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首页> 外文期刊>Cell cycle >c-Myc is targeted to the proteasome for degradation in a SUMOylation-dependent manner, regulated by PIAS1, SENP7 and RNF4
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c-Myc is targeted to the proteasome for degradation in a SUMOylation-dependent manner, regulated by PIAS1, SENP7 and RNF4

机译：c-Myc靶向蛋白酶体，以SUMOylation依赖性方式降解，受PIAS1，SENP7和RNF4调控

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摘要

c-Myc is the most frequently overexpressed oncogene in tumors, including breast cancer, colon cancer and lung cancer. Post-translational modifications comprising phosphorylation, acetylation and ubiquitylation regulate the activity of c-Myc. Recently, it was shown that c-Myc-driven tumors are strongly dependent on the SUMO pathway. Currently, the relevant SUMO target proteins in this pathway are unknown. Here we show that c-Myc is a target protein for SUMOylation, and that SUMOylated c-Myc is subsequently ubiquitylated and degraded by the proteasome. SUMO chains appeared to be dispensable for this process, polymerization-deficient SUMO mutants supported proteolysis of SUMOylated c-Myc. These results indicate that multiple SUMO monomers conjugated to c-Myc could be sufficient to direct SUMOylated c-Myc to the ubiquitin-proteasome pathway. Knocking down the SUMO-targeted ubiquitin ligase RNF4 enhanced the levels of SUMOylated c-Myc, indicating that RNF4 could recognize a multi-SUMOylated protein as a substrate in addition to poly-SUMOylated proteins. Knocking down the SUMO E3 ligase PIAS1 resulted in reduced c-Myc SUMOylation and increased c-Myc transcriptional activity, indicating that PIAS1 mediates c-Myc SUMOylation. Increased SUMOylation of c-Myc was noted upon knockdown of the SUMO protease SENP7, indicating that it also could regulate a multi-SUMOylated protein in addition to poly-SUMOylated proteins. C-Myc lacks KxE-type SUMOylation consensus motifs. We used mass spectrometry to identify 10 SUMO acceptor lysines: K52, K148, K157, K317, K323, K326, K389, K392, K398 and K430. Intriguingly, mutating all 10 SUMO acceptor lysines did not reduce c-Myc SUMOylation, suggesting that SUMO acceptor lysines in c-Myc act promiscuously. Our results provide novel insight into the complexity of c-Myc post-translational regulation.
机译：c-Myc是包括乳腺癌，结肠癌和肺癌在内的肿瘤中最常见的过度表达的癌基因。翻译后修饰包括磷酸化，乙酰化和泛素化，调节c-Myc的活性。最近，显示c-Myc驱动的肿瘤强烈依赖于SUMO途径。目前，该途径中的相关SUMO靶蛋白尚不清楚。在这里，我们显示c-Myc是SUMOylation的目标蛋白，SUMOylated c-Myc随后被蛋白酶体泛素化和降解。 SUMO链似乎是此过程不可或缺的，聚合不足的SUMO突变体支持SUMOylated c-Myc的蛋白水解。这些结果表明，缀合至c-Myc的多个SUMO单体足以将SUMO化的c-Myc引导至遍在蛋白-蛋白酶体途径。敲除SUMO靶向的泛素连接酶RNF4增强了SUMO酰化的c-Myc的水平，这表明RNF4可以将多SUMO酰化的蛋白质识别为底物，而不是多SUMO酰化的蛋白质。敲低SUMO E3连接酶PIAS1导致c-Myc SUMOylation减少和c-Myc转录活性增加，表明PIAS1介导c-Myc SUMOylation。敲低SUMO蛋白酶SENP7时，注意到c-Myc的SUMOylation增加，这表明除聚SUMOyylated蛋白外，它还可以调节多SUMOyylated蛋白。 C-Myc缺少KxE型SUMOylation共有基序。我们使用质谱法鉴定了10种SUMO受体赖氨酸：K52，K148，K157，K317，K323，K326，K389，K392，K398和K430。有趣的是，突变所有10个SUMO受体赖氨酸并不降低c-Myc SUMOylation，这表明c-Myc中的SUMO受体赖氨酸会混杂地起作用。我们的结果为c-Myc翻译后调控的复杂性提供了新颖的见解。

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