Spatial management of stress-induced protein aggregation is an integral part of the proteostasis network. Protein modification by the ubiquitin-like molecule NEDD8 increases upon proteotoxic stress and it is characterised by the formation of hybrid NEDD8/ubiquitin conjugates. However, the biological significance of this response is unclear. Combination of quantitative proteomics with biological analysis shows that, during proteotoxic stress, NEDDylation promotes nuclear protein aggregation, including ribosomal proteins as a major group. This correlates with protection of the nuclear Ubiquitin Proteasome System from stress-induced dysfunction. Correspondingly, we show that NEDD8 compromises ubiquitination and prevents targeting and processing of substrates by the proteasome. Moreover, we identify HUWE1 as a key E3-ligase that is specifically required for NEDDylation during proteotoxic stress. The study reveals a specific role for NEDD8 in nuclear protein aggregation upon stress and is consistent with the concept that transient aggregate formation is part of a defence mechanism against proteotoxicity.

中文翻译：

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NEDDylation促进蛋白毒性应激时，核蛋白聚集并保护泛素蛋白酶体系统。

应激诱导的蛋白质聚集的空间管理是蛋白质稳定网络不可或缺的一部分。当蛋白毒性应激时，类泛素样分子NEDD8对蛋白质的修饰增加，其特征是形成杂化NEDD8 /泛素缀合物。但是，这种反应的生物学意义尚不清楚。定量蛋白质组学与生物学分析相结合表明，在蛋白质毒性胁迫期间，NEDDylation促进核蛋白聚集，其中核糖体蛋白为主要组。这与保护核泛素蛋白酶体系统免受压力引起的功能障碍有关。相应地，我们表明NEDD8损害泛素化并防止蛋白酶体对底物的靶向和加工。而且，我们将HUWE1确定为蛋白毒性应激期间NEDDylation特需的关键E3连接酶。这项研究揭示了NEDD8在压力下核蛋白聚集中的特定作用，并且与瞬时聚集体形成是抵抗蛋白毒性的防御机制的一部分的概念相一致。