Negative regulation of TCR signaling by ubiquitination of Zap-70 Lys-217.
Negative regulation of TCR signaling by ubiquitination of Zap-70 Lys-217.
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DOI：
10.1016/j.molimm.2016.03.006
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发表时间：
2016-05
影响因子：
3.6
通讯作者：
Carpino N
中科院分区：
文献类型：
--
作者：
Ivanova E;Carpino N
酪氨酸激酶Zap-70是抗原呈递下游的T细胞受体（TCR）信号传导的关键调节剂，Zap-70激酶活性的协调调节对于免疫应答期间的适当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细胞中是胞质的，但在受体刺激后迅速募集到TCR复合物。其活性通过与TCR亚基的结合和多个酪氨酸残基上的磷酸化来调节。Zap-70也被报道在TCR刺激后被泛素化。在此，我们确认了Zap-70在T细胞系和原代人类和小鼠T细胞中的泛素化，并报告了9个新的Zap-70泛素化位点的鉴定。三个位点，包括Lys-193、Lys-217和Lys-376，在TCR刺激后显示修饰水平增加超过20倍。去除Lys-217泛素化导致TCR刺激后激酶活化增加、下游信号传导途径活化增强和IL-2产生升高。这些数据表明，Zap-70泛素化有助于TCR刺激后Zap-70信号转导的调节。
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.