Wilms tumor gene on X chromosome (WTX) inhibits degradation of NRF2 protein through competitive binding to KEAP1 protein.
Wilms tumor gene on X chromosome (WTX) inhibits degradation of NRF2 protein through competitive binding to KEAP1 protein.
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DOI：
10.1074/jbc.m111.316471
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发表时间：
2012-02-24
期刊：
影响因子：
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通讯作者：
Moon RT
中科院分区：
文献类型：
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作者：
Camp ND;James RG;Dawson DW;Yan F;Davison JM;Houck SA;Tang X;Zheng N;Major MB;Moon RT
背景：Keap1是一种泛素连接酶适配器，能促进NRF2的泛素化和降解，NRF2是一种驱动抗氧化反应的转录因子。结果：X染色体上的Wilms肿瘤基因(WTX)通过与NRF2竞争结合Keap1来稳定NRF2。结论：WTX对机体抗氧化反应具有调节作用。意义：这项研究揭示了一种新的调节抗氧化剂反应的机制。WTX是一种肿瘤抑制蛋白，在高达30%的肾母细胞瘤病例中丢失或突变。在其已知的功能中，WTx与含有β-转导蛋白重复序列的泛素连接酶适配器家族相互作用，并促进转录因子β-连环蛋白的泛素化和降解，该转录因子是WnT/β-连环蛋白信号通路中的关键控制点。在这里，我们报告了WTX与第二个泛素连接酶适配器Keap1的相互作用，Keap1的功能是调节转录因子NRF2的泛素化，NRF2是抗氧化反应中的一个关键控制点。令人惊讶的是，我们发现，与其促进β-连环蛋白泛素化的能力不同，WTX抑制了NRF2的泛素化。WTX和NRF2竞争与Keap1的结合，因此WTX的缺失导致NRF2的快速泛素化和降解，并降低对细胞毒损伤的反应。这些结果扩大了我们对WTX分子机制的理解，并揭示了一种新的调节抗氧化反应的机制。
Background: KEAP1 is a ubiquitin ligase adaptor that promotes the ubiquitination and degradation of NRF2, a transcription factor that drives the antioxidant response. Results: Wilms tumor gene on the X chromosome (WTX) stabilizes NRF2 by competing with NRF2 for binding to KEAP1. Conclusion: WTX regulates the antioxidant response. Significance: This study reveals a novel regulatory mechanism governing the antioxidant response. WTX is a tumor suppressor protein that is lost or mutated in up to 30% of cases of Wilms tumor. Among its known functions, WTX interacts with the β-transducin repeat containing family of ubiquitin ligase adaptors and promotes the ubiquitination and degradation of the transcription factor β-catenin, a key control point in the WNT/β-catenin signaling pathway. Here, we report that WTX interacts with a second ubiquitin ligase adaptor, KEAP1, which functions to regulate the ubiquitination of the transcription factor NRF2, a key control point in the antioxidant response. Surprisingly, we find that unlike its ability to promote the ubiquitination of β-catenin, WTX inhibits the ubiquitination of NRF2. WTX and NRF2 compete for binding to KEAP1, and thus loss of WTX leads to rapid ubiquitination and degradation of NRF2 and a reduced response to cytotoxic insult. These results expand our understanding of the molecular mechanisms of WTX and reveal a novel regulatory mechanism governing the antioxidant response.