCR triggers a Ca2+ influx and TCR-proximal Ca2+ concentration is higher than the average cytosolic Ca2+ concentration. Our biochemical, live-cell fluorescence resonance energy transfer and NMR experiments showed that an increase in Ca2+ concentration induced the dissociation of CD3CD from the membrane and the solvent exposure of tyrosine residues. As a consequence, CD3 tyrosine phosphorylation was significantly enhanced by Ca2+ influx. Moreover, when compared with wild-type cells, Ca2+ channel-deficient T cells had substantially lower levels of CD3 phosphorylation after stimulation. The effect of Ca2+ on facilitating CD3 phosphorylation is primarily due to the charge of this ion, as demonstrated by the fact that replacing Ca2+ with the non-physiological ion Sr2+ resulted in the same feedback effect. Finally, 31P NMR spectroscopy showed that Ca2+ bound to the phosphate group in anionic phospholipids at physiological concentrations, thus neutralizing the negative charge of phospholipids. Rather than initiating CD3 phosphorylation, this regulatory pathway of Ca2+ has a positive feedback effect on amplifying and sustaining CD3 phosphorylation and should enhance T-cell sensitivity to foreign antigens. Our study thus provides a new regulatory mechanism of Ca2+ to T-cell activation involving direct lipid manipulation.

原文地址

http://www.nature.com/nature/journal/v493/n7430/full/nature11699.html

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