Otud7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination.
Otud7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination.
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DOI：
10.1084/jem.20151426
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发表时间：
2016-03-07
期刊：
影响因子：
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通讯作者：
Sun SC
中科院分区：
文献类型：
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作者：
Hu H;Wang H;Xiao Y;Jin J;Chang JH;Zou Q;Xie X;Cheng X;Sun SC
Hu等人。证明去泛素酶OTUD7B通过去泛素化ZAP70在TCR-近端信号和T细胞激活中起到积极的调节作用。来自T细胞受体(TCR)的信号转导对T细胞介导的免疫反应至关重要，当解除调控时，也有助于自身免疫的发展。TCR信号是如何调节的，目前还不完全清楚。在这项研究中，我们证明了一种泛素依赖的机制，在这种机制中，脱泛素酶OTUD7B在促进TCR信号转导方面起着至关重要的作用。在TCR连接后，OTUD7B迅速被募集到酪氨酸激酶ZAP70，它是TCR-近端信号的中心媒介。OTUD7B缺陷减弱了ZAP70及其下游通路的激活，损害了T细胞的激活和分化，使小鼠对T细胞介导的自身免疫和炎症反应难以抵抗。OTUD7B通过去泛素化ZAP70促进了ZAP70的激活，从而阻止了ZAP70与负调节磷酸酶Sts1和Sts2的联系。这些发现证实了OTUD7B是TCR-近端信号和T细胞激活的积极调节因子，强调了去泛素化在调节ZAP70功能中的重要性。
Hu et al. demonstrate that the deubiquitinase Otud7b acts as a positive regulator of TCR-proximal signaling and T cell activation by deubiquitinating Zap70. Signal transduction from the T cell receptor (TCR) is crucial for T cell–mediated immune responses and, when deregulated, also contributes to the development of autoimmunity. How TCR signaling is regulated is incompletely understood. In this study, we demonstrate a ubiquitin-dependent mechanism in which the deubiquitinase Otud7b has a crucial role in facilitating TCR signaling. Upon TCR ligation, Otud7b is rapidly recruited to the tyrosine kinase Zap70, a central mediator of TCR-proximal signaling. Otud7b deficiency attenuates the activation of Zap70 and its downstream pathways and impairs T cell activation and differentiation, rendering mice refractory to T cell–mediated autoimmune and inflammatory responses. Otud7b facilitated Zap70 activation by deubiquitinating Zap70, thus preventing the association of Zap70 with the negative-regulatory phosphatases Sts1 and Sts2. These findings establish Otud7b as a positive regulator of TCR-proximal signaling and T cell activation, highlighting the importance of deubiquitination in regulating Zap70 function.