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Ubiquitin Depletion as a Key Mediator of Toxicity by Translational Inhibitors

机译：泛素耗竭是转化抑制剂的主要毒性介质。

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Cycloheximide acts at the large subunit of the ribosome to inhibit translation. Here we report that ubiquitin levels are critical for the survival of Saccharomyces cerevisiae cells in the presence of cycloheximide: ubiquitin overexpression confers resistance to cycloheximide, while a reduced ubiquitin level confers sensitivity. Consistent with these findings, ubiquitin is unstable in yeast (t1/2 = 2 h) and is rapidly depleted upon cycloheximide treatment. Cycloheximide does not noticeably enhance ubiquitin turnover, but serves principally to block ubiquitin synthesis. Cycloheximide also induces UBI4, the polyubiquitin gene. The cycloheximide-resistant phenotype of ubiquitin overexpressors is also characteristic of partial-loss-of-function proteasome mutants. Ubiquitin is stabilized in these mutants, which may account for their cycloheximide resistance. Previous studies have reported that ubiquitin is destabilized in the absence of Ubp6, a proteasome-associated deubiquitinating enzyme, and that ubp6 mutants are hypersensitive to cycloheximide. Consistent with the model that cycloheximide-treated cells are ubiquitin deficient, the cycloheximide sensitivity of ubp6 mutants can be rescued either by ubiquitin overexpression or by mutations in proteasome subunit genes. These results also show that ubiquitin wasting in ubp6 mutants is proteasome mediated. Ubiquitin overexpression rescued cells from additional translational inhibitors such as anisomycin and hygromycin B, suggesting that ubiquitin depletion may constitute a widespread mechanism for the toxicity of translational inhibitors.
机译：环己酰亚胺作用于核糖体的大亚基以抑制翻译。在这里，我们报道泛素水平对于存在环己酰亚胺的啤酒酵母细胞的存活至关重要：泛素的过表达赋予对环己酰亚胺的抗性，而泛素水平的降低则赋予敏感性。与这些发现一致，泛素在酵母中不稳定（ t 1/2 = 2 h），并在用环己酰亚胺处理后迅速耗尽。环己酰亚胺不会显着提高泛素的转化率，但主要起阻断泛素合成的作用。环己酰亚胺还诱导多泛素基因 UBI4 。泛素过表达子的抗环己酰亚胺表现型也是部分丧失功能的蛋白酶体突变体的特征。泛素在这些突变体中是稳定的，这可能解释了它们对环己酰亚胺的抗性。以前的研究报道，在缺乏蛋白酶体相关的去泛素化酶Ubp6的情况下，泛素不稳定，并且 ubp6 突变体对环己酰亚胺过敏。与环己酰亚胺处理的细胞泛素缺乏的模型一致，可以通过泛素过表达或蛋白酶体亚基基因的突变来挽救 ubp6 突变体对环己酰亚胺的敏感性。这些结果还表明， ubp6 突变体中的遍在蛋白浪费是蛋白酶体介导的。泛素过度表达从其他翻译抑制剂（如茴香霉素和潮霉素B）中拯救了细胞，这表明泛素耗竭可能构成了翻译抑制剂毒性的广泛机制。

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