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首页> 外文期刊>Molecular and Cellular Biology >Stabilization of the E3 Ubiquitin Ligase Nrdp1 by the Deubiquitinating Enzyme USP8
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Stabilization of the E3 Ubiquitin Ligase Nrdp1 by the Deubiquitinating Enzyme USP8

机译：去泛素化酶USP8对E3泛素连接酶Nrdp1的稳定作用。

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Nrdp1 is a RING finger-containing E3 ubiquitin ligase that physically interacts with and regulates steady-state cellular levels of the ErbB3 and ErbB4 receptor tyrosine kinases and has been implicated in the degradation of the inhibitor-of-apoptosis protein BRUCE. Here we demonstrate that the Nrdp1 protein undergoes efficient proteasome-dependent degradation and that mutations in its RING finger domain that disrupt ubiquitin ligase activity enhance stability. These observations suggest that Nrdp1 self-ubiquitination and stability could play an important role in regulating the activity of this protein. Using affinity chromatography, we identified the deubiquitinating enzyme USP8 (also called Ubpy) as a protein that physically interacts with Nrdp1. Nrdp1 and USP8 could be coimmunoprecipitated, and in transfected cells USP8 specifically bound to Nrdp1 but not cbl, a RING finger E3 ligase involved in ligand-stimulated epidermal growth factor receptor down-regulation. The USP8 rhodanese and catalytic domains mediated Nrdp1 binding. USP8 markedly enhanced the stability of Nrdp1, and a point mutant that disrupts USP8 catalytic activity destabilized endogenous Nrdp1. Our results indicate that Nrdp1 is a specific target for the USP8 deubiquitinating enzyme and are consistent with a model where USP8 augments Nrdp1 activity by mediating its stabilization.
机译：Nrdp1是含RING指的E3泛素连接酶，可与ErbB3和ErbB4受体酪氨酸激酶物理相互作用并调节其稳态细胞水平，并且与凋亡抑制蛋白BRUCE的降解有关。在这里，我们证明Nrdp1蛋白经历有效的蛋白酶体依赖性降解，并且其RING指域中破坏泛素连接酶活性的突变增强了稳定性。这些观察结果表明，Nrdp1自身泛素化和稳定性可能在调节该蛋白的活性中起重要作用。使用亲和色谱，我们确定去泛素化酶USP8（也称为Ubpy）是与Nrdp1发生物理相互作用的蛋白质。 Nrdp1和USP8可以共沉淀，在转染的细胞中USP8特异性结合Nrdp1，但不结合cbl，这是指由配体刺激的表皮生长因子受体下调的RING指E3连接酶。 USP8罗丹丹和催化域介导Nrdp1绑定。 USP8显着增强了Nrdp1的稳定性，这是一种破坏USP8催化活性的不稳定的内源Nrdp1的点突变体。我们的结果表明Nrdp1是USP8去泛素化酶的特异性靶标，并且与USP8通过介导其稳定作用来增强Nrdp1活性的模型一致。

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