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首页> 外文期刊>Molecular and Cellular Biology >IκB Kinase β Phosphorylates the K63 Deubiquitinase A20 To Cause Feedback Inhibition of the NF-κB Pathway
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IκB Kinase β Phosphorylates the K63 Deubiquitinase A20 To Cause Feedback Inhibition of the NF-κB Pathway

机译：IκB激酶β磷酸化K63去泛素酶A20，导致NF-κB途径的反馈抑制

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Misregulation of NF-κB signaling leads to infectious, inflammatory, or autoimmune disorders. IκB kinase β (IKKβ) is an essential activator of NF-κB and is known to phosphorylate the NF-κB inhibitor, IκBα, allowing it to undergo ubiquitin-mediated proteasomal degradation. However, beyond IκBα, few additional IKKβ substrates have been identified. Here we utilize a peptide library and bioinformatic approach to predict likely substrates of IKKβ. This approach predicted Ser381 of the K63 deubiquitinase A20 as a likely site of IKKβ phosphorylation. While A20 is a known negative regulator of innate immune signaling pathways, the mechanisms regulating the activity of A20 are poorly understood. We show that IKKβ phosphorylates A20 in vitro and in vivo at serine 381, and we further show that this phosphorylation event increases the ability of A20 to inhibit the NF-κB signaling pathway. Phosphorylation of A20 by IKKβ thus represents part of a novel feedback loop that regulates the duration of NF-κB signaling following activation of innate immune signaling pathways.
机译：NF-κB信号传导失调会导致传染性，炎性或自身免疫性疾病。 IκB激酶β（IKKβ）是NF-κB的必不可少的激活剂，已知会磷酸化NF-κB抑制剂IκBα，从而使其经历泛素介导的蛋白酶体降解。但是，除了IκBα外，几乎没有发现其他IKKβ底物。在这里，我们利用肽库和生物信息学方法来预测IKKβ的可能底物。该方法预测K63去泛素酶A20的Ser381是IKKβ磷酸化的可能位点。尽管A20是先天性免疫信号通路的负调节剂，但调节A20活性的机制知之甚少。我们显示IKKβ在体外和体内在丝氨酸381处使A20磷酸化，并且我们进一步表明该磷酸化事件增加了A20抑制NF-κB信号通路的能力。因此，IKKβ对A20的磷酸化代表了一种新型反馈环的一部分，该环调节了先天免疫信号通路激活后NF-κB信号通路的持续时间。

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