The identification of pathways that control elimination of protein inclusions is essential to understand the cellular response to proteotoxicity, particularly in the nuclear compartment, for which our knowledge is limited. We report that stress-induced nuclear inclusions related to the nucleolus are eliminated upon stress alleviation during the recovery period. This process is independent of autophagy/lysosome and CRM1-mediated nuclear export pathways, but strictly depends on the ubiquitin-activating E1 enzyme, UBA1, and on nuclear proteasomes that are recruited into the formed inclusions. UBA1 activity is essential only for the recovery process but dispensable for nuclear inclusion formation. Furthermore, the E3 ligase HUWE1 and HSP70 are components of the ubiquitin/chaperone systems that promote inclusion elimination. The recovery process also requires RNA Pol I-dependent production of the lncRNA IGS42 during stress. IGS42 localises within the formed inclusions and promotes their elimination by preserving the mobility of resident proteins. These findings reveal a protein quality control system that operates within the nucleus for the elimination of stress-induced nucleolus-related inclusions.

中文翻译：

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用于消除核仁相关包涵体的核蛋白质量控制系统。


确定控制蛋白质包涵体消除的途径对于了解细胞对蛋白毒性的反应至关重要，尤其是在我们的知识有限的核区室中。我们报告说，在恢复期间，在应力减轻时，与核仁相关的应力诱导的核包涵体被消除。这个过程独立于自噬/溶酶体和 CRM1 介导的核输出途径，但严格依赖于泛素激活的 E1 酶 UBA1 和被募集到形成包涵体中的核蛋白酶体。UBA1 活性仅对恢复过程是必需的，但对于核包涵体的形成是必不可少的。此外，E3 连接酶 HUWE1 和 HSP70 是促进包涵体消除的泛素/伴侣系统的组分。恢复过程还需要在应激期间依赖性地产生 RNA Pol I 依赖性 lncRNA IGS42。IGS42 定位于形成的包涵体内，并通过保持驻留蛋白的流动性来促进其消除。这些发现揭示了一种蛋白质质量控制系统，该系统在细胞核内运作，以消除应激诱导的核仁相关包涵体。