Involvement of Ymer in suppression of NF-κB activation by regulated interaction with lysine-63-linked polyubiquitin chain
Involvement of Ymer in suppression of NF-κB activation by regulated interaction with lysine-63-linked polyubiquitin chain
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DOI：
10.1016/j.bbamcr.2007.09.006
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发表时间：
2008-05-01
影响因子：
5.1
通讯作者：
Hatakeyama, Shigetsugu
中科院分区：
文献类型：
--
作者：
Bohgaki, Miyuki;Tsukiyama, Tadasuke;Hatakeyama, Shigetsugu
已知胞浆锌指蛋白A20通过抑制NF-κ B活化在功能上抑制炎症信号和细胞凋亡，并且在生物化学上作为具有dcubiquitmating活性和泛素连接酶活性的独特的泛素修饰蛋白起作用。然而，A20调节的信号转导影响正常免疫应答或肿瘤免疫的分子机制尚未完全阐明。利用酵母双杂交系统寻找与A20相互作用的蛋白质，发现了一个新的结合蛋白Ymer。据报道，Ymer通过EGF刺激在酪氨酸残基上高度磷酸化，与受体相互作用丝氨酸/苏氨酸蛋白激酶1（RIP 1）上的赖氨酸（K）-63-连接的多聚泛素链结合，RIP 1是与A20协作的NF-κ B信号传导所必需的。荧光素酶测定显示，NF-κ B信号传导通过Ymer的过表达而下调，而Ymer的敲低即使在没有刺激的情况下也上调NF-κ B信号传导。这些发现表明Ymer可能是NF-κ B信号通路的负调节剂。（C）007 Elsevier B.V保留所有权利。
It is known that the cytoplasmic zinc finger protein A20 functionally dampens inflammatory signals and apoptosis via inhibition of NF-kappa B activation and biochemically acts as a unique ubiquitin-modifying protein with dcubiquitmating activity and ubiquitin ligase activity. However, the molecular mechanisms of A20-modulated signal transduction that influence normal immune responses or tumor immunity have not been fully elucidated. Using a yeast two-hybrid system to search for proteins interacting with A20, we identified one novel binding protein, Ymer. Ymer, which has been reported to be highly phosphorylated on tyrosine residues via EGF stimulation, bound to lysine (K)-63-linked polyubiquitin chain on receptor-interacting serine/threonine-protein kinase 1 (RIP 1), which is essential for NF-kappa B signaling in collaboration with A20. A luciferase assay showed that NF-kappa B signaling was down-regulated by overexpression of Ymer, whereas knock-down of Ymer up-egulated NF-kappa B signaling even without stimulation. These findings demonstrate that Ymer is likely to be a negative regulator for the NF-kappa B signaling pathway. (C)007 Elsevier B.V All rights reserved.