The p97-UFD1L-NPL4 Protein Complex Mediates Cytokine-Induced IκBα Proteolysis
The p97-UFD1L-NPL4 Protein Complex Mediates Cytokine-Induced IκBα Proteolysis
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DOI：
10.1128/mcb.01190-13
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发表时间：
2014-02-01
影响因子：
5.3
通讯作者：
Jin, Jianping
中科院分区：
文献类型：
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作者：
Li, Ju-Mei;Wu, Hongyu;Jin, Jianping
I κ B α是NF-κ B的抑制剂，NF-κ B是转录因子家族，其反式激活与炎症相关的基因。在炎症刺激下，I κ B α通过泛素-蛋白酶体途径迅速降解。虽然SCF β-TRCP泛素连接酶在刺激时泛素化I κ B α是非常清楚的，但对I κ B α蛋白水解的泛素化后事件知之甚少。在这里，我们报告说，p97，一种含缬沙素的蛋白质（也称为VCP），在肿瘤坏死因子α（TNF-α）或白细胞介素-1 β（IL-1 β）治疗后I κ B α代谢的后稳态调节中起着重要作用。p97的ATP酶活性对于其在I κ B α蛋白水解中的作用是必不可少的。此外，我们还发现p97的两个辅因子UFD 1 L和NPL 4辅助p97控制I κ B α的后稳态调节。p97-UFD 1 L-NPL 4蛋白复合物通过p97和SCF β-TRCP泛素连接酶之间以及UFD 1 L的多聚泛素结合结构域和多聚泛素化I κ B α之间的相互作用与泛素化I κ B B α特异性结合。此外，我们观察到p97-UFD 1 L-NPL 4复合物对I κ B α的后稳态调节对于刺激下NF-κ B的激活是重要的。
I kappa B alpha is an inhibitor of NF-kappa B, a family of transcription factors that transactivate genes related to inflammation. Upon inflammatory stimuli, I kappa B alpha is rapidly degraded via the ubiquitin-proteasome pathway. While it is very clear that the SCF beta-TRCP ubiquitin ligase ubiquitinates I kappa B alpha upon stimulation, little is known about the postubiquitinational events of I kappa B alpha proteolysis. Here, we report that p97, a valosin-containing protein (also called VCP), plays an essential role in the postubiquitinational regulation of I kappa B alpha turnover after tumor necrosis factor alpha (TNF-alpha) or interleukin-1 beta (IL-1 beta) treatment. The ATPase activity of p97 is essential for its role in I kappa B alpha proteolysis. Moreover, we found that UFD1L and NPL4, two cofactors of p97, assist p97 to control the postubiquitinational regulation of I kappa B alpha. The p97-UFD1L-NPL4 protein complex specifically associates with ubiquitinated I kappa B alpha via the interactions between p97 and the SCF beta-TRCP ubiquitin ligase and between the polyubiquitin binding domain of UFD1L and polyubiquitinated I kappa B alpha. Furthermore, we observed that the postubiquitinational regulation of I kappa B alpha by the p97-UFD1L-NPL4 complex is important for NF-kappa B activation under stimuli.