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首页> 外文期刊>Molecular Immunology >Negative regulation of TCR signaling by ubiquitination of Zap-70 Lys-217
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Negative regulation of TCR signaling by ubiquitination of Zap-70 Lys-217

机译：Zap-70 Lys-217泛素化对TCR信号的负调控

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摘要

The tyrosine kinase Zap-70 is a key regulator of T cell receptor (TCR) signaling downstream of antigen presentation, with coordinated regulation of Zap-70 kinase activity critical for proper T cell proliferation, differentiation, and effector function during an immune response. Zap-70 is cytosolic in unstimulated T cells, but is rapidly recruited to the TCR complex following receptor stimulation. Its activity is regulated both by binding to subunits of the TCR and by phosphorylation on multiple tyrosine residues. Zap-70 also has been reported to be ubiquitinated following TCR stimulation. Herein, we confirm the ubiquitination of Zap-70 in T cell lines and in primary human and mouse T cells, and report the identification of nine novel Zap-70 ubiquitination sites. Three sites, including Lys-193, Lys-217, and Lys-376, displayed greater than 20-fold increase in modification levels following TCR stimulation. Abrogation of Lys-217 ubiquitination results in increased kinase activation, enhanced activation of downstream signaling pathways, and elevated IL-2 production following TCR stimulation. These data suggest that Zap-70 ubiquitination contributes to the regulation of Zap-70 signaling following TCR stimulation. (c) 2016 Elsevier Ltd. All rights reserved.
机译：酪氨酸激酶Zap-70是抗原呈递下游T细胞受体（TCR）信号的关键调节剂，对Zap-70激酶活性的协调调节对于免疫应答过程中适当的T细胞增殖，分化和效应子功能至关重要。 Zap-70在未刺激的T细胞中呈胞质状态，但在受体刺激后迅速募集到TCR复合物中。通过与TCR的亚基结合和在多个酪氨酸残基上的磷酸化来调节其活性。 Zap-70也据报道在TCR刺激后被泛素化。在本文中，我们确认了Zap-70在T细胞系以及原代人和小鼠T细胞中的泛素化，并报告了九个新型Zap-70泛素化位点的鉴定。 TCR刺激后，包括Lys-193，Lys-217和Lys-376在内的三个位点的修饰水平提高了20倍以上。废除Lys-217泛素化会导致激酶激活增加，下游信号传导通路激活增加以及TCR刺激后IL-2产生增加。这些数据表明Zap-70泛素化有助于TCR刺激后Zap-70信号传导的调节。 （c）2016 Elsevier Ltd.保留所有权利。

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