pVHL mediates K63-linked ubiquitination of IKKβ, leading to IKKβ inactivation
pVHL mediates K63-linked ubiquitination of IKKβ, leading to IKKβ inactivation
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pVHL 介导 IKK beta 的 K63 连接泛素化，导致 IKK beta 失活
DOI：
10.1016/j.canlet.2016.09.009
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发表时间：
2016-12-01
期刊：
影响因子：
9.7
通讯作者：
Fang, Jing
中科院分区：
文献类型：
--
作者：
Wang, Yuxin;Zhao, Wenting;Fang, Jing
核因子（NF）-κ B B是一种在许多生物学功能中起重要作用的转录因子。NF-κ B活性的调节是复杂的，并且泛素化对于NF-κ B活化是必需的。缺氧可激活NF-κ B B。然而，其潜在机制仍不清楚。pVHL是一种肿瘤抑制因子，并作为E3-连接酶的接头发挥作用。在这项研究中，我们证明pVHL通过介导依赖于氧的IKK β的K63泛素化来抑制NF-κ B B。我们发现pVHL介导了IKK β的K63连接的泛素化，IKK β是NF-κ B的上游调节因子。pVHL介导的IKK β的K63泛素化阻止了TAK 1结合，这导致IKK β磷酸化和NF-κ B活化的抑制。pVHL介导的IKK β的K63-泛素化在缺氧下被抑制。DMOG是脯氨酰羟化酶的特异性抑制剂，也抑制IKK β的K63泛素化。脯氨酰羟化酶（PHD）1增强IMP的K63-泛素化并抑制IKK β磷酸化。这些结果表明pVHL在介导IKK β的K63连接的泛素化中具有新的功能，其在IKK/NF-κ B信号传导的调节中起作用。这些结果也为缺氧时NF-κ B B的活化机制提供了新的见解。(C)2016爱思唯尔爱尔兰有限公司版权所有。
Nuclear factor (NF)-kappa B is a transcription factor that plays an important role in many biological functions. Regulation of NF-kappa B activity is complicated, and ubiquitination is essential for NF-kappa B activation. Hypoxia can activate NF-kappa B. However, the underlying mechanism remains unclear. pVHL is a tumour suppressor and functions as an adaptor of E3-ligase. In this study, we demonstrated that pVHL inhibits NF-kappa B by mediating K63-ubiquitination of IKK beta, which is dependent on oxygen. We found that pVHL mediates K63-linked ubiquitination of IKK beta, which is an upstream regulator of NF-kappa B. The pVHL-mediated K63-ubiquitination of IKK beta prevents TAK1 binding, which leads to the inhibition of IKK beta phosphorylation and NF-kappa B activation. pVHL-mediated K63-ubiquitination of IKK beta is inhibited under hypoxia. DMOG, which is a specific inhibitor of prolyl hydroxylases, also suppresses K63-ubiquitination of IKK beta. Prolyl hydroxylase (PHD) 1 enhances K63-ubiquitination of imp and inhibits IKK beta phosphorylation. These results suggest a novel function for pVHL in mediating K63-linked ubiquitination of IKK beta, which plays a role in the regulation of IKK/NF-kappa B signalling. The results also provide new insight into the mechanism of NF-kappa B activation through hypoxia. (C) 2016 Elsevier Ireland Ltd. All rights reserved.