ERK5 is involved in TCR-induced apoptosis through the modification of Nur77
ERK5 is involved in TCR-induced apoptosis through the modification of Nur77
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DOI：
10.1111/j.1365-2443.2008.01177.x
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发表时间：
2008-05-01
期刊：
影响因子：
2.1
通讯作者：
Koyasu, Shigeo
中科院分区：
文献类型：
--
作者：
Fujii, Yasushi;Matsuda, Satoshi;Koyasu, Shigeo
Nur 77是一种核孤儿类固醇受体，当未成熟的T细胞通过与自身肽-MHC复合物相互作用而被强烈激活时，其参与负选择。Nur 77在胸腺细胞和T细胞系中的表达以依赖于其转录活性的方式导致细胞凋亡。已经确定Nur 77的功能受翻译后修饰的负调控。在这里，我们证明了MAPK诱导的Nur 77在T细胞活化过程中的磷酸化在诱导细胞凋亡中起着至关重要的作用。在T细胞受体（TCR）刺激时，MAPK家族的成员ERK 5（也称为大MAP激酶1，BMK 1）磷酸化Nur 77，导致其转录激活。相反，ERK 2信号通路的激活不能激活Nur 77，尽管ERK 2也能够磷酸化Nur 77。此外，阻断ERK 5信号通路可抑制TCR诱导的细胞死亡。这些结果表明ERK 5通过其磷酸化调节Nur 77功能。
Nur77 is a nuclear orphan steroid receptor that has been implicated in negative selection when immature T cells are strongly activated through interaction with self peptide-MHC complexes. The expression of Nur77 in thymocytes and T cell lines leads to apoptosis in a manner dependent on its transcriptional activity. It is well established that Nur77 function is negatively regulated by post-translational modification. Here we demonstrate that the MAPK-induced phosphorylation of Nur77 during T cell activation plays a critical role in the induction of apoptosis. Upon T cell receptor (TCR) stimulation, ERK5 (also known as big MAP kinase 1, BMK1), a member of the MAPK family, phosphorylates Nur77, leading to its transcriptional activation. In contrast, the activation of the ERK2 signaling pathway failed to activate Nur77 although ERK2 is also able to phosphorylate Nur77. Furthermore, the blockade of ERK5 signaling pathway suppressed TCR-induced cell death. These results indicate that ERK5 regulates Nur77 function through its phosphorylation.