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LAT蛋白中酪氨酸残基慢磷酸化可优化T细胞配体识别
作者:小柯机器人 发布时间:2019/10/15 14:07:16

美国加州大学John Kuriyan和Arthur Weiss研究组合作发现,T细胞适配器蛋白(LAT)中酪氨酸残基的慢磷酸化优化T细胞的配体识别。2019年10月14日,《自然—免疫学》在线发表了这一成果。

研究人员表示,LAT在位置Y132的酪氨酸磷酸化是配体识别的关键动力学瓶颈。Y132处的LAT磷酸化由ZAP-70激酶介导,导致磷脂酶C-γ1(PLC-γ1)(T细胞活化的重要效应分子)的募集和激活。相对于LAT上的其他磷酸位点,Y132的缓慢磷酸化是由前面的甘氨酸残基(G131)控制的,但可以通过用天冬氨酸或谷氨酸取代该甘氨酸来加速其磷酸化。

Y132磷酸化的加速提高了PLC-γ1活化的速度和幅度,并增强了T细胞对弱刺激(包括弱激动剂和自肽)的敏感性。这些观察结果表明,Y132的缓慢磷酸化充当校对步骤,以促进T细胞配体的识别。

研究人员介绍,自我与非自我辨别对于T细胞介导的免疫至关重要。动力学校对模型可以解释T细胞抗原受体(TCR)配体的区别。但是,尚未确定限速步骤。

附:英文原文

Title: Slow phosphorylation of a tyrosine residue in LAT optimizes T cell ligand discrimination

Author: Wan-Lin Lo, Neel H. Shah, Sara A. Rubin, Weiguo Zhang, Veronika Horkova, Ian R. Fallahee, Ondrej Stepanek, Leonard I. Zon, John Kuriyan, Arthur Weiss

Issue&Volume: 2019-10-14

Abstract: 

Self–non-self discrimination is central to T cell-mediated immunity. The kinetic proofreading model can explain T cell antigen receptor (TCR) ligand discrimination; however, the rate-limiting steps have not been identified. Here, we show that tyrosine phosphorylation of the T cell adapter protein LAT at position Y132 is a critical kinetic bottleneck for ligand discrimination. LAT phosphorylation at Y132, mediated by the kinase ZAP-70, leads to the recruitment and activation of phospholipase C-γ1 (PLC-γ1), an important effector molecule for T cell activation. The slow phosphorylation of Y132, relative to other phosphosites on LAT, is governed by a preceding glycine residue (G131) but can be accelerated by substituting this glycine with aspartate or glutamate. Acceleration of Y132 phosphorylation increases the speed and magnitude of PLC-γ1 activation and enhances T cell sensitivity to weaker stimuli, including weak agonists and self-peptides. These observations suggest that the slow phosphorylation of Y132 acts as a proofreading step to facilitate T cell ligand discrimination.

DOI: 10.1038/s41590-019-0502-2

Source: https://www.nature.com/articles/s41590-019-0502-2

期刊信息

Nature Immunology:《自然—免疫学》,创刊于2000年。隶属于施普林格·自然出版集团,最新IF:23.53
官方网址:https://www.nature.com/ni/
投稿链接:https://mts-ni.nature.com/cgi-bin/main.plex