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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >The HECT Type Ubiquitin Ligase NEDL2 Is Degraded by Anaphase-promoting Complex/Cyclosome (APC/C)-Cdh1 and Its Tight Regulation Maintains the Metaphase to Anaphase Transition
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The HECT Type Ubiquitin Ligase NEDL2 Is Degraded by Anaphase-promoting Complex/Cyclosome (APC/C)-Cdh1 and Its Tight Regulation Maintains the Metaphase to Anaphase Transition

机译：HECT型泛素连接酶NEDL2会被后期促进复合物/脂质体（APC / C）-Cdh1降解并且其严格的调控维持了从中期到后期的过渡

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NEDD4-like ubiquitin ligase 2 (NEDL2) is a HECT type ubiquitin ligase. NEDL2 enhances p73 transcriptional activity and degrades ATR kinase in lamin misexpressed cells. Compared with the important functions of other HECT type ubiquitin ligase, there is less study concerning the function and regulation of NEDL2. Using primary antibody immunoprecipitation and mass spectrometry, we identify a list of potential proteins that are putative NEDL2-interacting proteins. The candidate list contains many of mitotic proteins, especially including several subunits of anaphase-promoting complex/cyclosome (APC/C) and Cdh1, an activator of APC/C. Cdh1 can interact with NEDL2 in vivo and in vitro. Cdh1 recognizes one of the NEDL2 destruction boxes (R740GSL743) and targets it for degradation in an APC/C-dependent manner during mitotic exit. Overexpression of Cdh1 reduces the protein level of NEDL2, whereas knockdown of Cdh1 increases the protein level of NEDL2 but has no effect on the NEDL2 mRNA level. NEDL2 associates with mitotic spindles, and its protein level reaches a maximum in mitosis. The function of NEDL2 during mitosis is essential because NEDL2 depletion prolongs metaphase, and overexpression of NEDL2 induces chromosomal lagging. Elevated expression of NEDL2 protein and mRNA are both found in colon cancer and cervix cancer. We conclude that NEDL2 is a novel substrate of APC/C-Cdh1 as cells exit mitosis and functions as a regulator of the metaphase to anaphase transition. Its overexpression may contribute to tumorigenesis.
机译：NEDD4样泛素连接酶2（NEDL2）是一种HECT型泛素连接酶。 NEDL2增强p73转录活性并降解层粘连蛋白错误表达细胞中的ATR激酶。与其他HECT型泛素连接酶的重要功能相比，关于NEDL2的功能和调节的研究较少。使用一抗免疫沉淀和质谱，我们确定了可能的NEDL2相互作用蛋白的潜在蛋白的列表。候选列表包含许多有丝分裂蛋白，特别是后期促进复合物/环体（APC / C）和Cdh1（APC / C的激活剂）的几个亚基。 Cdh1可以在体内和体外与NEDL2相互作用。 Cdh1识别NEDL2破坏盒之一（R 740 GSL 743 ），并在有丝分裂退出期间以APC / C依赖性方式将其靶向降解。 Cdh1的过表达降低了NEDL2的蛋白质水平，而敲低Cdh1则增加了NEDL2的蛋白质水平，但对NEDL2 mRNA的水平没有影响。 NEDL2与有丝分裂纺锤体相关联，其蛋白质水平在有丝分裂中达到最高。 NEDL2在有丝分裂过程中的功能至关重要，因为NEDL2的耗竭延长了中期，而NEDL2的过表达导致染色体滞后。在结肠癌和子宫颈癌中均发现NEDL2蛋白和mRNA的表达升高。我们得出结论，NEDL2是APC / C-Cdh1的新型底物，因为细胞退出有丝分裂，并充当中期到后期过渡的调节剂。它的过度表达可能有助于肿瘤发生。

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