K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8+ T cell activation
K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8+ T cell activation
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DOI：
10.1038/ni.3258
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发表时间：
2015-12
影响因子：
30.5
通讯作者：
Mingjin Yang;Taoyong Chen;Xuelian Li;Zhou Yu;Songqing Tang;Chen Wang;Yan Gu;Yanfang Liu;Sheng Xu;Weihua Li;Xuemin Zhang;Jianli Wang;Xuetao Cao
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文献类型：
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作者：
Mingjin Yang;Taoyong Chen;Xuelian Li;Zhou Yu;Songqing Tang;Chen Wang;Yan Gu;Yanfang Liu;Sheng Xu;Weihua Li;Xuemin Zhang;Jianli Wang;Xuetao Cao
通过T细胞抗原受体(TCR)控制信号的关键分子机制仍未完全阐明。在这里，我们发现Nrdp1，一种环指型E3连接酶，介导了Lys33(K33)连接的信号激酶ZAP70的多泛素化，并促进了酸性磷酸酶样蛋白Sts1和Sts2对ZAP70的去磷酸化，从而终止了CD8+T细胞的早期TCR信号。与TCR结合后，Nrdp1缺乏可显著促进初治CD8+T细胞的活化，但不能促进初治CD4+T细胞的活化。Nrdp1与ZAP70、Sts1和Sts2相互作用，并将ZAP70的K33连接到Sts1和Sts2介导的去磷酸化。我们的研究表明，Nrdp1通过失活ZAP70来终止早期的TCR信号，并为E3连接酶对TCR信号的非蛋白水解性调节提供了新的机制。
The key molecular mechanisms that control signaling via T cell antigen receptors (TCRs) remain to be fully elucidated. Here we found that Nrdp1, a ring finger–type E3 ligase, mediated Lys33 (K33)-linked polyubiquitination of the signaling kinase Zap70 and promoted the dephosphorylation of Zap70 by the acidic phosphatase–like proteins Sts1 and Sts2 and thereby terminated early TCR signaling in CD8+T cells. Nrdp1 deficiency significantly promoted the activation of naive CD8+T cells but not that of naive CD4+T cells after engagement of the TCR. Nrdp1 interacted with Zap70 and with Sts1 and Sts2 and connected K33 linkage of Zap70 to Sts1- and Sts2-mediated dephosphorylation. Our study suggests that Nrdp1 terminates early TCR signaling by inactivating Zap70 and provides new mechanistic insights into the non-proteolytic regulation of TCR signaling by E3 ligases.